REVIEW
published: 14 October 2019
doi: 10.3389/fmolb.2019.00105
Immunometabolism of Phagocytes
During Mycobacterium tuberculosis
Infection
Ranjeet Kumar, Pooja Singh † , Afsal Kolloli † , Lanbo Shi, Yuri Bushkin, Sanjay Tyagi and
Selvakumar Subbian*
Public Health Research Institute, New Jersey Medical School, Rutgers, The State University of New Jersey, Newark, NJ,
United States
Edited by:
Hannes Findeisen,
University Hospital Münster, Germany
Reviewed by:
Rob J. W. Arts,
Radboud University Nijmegen Medical
Centre, Netherlands
Prasun K. Datta,
Temple University, United States
*Correspondence:
Selvakumar Subbian
subbiase@njms.rutgers.edu
† These
authors have contributed
equally to this work
Specialty section:
This article was submitted to
Cellular Biochemistry,
a section of the journal
Frontiers in Molecular Biosciences
Received: 31 July 2019
Accepted: 26 September 2019
Published: 14 October 2019
Citation:
Kumar R, Singh P, Kolloli A, Shi L,
Bushkin Y, Tyagi S and Subbian S
(2019) Immunometabolism of
Phagocytes During Mycobacterium
tuberculosis Infection.
Front. Mol. Biosci. 6:105.
doi: 10.3389/fmolb.2019.00105
Tuberculosis (TB), caused by Mycobacterium tuberculosis (Mtb) remains as a leading
killer among infectious diseases worldwide. The nature of the host immune response
dictates whether the initial Mtb infection is cleared or progresses toward active
disease, and is ultimately determined by intricate host-pathogen interactions that are
yet to be fully understood. The early immune response to infection is mediated by
innate immune cells, including macrophages and neutrophils that can phagocytose
Mtb and mount an antimicrobial response. However, Mtb can exploit these innate
immune cells for its survival and dissemination. Recently, it has become clear that the
immune response and metabolic remodeling are interconnected, which is highlighted
by the rapid evolution of the interdisciplinary field of immunometabolism. It has been
proposed that the net outcome to Mtb infection—clearance or chronic disease—is
likely a result of combined immunologic and metabolic activities of the immune
cells. Indeed, host cells activated by Mtb infection have strikingly different metabolic
requirements than naïve/non-infected cells. Macrophages activated by Mtb-derived
molecules or upon phagocytosis acquire a phenotype similar to M1 with elevated
production of pro-inflammatory molecules and rely on glycolysis and pentose phosphate
pathway to meet their bioenergetic and metabolic requirements. In these macrophages,
oxidative phosphorylation and fatty acid oxidation are dampened. However, the
non-infected/naive, M2-type macrophages are anti-inflammatory and derive their energy
from oxidative phosphorylation and fatty acid oxidation. Similar metabolic adaptations
also occur in other phagocytes, including dendritic cells, neutrophils upon Mtb infection.
This metabolic reprogramming of innate immune cells during Mtb infection can
differentially regulate their effector functions, such as the production of cytokines and
chemokines, and antimicrobial response, all of which can ultimately determine the
outcome of Mtb-host interactions within the granulomas. In this review, we describe key
immune cells bolstering host innate response and discuss the metabolic reprogramming
in these phagocytes during Mtb infection. We focused on the major phagocytes,
including macrophages, dendritic cells and neutrophils and the key regulators involved
in metabolic reprogramming, such as hypoxia-inducible factor-1, mammalian target of
rapamycin, the cellular myelocytomatosis, peroxisome proliferator-activator receptors,
sirtuins, arginases, inducible nitric acid synthase and sphingolipids.
Keywords: tuberculosis, Mycobacteria, innate immunity, immunometabolism, immune cells, epigenetics,
metabolic regulators, infection
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Immunometabolism and Innate Immunity in Tuberculosis
INTRODUCTION
(Russell et al., 2009). In majority of cases, granuloma maintains
a dynamic state where Mtb is contained, and disease is resolved.
However, in some cases there is increased accumulation of
caseum in central region of granuloma, which leads to necrosis
of cells and subsequent release of Mtb into the airways (Russell
et al., 2009).
Other cell types that are present in the granulomas
are neutrophils, dendritic cells (DCs), various subtypes of
B and T lymphocytes, natural killer cells, fibroblasts, and
epithelial cells (Ramakrishnan, 2012). Findings from rabbit
and non-human primate models of Mtb infection, which are
immunopathologically “relevant-to-human,” have shown that
granulomas contain a macrophage-rich core with necrosis of
infected cells surrounded by a lymphocytic cuff, consisting
mainly of T and B cells (Capuano et al., 2003; Subbian
et al., 2011, 2013; Mattila et al., 2013). However, findings in
human pulmonary TB cases and relevant experimental animal
models have revealed many different types of granulomas based
on the presence and arrangement of various immune cell
types. These divergent types include highly cellular, “solid”
granulomas, caseating, necrotic and non-necrotic, fibrotic
nodules, suppurative (comprising a surge of neutrophils), and
closed and open cavitary lesions (Capuano et al., 2003; Subbian
et al., 2011, 2013; Mattila et al., 2013). These granulomas vary
in size, maturation state, and the quantity and quality of the
resident immune cells. Partially mineralized and highly fibrotic
(fibrocalcific) granulomas are primarily found in latent infection,
while the number and cellular complexity of granulomas is of
a higher order during active TB (Gideon and Flynn, 2011).
However, different types of granulomas have been reported in
the tissues of active TB and latent infection, making it difficult
to assess the infection status of a host-based on the type of
granulomas present in the organ (Mattila et al., 2013).
Although granulomas are thought to restrict bacterial growth
and expansion by “walling off,” Mtb can exploit the immune
cells within and outside of the granuloma for its persistence,
proliferation, and dissemination (Davis and Ramakrishnan, 2009;
Volkman et al., 2010). Based on the intricate interaction between
the host immune response and bacterial determinants that are
yet to be fully understood, the infecting Mtb is either contained
and/or cleared or replicates and disseminates in the granuloma.
The outcome of this interaction also results in a spectrum
of clinical manifestations in the infected host, ranging from
symptomatic active disease to sub-clinical, incipient, percolator,
and intermittent disease to persistent, asymptomatic latent
infection (Vynnycky and Fine, 2000).
The infection of host immune cells by Mtb causes
several changes including metabolic reprogramming, which
differentially regulates various cytokines and chemokines
associated with clearance, containment, or progression of
Mtb infection in host cells (Olakanmi et al., 2002; Gleeson
et al., 2016; Qualls and Murray, 2016). In particular, a shift in
glucose and lipid metabolism is critical for defining the fate
of host cell function in the context of mycobacterial survival
within the granuloma (Shi et al., 2016). Rapid advances in the
field of immunology and metabolism have given rise to an
interdisciplinary field termed immunometabolism (Mathis and
Tuberculosis (TB) remains as significant cause of mortality and
morbidity among infectious diseases around the world. In 2017,
an estimated 10 million people developed active disease, while 1.6
million died from TB (WHO, 2018). About a third of the world’s
population is believed to be latently infected with Mycobacterium
tuberculosis (Mtb) without obvious disease symptoms. Of these,
5–10% will develop active TB in their lifetime, if/when their host
immunity wanes (WHO, 2018).
The host immune response during the various stages of Mtb
infection is complex and not fully understood. Studies on human
patients and experimental animal models of TB have shown that
phagocytes such as macrophages and neutrophils are the primary
immune effector cells against Mtb (Keane et al., 2001; North and
Jung, 2004; Alcais et al., 2005). Engagement of surface receptors
in these cells with mycobacterial cell wall molecules such as
lipoarabinomannan and secreted proteins ultimately activates the
immune cells to secrete a plethora of cytokines and chemokines,
which aid in the recruitment of other leukocytes from circulation
to the site of infection. A hallmark of successful initial Mtb
infection is the formation of granuloma in the infected tissues,
which is an organized cellular structure comprised of a variety
of innate and adaptive immune cells (Ramakrishnan, 2012).
Mature macrophages, characterized by an increased cytoplasmto-nucleus ratio and larger number of organelles, are capable of
developing into multinucleated giant cells as well as foam cells
that accumulate lipid bodies. These cells are critical constituents
of TB granulomas, which undergo structural changes over time
(Russell et al., 2009; Guerrini et al., 2018). Initial development
of granuloma is marked by its extensive vascularization through
vascular endothelial growth factor (VEGF) mediated responses,
leading to recruitment of macrophages, lymphocytes, and DCs,
into the site of infection (Caceres et al., 2009). Further structural
changes in granuloma are marked with the presence of different
morphotypes of macrophages, including multinucleated giant
cells, epithelioid cells, and foamy macrophages (Murphy, 2001;
Ordway et al., 2005; D’Avila et al., 2006). The later cells are
generated as a result of intracellular accumulation of lipid
droplets consisting of neutral lipids, mainly cholesteryl esters
(CE) and/or triglycerides (TAG) surrounded by a monolayer of
phospholipids comprising structural proteins, cholesterol and
enzymes (Martin and Parton, 2006; Saka and Valdivia, 2012;
Guerrini et al., 2018). Accumulation of TAG, a significant
constituent of foam cells within the granuloma, in Mtb-infected
human primary macrophages requires tumor necrosis factor
receptor (TNFR) signaling, activation of caspase cascade and
mTORC1 (Russell et al., 2009). Rupture of foam cells due
to exacerbated infection and/or inflammation and the release
of their contents likely sustains the disease pathology and
generation of caseum, which leads to progressive destruction of
lung tissues (Russell et al., 2009). Foamy macrophages (FM) are
also reported to provide Mtb their physiological niche similar to
non-replicative vegetative state (Russell et al., 2009). In response
to strong anti-mycobacterial response, the structure tends to
become stratified, and a fibrous cuff is formed delineating central
macrophages rich region from peripheral lymphocytic milieu
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Immunometabolism and Innate Immunity in Tuberculosis
(van Crevel et al., 2002; Gutierrez et al., 2004). Although
macrophages elicit an early host protective immunity against
Mtb, these innate cells are also thought to provide an intracellular
niche where Mtb thrives (Schluger and Rom, 1998). Macrophages
demonstrate a high level of heterogeneity in morphology and
function (Austyn and Gordon, 1981; Kaplan and Gaudernack,
1982). Based on the heterogeneity observed mainly in in vitro
cell culture systems, macrophages are categorized into four major
groups: type I, type II, alternatively activated and deactivated
macrophages (Figure 1) (Gordon, 2003; Gordon and Taylor,
2005). Type I macrophages are activated through lymphoid cell
mediators such as IFN-γ and LPS, while type II is differentiated
upon ligation of receptors by immune complexes (Guirado et al.,
2013). Both of these macrophage types possess high microbicidal
activity by producing pro-inflammatory cytokines such as TNFα, IL-1β, and IL-6, and reactive oxygen species (ROS) and
inducible nitric oxide synthase (iNOS), which leads to the
production of nitric oxide (NO) (Bogdan, 2001). The third group,
alternatively activated macrophages, is generated in response to
Th-2 type cytokines such as IL-4 or IL-13 (Gordon, 2003). These
macrophages secrete anti-inflammatory cytokines such as IL-10
and TGF-β and are mostly involved in tissue repair and humoral
immunity (Gordon, 2003; Mosser, 2003). Finally, deactivated
macrophages are produced in response to anti-inflammatory
cytokines IL-10 or TGF-β, and are involved in the production
of anti-inflammatory cytokines and prostaglandin E2, and have
reduced MHC II expression (Guirado et al., 2013).
One of the initial events following inhalation of Mtb is
phagocytosis by alveolar macrophages that secrete IL-8 and
facilitate the recruitment of neutrophils to the infection site
(Schlesinger, 1996). Various host cell receptors, including
complement receptors, C-type lectins, mannose receptors,
surfactant proteins (SpA), and CD14, are involved in the uptake
of Mtb by macrophages (Kleinnijenhuis et al., 2011). The
association between the type of receptor involved in phagocytosis
and the fate of engulfed Mtb within the macrophages remains
poorly understood. The nature of the engulfing receptor can
influence the downstream signaling and subsequent processing
of the bacilli (Sanchez et al., 2010; Marakalala and Ndlovu,
2017; Queval et al., 2017). Thus, Mtb phagocytosed by specific
cell surface receptors is thought to be processed differentially
that can favor intracellular bacillary growth, while engagement
and signaling by other receptors destroy the bacteria (Killick
et al., 2013; Mortaz et al., 2015; Liu et al., 2017). Ultimately, the
fusion of mycobacteria-containing phagosomes with lysosomes
results in bacterial killing within the phagocyte. Similarly, host
cell production of ROS and nitrogen (RNS) intermediates
facilitate intracellular bacterial killing (MacMicking et al.,
1997; Cooper et al., 2000; Ehrt and Schnappinger, 2009).
Besides, macrophages phagocytose and eliminate Mtb through
autophagy and apoptosis (Eruslanov et al., 2005; Wolf et al.,
2007; Eum et al., 2010; Behar et al., 2011; Lowe et al.,
2012). In general, these antibacterial mechanisms of phagocytes
are successful in eliminating non-virulent bacillus; however,
virulent Mtb strains have developed mechanisms to bypass
these efforts, by preventing phagolysosome fusion, and surviving
in the presence of ROS and RNS, thereby adapting to the
Shoelson, 2011). Core metabolic processes such as glycolysis,
Krebs cycle, fatty acid metabolism, and nitrogen metabolism are
vital for the proper functioning of any cell (DeBerardinis and
Thompson, 2012; Escoll and Buchrieser, 2018). In general, cells
in a “resting” condition mostly rely on oxidative phosphorylation
(OXPHOS) to generate ATP from NADH, and FADH made
during the Krebs cycle. However, under oxygen-depleting or
hypoxic conditions and during high-energy requirements, the
cells switch to aerobic glycolysis to generate ATP (Escoll and
Buchrieser, 2018). Although aerobic glycolysis produces ATP
less efficiently than OXPHOS, it produces more ATP at a faster
rate, which meets the high energy demands of the immune cells.
Apart from energy needs, aerobic glycolysis also provides the
precursors for chemical constituents, such as nucleotides, amino
acids, and lipids (Lunt and Vander Heiden, 2011). Therefore,
metabolic reprogramming fulfills both the bioenergetic and
biosynthetic needs of cells for rapid proliferation, differentiation,
and/or production of secretory components (DeBerardinis and
Thompson, 2012; Escoll and Buchrieser, 2018).
Metabolic reprogramming in immune cells is controlled by
host-derived transcriptional regulators such as hypoxia-inducible
factor (HIF), mechanistic/mammalian target of rapamycin
(mTOR), myelocytomatosis virus oncogene (Myc), and glycogen
synthase kinase 3 (GSK3) (Wahl et al., 2012; O’Neill and
Pearce, 2016; Jellusova and Rickert, 2017) (Table 1). Besides,
immune cells can initiate metabolic reprogramming through
signaling pathways elicited in response to host-pathogen
interactions through receptors, such as pattern recognition
receptors (PRR), cytokine receptors, and antigen receptors
(Escoll and Buchrieser, 2018). In these cases, the onset of
aerobic glycolysis is essential for immune cell activation
and corresponding production of cytokines, chemokines, and
antibacterial molecules. Therefore, the metabolic needs of
an infected and/or activated immune cell are significantly
different from a resting or non-infected cell. Taken together,
recent advances focused on the immunometabolism during
microbial infections have provided new insights into host
immune regulation mechanisms, opening up new avenues for
the development of host-directed therapies to enhance treatment
outcomes (Eisenreich et al., 2019; Prusinkiewicz and Mymryk,
2019; Wang et al., 2019).
In this review, we describe the role of metabolic
reprogramming in various phagocytic cells that bolster host
innate immune response and their relevance to Mtb infection.
Since a full report on the host immune response and the
cells involved is beyond the scope of this article, we focus on
major phagocytes and the key regulators that control metabolic
reprogramming in these cells during Mtb infection.
PRIMARY PHAGOCYTES INVOLVED IN TB
PATHOGENESIS
Macrophages
Macrophages shape the nature and course of host immunity
against Mtb infection by playing a crucial early role, such as
phagocytosis of Mtb and triggering an antimicrobial response
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TABLE 1 | Key metabolic regulators that modulate immune responses.
Metabolic regulators
Mechanism of action
Biological effect
HIF-1α
Upregulates expression of glycolytic enzymes Increases glycolysis and Th1 immune response
and IL-1β
Nizet and Johnson, 2009; Shi
et al., 2015; Braverman et al.,
2016
mTORC1
Activates SREBP/MYC signaling pathway
Augments NK cell development and its activation
Donnelly et al., 2014; O’Brien
et al., 2019
cMyc
Induces cell proliferation, and glucose and
glutamine metabolism
Regulates inflammatory response
Stine et al., 2015
GSH
Induces mTOR and NFAT activities, and
promotes glycolysis and glutaminolysis in
activated T cells
Augments T cell growth, activates T cell-mediated
inflammatory response and fine-tunes innate immunity
during infections
Diotallevi et al., 2017; Mak
et al., 2017
Sirtuins
Inhibit NF-κB signaling and glucose
metabolism
Suppress inflammation and regulate
immuno-pathogenesis during infection
Vachharajani et al., 2016;
Cheng et al., 2017
PPAR-γ
Upregulates PGE2 production and inhibits
NF-κB signaling
Enhances lipid droplet formation and suppresses the
pro-inflammatory response
Almeida et al., 2012; Salamon
et al., 2014
PPAR-α
Activates TFEB signaling and promotes fatty
acid oxidation
Downregulates lipid accumulation and augments the
innate immune response
Kim et al., 2017
Arginase-1
Downregulates production of NO and RNS
Augments macrophage polarization toward M2 and
promotes pathogen survival
Duque-Correa et al., 2014
Arginase-2
Activates the LXR-mediated
anti-inflammatory signaling pathway
Suppresses macrophage immunity during infection
Lewis et al., 2011; Koo et al.,
2012
iNOS
Promotes NO production and nitrosylates
enzymes involved in metabolic pathways
NO exerts microbicidal activities, inhibits mitochondrial Braverman and Stanley, 2017
respiration, and promotes a metabolic shift to glycolysis
and fatty acid oxidation
Sphingolipids (S1P, C1P) and
associated enzymes (SK1)
Promotes cell membrane integrity and
phagosome maturation
Stimulates macrophage activation, cell repair, and
division, and a shift to lipid metabolism in granulomas
hostile intracellular environment (Sturgill-Koszycki et al., 1994).
Successful pathogenesis by Mtb further relies on subverting host
cell death pathways; for example, Mtb inhibits host cell apoptosis
and induces necrosis as a strategy to survive intracellularly and
disseminate to other cells (Hinchey et al., 2007; Behar et al., 2011;
Welin et al., 2011; Wong and Jacobs, 2011).
German Nobel laureate Otto Heinrich Warburg first described
aerobic glycolysis for tumor cells in the 1920s (Warburg, 1956).
Recent reports have revealed that Mtb can induce a Warburglike metabolic reprogramming in infected cells both in vivo and
in vitro (Shin et al., 2011; Somashekar et al., 2011; Appelberg
et al., 2015; Shi et al., 2015; Gleeson et al., 2016; Lachmandas
et al., 2016a,b; Billig et al., 2017). This effect is characterized by
classical upregulation of glucose uptake and glycolysis-coupled
deviation of glycolytic intermediates to the synthesis of large
lipid bodies, which accumulate in the macrophages (Kelly and
O’Neill, 2015). Fatty acids in these lipid bodies of infected
macrophages provide a nutritional niche for the intracellular
bacteria (Lee et al., 2013; Podinovskaia et al., 2013; VanderVen
et al., 2015; Nazarova et al., 2017). It has also been reported
that induction of aerobic glycolysis by Mtb in human monocytederived macrophages and primary human alveolar macrophages
are required for the optimal production of IL-1β and suppression
of the anti-inflammatory cytokine IL-10, leading to reduced
bacterial load (Gleeson et al., 2016).
One of the critical virulent factors of pathogenic Mtb, ESAT6, stimulates translocation of the glucose transporters Glut-1 and
Glut-3 from the cytosol to the cell membrane, which correlates
Frontiers in Molecular Biosciences | www.frontiersin.org
References
Malik et al., 2003; Liu et al.,
2010
with enhanced uptake of glucose into human macrophages
(Singh et al., 2015). Glucose uptake by THP-1 macrophages
increases proportionately with the virulence of the Mtb strain,
supporting a key metabolic function in Mtb progression (Singh
et al., 2015). In addition, augmentation of aerobic glycolysis
promoted activation of the cellular apoptotic response upon Mtb
infection (Matta and Kumar, 2016). However, Mtb adapts to the
host cell environment by switching its central carbon metabolism
(CCM) toward catabolism of host lipid substrates, which includes
the pathogen-induced lipid bodies accumulated within the
macrophages (Lee et al., 2013). Recent studies also suggest that
this lipid body accumulation in human macrophages relies on
the induction of de novo cholesterol and fatty acid synthesis
(FAS), and the generation of ketone body D-3-hydroxybutyrate
by the host cell (Kim et al., 2010; Singh et al., 2012). Although
Mtb ESAT-6 is involved in the initiation of lipid body formation,
BCG, a non-pathogenic vaccine strain of M. bovis can also induce
lipid bodies in infected macrophages (Melo and Dvorak, 2012).
Therefore, lipid body formation may be a general consequence
of mycobacterial infection rather than playing a key role in
TB pathogenesis.
An important metabolic regulator, PPAR-γ, is highly
upregulated in human and mouse macrophages upon
mycobacterial infection (Almeida et al., 2009; Lagranderie et al.,
2010; Rajaram et al., 2010). The increased expression of PPAR-γ
leads to enhanced lipid droplet formation inside macrophages
and down-modulation of immune responses against Mtb
(Rajaram et al., 2010; Mahajan et al., 2012). This observation
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Immunometabolism and Innate Immunity in Tuberculosis
FIGURE 1 | M1 and M2 macrophages orchestrate host immunity in response to a variety of stimuli. Macrophages are activated to M1-type upon challenge with
pro-inflammatory IFN-γ/LPS or microbial infection, while M2-type macrophages are induced upon IL-4/IL-10/IL-13 or TGF-β exposure. The M1 state is marked by
increase in aerobic glycolysis induced by HIF-1α, GLUT-1, and mTOR expression, and is involved in microbicidal activities. In contrast, the M2 state is marked by
OXPHOS and enhanced lipid metabolic activities, such as fatty acid oxidation, and predominantly elicits an anti-inflammatory response and tissue repair.
arginine metabolism and express inflammatory cytokines such
as TNF-α, IL-1β, IFN-γ, and IL-12 (McClean and Tobin,
2016) (Figure 1). During the advanced disease stage, the
macrophages adapt to an M2- polarization state, whereby
metabolic reprogramming leads to a dependence on oxidative
phosphorylation to supply energy needs and the expression of
anti-inflammatory cytokines such as IL-4, IL-10, and TGF-β
(McClean and Tobin, 2016). The M2-polarized state is also partly
required to maintain homeostasis and prevent self-destruction
from an over-active immune response (O’Neill and Pearce,
2016; Escoll and Buchrieser, 2018). However, a study using
computational genome-scale metabolic models predicted that
Mtb decelerates OXPHOS and glycolysis in human alveolar
macrophages, which results in decreased ATP production
(Bordbar et al., 2010). This study also predicted that BCG and
other non-pathogenic or dead mycobacteria could accelerate
glycolysis and OXPHOS (Bordbar et al., 2010). In this study,
a reduced glycolytic proton efflux rate was observed in Mtbinfected hMDMs and THP-1 macrophages. In contrast, an
increased glycolytic proton efflux rate was noted in macrophages
upon BCG infection. Therefore, reducing the glycolytic rate
could be a strategy through which Mtb subverts the host
immune response. It was also proposed that citrate is involved
suggests that increased PPAR-γ expression is a strategy adopted
by Mtb to establish infection in the host. Consistent with this,
inhibition of PPAR-γ expression in macrophages resulted in
enhanced mycobacterial killing (Almeida et al., 2012).
Different lineages of macrophages have differential responses
to Mtb infection (Epelman et al., 2014; Gibbings et al., 2015;
van de Laar et al., 2016), although macrophages derived from
different ontogenies coexist in several tissues. A recent study
in mice showed that alveolar macrophages are committed to
fatty acid oxidation, which serves as a favorable niche for
Mtb, while interstitial macrophages are glycolytically active,
restricting bacterial growth (Huang et al., 2018). Further, studies
using Mtb-infected mouse bone marrow-derived macrophages
(BMDM) treated with 2-DG (2-D-Glucose, a glycolysis inhibitor)
or etomoxir (ETO; a fatty acid oxidation inhibitor) showed
that inhibition of glycolysis enhanced bacterial growth, while
inhibition of fatty acid oxidation reduced bacterial count
(Huang et al., 2018). Thus, it was proposed that restricting
alveolar macrophages and increasing the number of interstitial
macrophages might be an effective strategy to combat Mtb.
Activation of macrophages by signals emerging from Mtb
infection leads to their polarization toward an M1 state. These
cells undergo a metabolic shift toward aerobic glycolysis and
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their ability to inhibit Mtb by innate immune mechanisms, and
facilitated an efficient adaptive immune response (Morris et al.,
2013a). However, several microbial factors, including cell wall
components and secretion products, can interfere with DC-T cell
signaling in vivo (Ting et al., 1999; Fortune et al., 2004; Reed
et al., 2004; Banaiee et al., 2006; Pathak et al., 2007). Recently, Mtb
Hip1 was identified as a critical factor that impairs DC function;
infection of DCs with hip1-mutant Mtb resulted in significantly
higher expression of pro-inflammatory cytokines such as IL-12
and enhanced surface expression of MHCII, CD4, and CD86,
which are required for DC maturation (Madan-Lala et al., 2014).
The metabolic requirements for DCs are distinct among
different subtypes, tissues, and stages of maturation (Figure 2).
Bone marrow-derived dendritic cells (BMDCs) can adopt
Warburg effect, i.e., aerobic glycolysis, upon stimulation with
TLR agonists, leading to optimal maturation and effector
functions in both human and mouse DCs (Krawczyk
et al., 2010). This induction of glycolysis is regulated by
PI3K/TBK1/IKKε/AKT signaling, which promotes rapid
translocation of Hexokinase-2 to mitochondria, facilitating
glucose catabolism required for DC maturation (Miyamoto
et al., 2008; van der Windt et al., 2012). The by-products of
glucose metabolism are used in pentose phosphate pathway
(PPP) metabolism, lactate production, and fatty acid synthesis.
This metabolic reprogramming regulates the breadth and
depth of adaptive immune response induced by the DCs
(Pearce and Everts, 2015). One of the essential regulators of DC
metabolic remodeling, mTOR, is activated upon interaction of
mycobacterial pathogen-associated molecular pattern (PAMP)
molecules with DC surface receptors, which promotes protein
synthesis and cell growth (Pearce and Everts, 2015).
Alteration in fatty acid metabolism of DCs in response to
Mtb infection is another area of intense research. Differentiation
of human monocytes to DCs in response to GM-CSF
and IL-4 is accompanied by increased expression of the
peroxisome proliferator-activated receptor-gamma (PPAR-γ), a
transcription factor involved in lipid metabolism that is also
upregulated in macrophages in response to Mtb infection
(Le Naour et al., 2001; Ishikawa et al., 2007). Monocyte
differentiation to DCs is dependent on phosphoinositol-3
kinase (PI3K)-mediated activation of the mTOR complex1
(mTORC1) that in turn activates its downstream target PPARγ, which affects cell maturation and function by controlling
lipid metabolism (Nencioni et al., 2002; Szatmari et al., 2004,
2007; Gogolak et al., 2007). Further, inhibiting cytosolic fatty
acid synthase (FASN) by blocking acetyl CoA-carboxylase
(AAC1) reduced monocyte-derived dendritic cell (moDC)
differentiation (Rehman et al., 2013). Differentiated moDCs
contain higher numbers of mitochondria, show a higher oxygen
consumption rate (OCR), and produce more ATPs than other
non-differentiated monocytes (Del Prete et al., 2008; Zaccagnino
et al., 2012). Consistent with this, moDC differentiation can
be partially prevented by blocking the mitochondrial electron
transport chain (ETC) with complex-I inhibitor, rotenone (Del
Prete et al., 2008; Zaccagnino et al., 2012). Thus, differentiation
of DCs from human monocytes is governed by OXPHOS and
fatty acid metabolism. Glycolysis has also been shown to be
essential for the development and proliferation of murine DCs
in this glycolysis reduction. Because citrate is an inhibitor of
phosphofructokinase, an enzyme responsible for the conversion
of fructose-6-phosphate to fructose-1, 6 biphosphate, and ADP,
which is a rate-limiting step in glycolysis, predictions from
this study challenge the model that Mtb infection induces the
Warburg effect in macrophages (Bordbar et al., 2010).
In addition to glucose and fatty acid metabolism, amino
acid metabolism has also been investigated in the context of
Mtb pathogenesis. In a recent study, it was observed that in
murine and macaque macrophages, as well as in their lungs,
Mtb induced the expression of indoleamine 2, 3 dioxygenases
(IDO), an enzyme involved in tryptophan catabolism (Mehra
et al., 2013; Gautam et al., 2018). In these experimental models,
suppression of IDO activity resulted in reduced bacterial load and
increased host survival (Gautam et al., 2018). IDO catabolizes
tryptophan (Trp) to Kynurenine (Kyn) and other metabolites.
It also suppresses the host immune response, particularly IFNγ production by CD4+ T cells (Mbongue et al., 2015). Since
Mtb can synthesize its own Trp de novo in infected host
phagocytes, the production of IDO by the host cells have less
effect on intracellular Mtb metabolism; yet both Mtb-Trp and
host-IDO impact the protective host immune response. Indeed,
IDO is particularly enriched in the macrophage-rich, inner
layer of granulomas in the lungs of Mtb-infected non-human
primates (Mehra et al., 2013). Inhibition of IDO activity [e.g.,
using 1-methyltryptophan (1-MT, D-1MT)] was also associated
with reorganization of the granuloma that allowed lymphocytic
trafficking into the macrophage-tropic internal layers (Gautam
et al., 2018). Taken together, macrophages, as the primary
phagocytes of Mtb infection, can rewire their metabolic pathways
upon infection and/or activation through multiple mechanisms,
which are yet to be fully explored.
Dendritic Cells
Dendritic cells (DC) serve as a bridge between the host innate
and adaptive immune response during Mtb infection (Mellman
and Steinman, 2001; Kapsenberg, 2003). DCs carrying live Mtb
and/or its antigens migrate to the regional lymph nodes where
they prime T cells, leading to generation and proliferation
of effector and memory T cells (Gallegos et al., 2008; Reiley
et al., 2008; Wolf et al., 2008). Migration of DCs to lymph
nodes is facilitated by IL-12-p40-dependent mechanisms and
upregulation of CCR-7 (Khader et al., 2006). DCs are crucial
for mounting CD4+ T cell response involving Th1 cytokines,
such as IFN-γ and TNF-α (Tascon et al., 2000; Humphreys
et al., 2006). The depletion of CD11C+ cells, which includes
DCs, delays the CD4+T cell response in mice infected with
Mtb (Tian et al., 2005). This shows that the early interaction of
DCs with Mtb shapes the development of subsequent adaptive
immune response (Figure 2). Since DCs are a heterogeneous cell
population, the effectiveness of immune responses against Mtb
is coordinated among the different subtypes. Lai et al. recently
found in a mouse model that migratory CD11b+ DCs are
involved in Th1 priming and activation following Mtb infection,
while their counterpart, CD103+ DCs, plays a regulatory role
through production of IL-10 and inhibiting priming of Th1
cells (Lai et al., 2018). It has also been reported that treatment
of DCs with glutathione (GSH) precursor in vitro enhanced
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FIGURE 2 | Immunometabolic changes associated with DC maturation. Immature DCs produce no or meager amount pro-inflammatory cytokines. These DCs have
elevated oxidative phosphorylation (OXPHOS), fatty acid (FA) metabolism and mitochondrial biogenesis while dampening FA synthesis and glycolysis. Mtb infection
activates ATK, TBK-1, and hexokinase-2 signaling pathways and induces DC maturation. The mature DCs express higher levels of major histocompatibility complex II
(MHC-II) and co-stimulatory molecules (CD80, CD83, CD86). These DCs up-regulate molecules involved in mTOR and HIF-1α signaling pathways, elevate glycolysis,
fatty acid synthesis and pentose phosphate pathway (PPP), and dampens OXPHOS. Mature DCs also produce significant amount pro-inflammatory cytokines such
as IL-6, TNF-α, IL-1β.
bacterial infections, including TB. However, among the various
phagocytes, the specific role of neutrophils during Mtb infection
is less well-characterized.
Neutrophils are efficient phagocytes that also facilitate the
killing of pathogens by secreting human neutrophil peptides
(HNP), which are cationic proteins of the α-defensin family
that bind to anionic components of plasma membranes and
disrupt their integrity (Fu, 2003). After phagocytosis of Mtb,
neutrophils secrete several chemokines and cytokines that attract
inflammatory monocytes from the circulation (Petrofsky and
Bermudez, 1999; Seiler et al., 2003; Mantovani et al., 2011).
Monocyte recruitment and maturation at the site of infection
can redefine the microenvironment at both metabolic and
immunologic levels (Blomgran and Ernst, 2011). Studies suggest
that upon mycobacterial infection, neutrophils facilitate the
activation of naïve antigen-specific CD4+ T cells, triggering
an adaptive immune response (Blomgran and Ernst, 2011).
However, there are also reports indicating that neutrophils can
act as permissive hosts for Mtb (Abadie et al., 2005; Sutherland
et al., 2009; Eum et al., 2010). Depending on host- and pathogenassociated factors, and their interactions, neutrophils can also
contribute to disease progression. Specifically, recruitment of
neutrophils during early stages of Mtb infection has been shown
to halt infection (Lyadova, 2017). However, initial activation and
(Kratchmarov et al., 2018). Similarly, DC-like cells differentiated
from mouse BMDMs using GM-CSF also showed higher glucose
uptake and high mitochondrial membrane potential and oxygen
consumption (Krawczyk et al., 2010).
As well as promoting monocyte differentiation to DCs, fatty
acid metabolism is also essential for immunogenicity and the
antigen-presenting capacity of DCs in human and mouse liver
(Ibrahim et al., 2012). And recently, it has been reported
that, apart from glucose, DCs store glycogen and express
enzymes required for its metabolism. Indeed, defective glycogen
metabolism in DCs impaired their activation and effector
functions (Thwe et al., 2017). Taken together, although DCs
are phagocytes and antigen-presenting cells like macrophages,
that have different metabolic requirements and utilize various
signaling pathways to regulate their metabolic remodeling during
cell growth and development vs. Mtb infection. While it is clear
that glycolysis and fatty acid metabolism in particular play a vital
role in DC function, the relevance of these metabolic pathways
specifically during Mtb infection needs further investigation.
Neutrophils
Neutrophils or polymorphonuclear (PMN) cells are the most
abundant constituent of white blood cells or granulocytes
and are some of the first cells to arrive at the site of
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conditions, PHD activity is down-regulated resulting in HIF-1α
accumulation and heterodimerization with HIF-1β (Semenza,
2001). This complex then binds to the promoter regions of
several hypoxia-inducible genes and upregulates their expression
(Corcoran and O’Neill, 2016). Hypoxia-inducible genes encode
proteins involved in a myriad of cellular pathways that regulate
cell survival, apoptosis, angiogenesis, erythropoiesis, glucose
metabolism, and pH regulation (Semenza, 2000).
Various stimuli activate HIF-1α and, together with NF-κB,
these signaling pathways regulate the immune response in
hypoxic conditions (Rius et al., 2008). Under hypoxic conditions,
HIF-1α fulfills the energy needs of cells by promoting aerobic
glycolysis via inducing the expression of the glycolytic enzymes,
such as hexokinase and phosphofructokinase (Riddle et al., 2000;
Obach et al., 2004). Hypoxia and inflammation are inherently
linked, as upon activation, immune cells undergo considerable
metabolic reprogramming to sustain energy needs, thereby
mostly switching to aerobic glycolysis. Thus, HIF-1α mediated
pathways are essential in regulating immunity and inflammation.
The role of HIF-1α in inducing aerobic glycolysis was elucidated
in macrophages activated by LPS, and in Th-17 cells, which
produce IL-17 (Tannahill et al., 2013; Gerriets et al., 2015). HIF1α was also found to be upregulated in murine lungs upon Mtb
infection inducing the Warburg effect (Shi et al., 2015).
HIF-1α is expressed in primary innate immune cells like
macrophages, DCs, neutrophils, and Th-17 cells (Corcoran and
O’Neill, 2016). In DCs, HIF-1α was shown to play a role
in activation-induced by LPS, as blocking glycolysis using 2DG inhibited DC maturation, measured through the reduced
expression of costimulatory molecules CD80 and CD86 (Jantsch
et al., 2008). A similar role for HIF-1α in macrophage activation
by LPS was also demonstrated: inhibition of glycolysis using 2DG caused a HIF-1α-mediated downregulation of IL-1β that
blocked macrophage activation (Zhang et al., 2006; Tannahill
et al., 2013). Additional roles for HIF-1α in macrophage
differentiation and function have also been demonstrated.
Specifically, HIF-1α-mediated metabolic reprogramming plays
a significant role in polarization of macrophages toward the
M1 or M2 phenotype (Corcoran and O’Neill, 2016). TCA cycle
intermediates succinate and citrate accumulate in macrophages
upon LPS stimulation, which stabilizes HIF-1α (Newsholme
et al., 1986; Tannahill et al., 2013; Jha et al., 2015). Succinate
increases the transcription of target gene IL-1β, whereas citrate
accumulation leads to increased production of pro-inflammatory
mediators- NO, ROS, and prostaglandins (Infantino et al., 2011;
Tannahill et al., 2013). In neutrophils, HIF signaling leads
to production of the PHD enzymes, especially PHD3, which
prolong the survival of neutrophils under hypoxic conditions in
both human and mice (Walmsley et al., 2011). Thus, HIF-1α
plays a critical role in the homeostasis of immune cells through
metabolic reprogramming during inadequate oxygen levels and
also governs immune responses. In a recent study, it was shown
that HIF-1α-dependent MMP-1 (collagenase) expression and
secretion were synergistically upregulated by hypoxia during
Mtb infection in MDMs and normal human bronchial epithelial
cells (NHBFs) (Belton et al., 2016). They also showed that
HIF-1α is stabilized by Mtb even in the absence of hypoxia
presence of neutrophils in lungs infected by a hypervirulent
strain of Mtb resulted in exacerbation of inflammation and
disease progression (Koo et al., 2012). During mycobacterial
infection, neutrophils also induce transcriptional changes in
macrophages leading to the generation of pro-inflammatory
cytokines (Andersson et al., 2014). Alternatively, Mtb-infected,
necrotic macrophages can be engulfed by neutrophils, thereby
clearing cellular debris during Mtb infection. Neutrophils affect
T cell development and maturation during Mtb infection by
releasing IL-12 (p40 and p70), IL-10, IP-10 (interferon γ induced
protein 10), and MIP-1α (macrophage inflammatory protein)
(Petrofsky and Bermudez, 1999; Seiler et al., 2003; Mantovani
et al., 2011). Neutrophils also communicate with DCs to deliver
signals and for antigen presentation (Hedlund et al., 2010).
It has been shown that the enhanced levels of GSH inside
neutrophils increase the fusion of phagosomes containing Mtb
with lysosomes, which inhibits mycobacterial growth (Morris
et al., 2013b).
Only a few studies have explored the metabolic changes
associated with neutrophil maturation and activation. One
reason for the lack in this area is the relatively short life
span and rapid activation of neutrophils that limit technical
manipulations for long term studies. In humans, Mtb infectioninduced hypoxic conditions stabilize HIF-1α in neutrophils (Ong
et al., 2018). This event leads to increased secretion of matrix
metalloproteases (MMP)-8 and MMP-9, which contribute to the
destruction of the matrix of type1 collagen, gelatin and elastin,
which are the main structural proteins of the human lung (Ong
et al., 2018). In summary, more research is needed to identify
the metabolic changes occurring in neutrophils and to link
them to the corresponding immune responses in the context of
Mtb infection.
MEDIATORS OF HOST METABOLISM
DURING MTB INFECTION
Cellular signals sensed by host cells activate specific regulators
that control immunometabolism (Figure 3). These signals can
originate either from intrinsic stimuli of the host, such as
starvation or from extrinsic factors such as microbes. Similarly,
the downstream response to these stimulants shares many
common molecules and pathways between homeostatic and
disease conditions (Linke et al., 2017; Patsoukis et al., 2017;
Krzywinska and Stockmann, 2018). The following are the key
host transcriptional regulators involved in immunometabolic
changes relevant for Mtb infection (Figure 4).
HIF-1
The hypoxia-inducible factor-1 (HIF-1) is a heterodimeric
transcription factor composed of two subunits: oxygen
responsive HIF-1α, and constitutively expressed HIF-1β
(Nizet and Johnson, 2009). In human colon and ovarian cancer
cells, under non-hypoxic conditions, prolyl-1-4 hydroxylase
proteins (PHDs) hydroxylate HIF-1α, which then binds vonHippel-Lindau proteins, causing proteasomal degradation of
HIF-1α (Huang et al., 1998; Semenza, 2000). Under hypoxic
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FIGURE 3 | Progression of the immune response and metabolic changes in immune cells following Mtb infection. Following infection, Mtb reaches the lung where it
encounters various immune cells. Macrophages and DCs are among the first immune cells to encounter Mtb. Activation of macrophages leads to the generation of
antimicrobial peptides or dissemination of Mtb through the autophagy machinery. Neutrophil interaction with Mtb leads to either bacterial containment or dissemination
through necrosis. DCs infected with Mtb migrate to the draining lymph nodes where they drive T cell differentiation toward a Th-1 phenotype. The activated Th-1 cells
migrate back to the lungs, where they produce IFN-γ and TNF-α, which further activate macrophages leading to bacterial clearance. Metabolic reprogramming, mainly
via the activation of aerobic glycolysis in macrophages, neutrophils, and dendritic cells, plays a significant role in effective functioning of these cells.
suggested to stabilize the HIF-1α-induced immune response in
IFNγ-activated macrophages during Mtb infection (Braverman
and Stanley, 2017).
(Belton et al., 2016). Consistent with this, in mice models of Mtb
infection, IFNγ-activated macrophages exhibited increased HIF1α levels (Braverman et al., 2016). In a zebrafish model of M.
avium infection, increasing HIF-1α levels were associated with
increased bacterial killing (Elks et al., 2013). Similarly, HIF-1α
deficiency in the myeloid lineage blocked IFNγ-induced killing
of Mtb (Braverman et al., 2016).
HIF-1α, which regulates half of the transcriptional responses
to IFNγ, induces the cellular metabolic shift from OXPHOS to
aerobic glycolysis in IFNγ-activated macrophages by inducing
LDH (lactate dehydrogenase) activity to catalyze lactate
production, and by limiting acetyl CoA for the TCA cycle
(Nagao et al., 2019). HIF-1α also regulates the inflammatory
response and NO production in IFNγ-activated macrophages
against infection. Indeed, lack of HIF-1α reduces ATP levels
and NO production at the inflammatory sites (Nagao et al.,
2019). In contrast, HIF-2α reduces the levels of RNS in infected
neutrophils and opposes control of bacterial burden (Elks et al.,
2013). The IFNγ signaling cascade involves the induction of
iNOS, which reduces the expression of RelA (NF-kB family),
thereby negatively regulating the inflammatory response
(Braverman and Stanley, 2017). This activity of iNOS has been
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mTOR
The mammalian target of rapamycin (mTOR) belongs to
the PI3K- related serine/threonine protein kinase family and
comprises two distinct molecular complexes: mTOR complex1
(mTORC1) and mTOR complex 2 (mTORC2) (Laplante and
Sabatini, 2012; Singh and Cuervo, 2012). mTOR is involved in
balancing anabolic vs. catabolic reactions to maintain cellular
homeostasis. mTOR is a master regulator of a myriad of
cellular pathways and functions, including protein synthesis,
metabolism, disease progression, and cell death (Saxton and
Sabatini, 2017). mTOR phosphorylates the kinase p70S6 kinase1
(S6K1) (Holz et al., 2005). Upon activation, S6K1 phosphorylates
and activates several downstream substrates including eIF4B
(a positive regulator of the eIF4F complex) and PDCD4 (an
inhibitor of eIF4B), which promotes translation (Dorrello et al.,
2006). 4EBP is an essential cellular regulator of translation.
It inhibits translation by binding and sequestering eIF4E,
thereby preventing assembly of the eIF4E complex. Upon
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FIGURE 4 | Key metabolic regulators involved in Mycobacterial infection. Infection with Mtb results in a plethora of metabolic reprogramming in immune cells leading
to the induction of HIF-1α, which induces aerobic glycolysis. In the latter stages of the disease, when host immunity wanes, Mtb modulates the immune response by
inducing PPAR-γ expression, which facilitates lipid droplet formation and prostaglandin synthesis, which augment bacterial survival.
mice, prolonged exposure to rapamycin before Mtb aerosol
infection inhibited T cell activation and production of proinflammatory cytokines (Lachmandas et al., 2016a). This was
also shown in human PBMCs. Studies using inhibitors have
demonstrated a role specifically for mTORC1 in Th1 and Th17
activation, and associated metabolic changes; however, no role
for mTORC2 has been shown in immune cell metabolic shift
(Delgoffe et al., 2011). One of the signaling pathways through
which mTORC1 induces metabolic reprogramming involves
HIF-1α (Yecies and Manning, 2011). Using immortalized
human retinal pigment epithelial cells, mTORC1 activation
was shown to upregulate glycolytic genes like Glut-1, which
promotes cholesterol and fatty acid synthesis involving a pathway
regulated by SREBPs and PPAR-γ (Porstmann et al., 2008). In
contrast, mTORC2 activates metabolic reprogramming through
Myc and AKT in the human breast cancer cell line MCF-7
(Sarbassov et al., 2005; Zou et al., 2015).
phosphorylation by mTORC1 at multiple sites, 4EBP dissociates
′
from eIF4E, and 5 cap-dependent mRNA translation is
facilitated (Brunn et al., 1997; Gingras et al., 1999). mTOR is
also involved in de novo lipid synthesis through the transcription
factor, sterol responsive element binding protein (SERBP), which
controls the expression of genes involved in fatty acid and
cholesterol biosynthesis (Singh and Subbian, 2018). mTORC1
also promotes nucleotide biosynthesis by inducing ATF-4
dependent methylenetetrahydrofolate dehydrogenase (NADP+
dependent) 2 (MTHFD2) expression, which is a vital component
of the mitochondrial tetrahydrofolate cyclase that provides onecarbon units for purine biosynthesis (Ben-Sahra et al., 2016).
mTORC1 also activates CAD (carbamoyl- phosphate synthetase),
a key component required for pyrimidine synthesis (Ben-Sahra
et al., 2013; Robitaille et al., 2013). mTOR also increases HIF1α translation and thus is involved in the metabolic shift to
aerobic glycolysis (Saxton and Sabatini, 2017). In addition, the
Mtb-induced metabolic switch of the host cellular machinery
toward aerobic glycolysis is mediated by a TLR-2-dependent
pathway in human monocytes and macrophages, which requires
the AKT-mTOR axis (Lachmandas et al., 2016a).
Together with positively regulating anabolic processes, mTOR
also suppresses catabolic processes to promote cellular growth.
One of the major cellular processes regulated by mTOR
is autophagy. mTOR phosphorylates, and thereby inactivates
ULK1, which is a kinase that triggers autophagy by forming
a complex with ATG13, FIP2000, and ATG10, to drive
autophagosome formation (Kim et al., 2011). One of the
survival strategies adopted by Mtb in host cells is to subvert
the autophagy pathway for its benefit (Zhai et al., 2019). In
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cMyc
The cellular myelocytomatosis (cMyc) is a member of a
proto-oncogene family of transcription factors involved in
regulating cell proliferation (Stine et al., 2015). Structurally,
cMyc consists of an N-terminal transactivation domain and a
C-terminal basic helix-loop-helix (HLH) leucine zipper (LZ)
domain, which binds to a CACGTG E-box DNA sequence
(Meyer and Penn, 2008). This binding facilitates the recruitment
of histone acetyltransferase and elongation factors that can
modify the transcriptional response of several genes. Deregulated
and sustained Myc expression is a hallmark of cancer cells,
and it constitutively activates a cell growth program in an
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in host immune cells, which downregulates NF-κB signaling
and enhances prostaglandin (PG) E2 production that represses
pro-inflammatory cytokines and Th1 responses (Almeida et al.,
2012; Mahajan et al., 2012). Increased PPAR-γ expression
in Mtb-infected macrophages has also been associated with
lipid droplet formation (Mahajan et al., 2012; Salamon et al.,
2014). The accumulated lipids in these infected cells provide
nutrients and promote bacterial growth. In addition, this PPAR-γ
mediated lipid accumulation positively correlates with increased
expression of scavenger receptors, including macrophage
receptor with collagenous structure (MARCO), macrophage
scavenger receptor (MRS), and CD36 in macrophages within
human leprosy lesions (Cruz et al., 2008). These findings suggest
that PPAR-γ promotes intracellular lipid accumulation by
modulating the expression of several genes involved in lipid
absorption as well as fatty acid synthesis during Mtb infection.
PPAR-α is another isoform of the PPAR family. It is a
transcription factor that binds to cis-acting DNA elements and
regulates the expression of several genes involved in lipid and
glucose metabolism (Rakhshandehroo et al., 2010). PPAR-α
regulates mitochondrial as well as peroxisome function and
thus energy metabolism (Kersten, 2014). It enhances fatty acid
oxidation and ketogenesis, whereas it inhibits fatty acid synthesis
and glycolysis (Mandard et al., 2004). Thus, PPAR-α activation
helps prevent lipid accumulation in Mtb-infected cells. PPAR-α
activation also upregulates expression of transcription factor EB
(TFEB) and promotes autophagy as well as host innate immunity
during Mtb infection (Kim et al., 2017). The induction of TFEB
also promotes lipid catabolism, which reduces intracellular Mtb
growth in bone marrow-derived macrophages (Kim et al., 2017).
mTOR-dependent manner (Dang, 2011). Myc controls metabolic
reprogramming by binding to open chromatin of target genes
involved in glycolysis and glutaminolysis, which promotes their
efficient transcription. Myc dimerizes with Max, which is also
a DNA-binding helix-loop-helix leucine zipper protein, to alter
gene expression (Stine et al., 2015).
Upon mycobacterial infection of human PBMCs with
different pathogenicity M. bovis (BCG), M. avium, M. kansasii,
and M. chelonae, the Wnt/beta-catenin signaling pathway was
found to stimulate cMyc through the MAPK/ERK pathway,
resulting in the upregulation of key cytokines, including TNF-α
and IL-6, which inhibit mycobacterial growth (Yim et al., 2011).
In this context, Myc played a role in the anti-mycobacterial
response without influencing cell proliferation or changing the
G0/G1 cell cycle phase of the macrophages.
Sirtuins (SIRTs)
Sirtuins are a family of seven proteins with deacetylase activity
that requires NAD+ for their function (Sauve and Youn, 2012).
Generally, sirtuins modulate cellular processes by inhibiting
NFκB signaling and associated pro-inflammatory responses in
several clinical conditions associated with chronic and acute
inflammation and other metabolic disorders such as diabetes
and obesity (Kauppinen et al., 2013; Vachharajani et al., 2016).
TLR4 stimulation in THP-1 macrophages leads to a sirtuinmediated metabolic shift from enhanced glycolysis to increased
fatty acid oxidation, which typically delays early inflammation
(Liu et al., 2012). In addition, the role of sirtuins in modulating
the host immune response toward a more anti-inflammatory
response during Mtb infection has been reported (Cheng et al.,
2017). Mtb infection down-regulates SIRT1 expression in THP1 macrophages, as well as in mice lung, which downregulates
the expression of the RelA/p65 units of NFκB and promotes
inflammatory resolution (Cheng et al., 2017). Furthermore,
in contrast to an earlier observation, it has been shown
that inhibition of SIRT6 increases the expression of glucose
transporters such as GLUT1 and GLUT4, which promote glucose
absorption and glycolysis in a mouse model of type 2 diabetes
(Sociali et al., 2017). Another study reported increased SIRT6
expression during the early stages of Mtb infection in murine
macrophages, which suppresses both pro-inflammatory and
other anti-microbial responses at this early stage of infection (Shi
et al., 2019). This observation suggests that clinical intervention
or host-directed therapeutic strategies that regulate availability
of sirtuins might help control disease by promoting a proinflammatory immune response.
Arginases
Arginases are involved in the final steps of the urea cycle, where
they convert arginine to ornithine and urea. Arginases exist in
two isoforms; a cytosolic Arginase 1(ARG1) and a mitochondrial
Arginase 2 (ARG2). Arginases compete with nitric oxide synthase
(NOS) for a common substrate, arginine (Mori, 2007). While
inducible NOS promotes a pro-inflammatory response, ARG is
associated with the anti-inflammatory response in host immune
cells (Yang and Ming, 2014). Thus, a shift in arginine metabolism
is associated with the outcome of both innate and adaptive
immune responses. ARG1 is predominantly present in M2
macrophages, which are mainly localized in the periphery of
granulomas (Mattila et al., 2013). Increased expression of ARG1
in macrophages suppresses their antimicrobial activities by
downregulating the production of nitric oxide (NO) and reactive
RNS. In contrast, another study suggested a host-protective
role for ARG1 in hypoxic TB granulomas: ARG1 regulated T
cell proliferation and hyper-inflammation that controlled tissue
necrosis and inflammatory lung pathology in murine TB model
granulomas (Duque-Correa et al., 2014). This study underscored
the crucial role of ARG1 in controlling inflammation and
necrosis in hypoxic granulomas, where NO is ineffective. Similar
to ARG1, ARG2 also has been shown to downregulate NO
production and restrict an effective immune response during
Helicobacter pylori infection (Lewis et al., 2011). This process
involved the positive regulation of ARG2 by the liver X receptor,
PPARs
PPAR-γ is a member of the ligand-activated transcription
factor family (Theocharis et al., 2004). It forms a heterodimer
with the retinoid X receptor (RXR) that binds to specific
PPAR-response elements (PPREs) on the promoter regions of
target genes (Kota et al., 2005). Expression of PPAR-γ can be
activated by lipid metabolites; PPAR-γ also modulates lipid
and glucose metabolism, and other cellular functions such
as proliferation, differentiation, and inflammation (Almeida
et al., 2012). Mtb infection increases PPAR-γ gene expression
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shifting arginine metabolism toward polyamine synthesis to exert
an anti-inflammatory response in macrophages. In the same
study, the authors also reported a decreased bacterial burden in
Agr2−/− mice as compared to wild type, which was associated
with increased NO production in the absence of ARG (Lewis
et al., 2011). Thus, the metabolic shift mediated by ARG1 and
2 exerts an anti-inflammatory response in immune cells, which
helps immune evasion by the pathogen.
overload produced during inflammatory disorders (Sharma
and Prakash, 2017). The reversible/interconvertible nature of
these metabolites establishes their roles as physiological (cell
membrane integration) and functional (macrophage-activation)
components of cells to maintain homeostasis (Ohanian and
Ohanian, 2001). S1P, one of the most studied sphingolipids
produced by the enzymatic activity of sphingosine-1 kinase
(SK1), signals through five G-coupled receptors (S1PRs). Among
these S1PRs, S1PR-1, 2, and 3 are immune regulators involved
in pathogen control (Sanchez and Hla, 2004). Induction of
S1PR2 has been shown to enhance the anti-mycobacterial
activity of alveolar macrophages. SK1 activity is also important
for phagosome maturation, innate activation of macrophages,
and control of Mtb replication. Mtb is capable of inhibiting
SK1 activity leading to a decrease in Ca2+ ion concentration
that can block phagolysosome maturation (Malik et al., 2003).
This process is facilitated by the increased levels of sialylated
glycosphingolipid content in epithelial lung cells due to
environmental or genetic factors. In pulmonary TB patients,
the low serum level of S1P is suggested to be the result of
reduced activity of SK1 by Mtb. Enhanced S1P levels are also
shown to promote phagosome maturation and reduce the lung
Mtb burden, thus improving histopathology in mouse models of
infection (Anes et al., 2003; Garg et al., 2004). While S1P and
C1P are known to promote cell repair, division, and survival,
other sphingolipids such as ceramide are involved in cell death
and inflammation (Sawai and Hannun, 1999). Ceramides are
also suggested to induce drug resistance against rifampin in
Mtb clinical isolates, and establish persistent survival of Mtb
(Speer et al., 2015). This prolonged survival of Mtb is also
linked with the S1P-pAKT-mediated upregulation of mTOR
signaling in macrophages (Liu et al., 2009, 2010). During Mtb
infection, FM formation indicates lipid overload in the host
cells (Russell, 2011). To maintain sphingolipid balance in FM,
saponin C (SapC) degrades glycosphingolipids to ceramide;
SapC also mediates transfer of Mtb lipid antigen from intralysosomal membranes to CD1b to activate antigen-specific T cells
(Kim et al., 2010). Upregulation of SapC seen in granulomas
justifies the accumulation of LacCer, an important intermediate
of sphingolipid metabolism found in abundance in the caseum
compartment of granulomas, but only in trace amounts in other
regions/cells (Kolter and Sandhoff, 2005, 2006). Since FM favors
Mtb growth, accumulation of sphingolipid and its metabolites
indicates altered phagolysosome biogenesis in Mtb-infected host
cells. This lipid overload in granulomas also suggests a shift in
lipid metabolism conferred by infection, which is crucial for
Mtb survival.
Inducible Nitric Oxide Synthase (iNOS)
Inducible nitric oxide synthase (iNOS) catalyzes the production
of NO, especially in macrophages activated by IFN-γ (Riquelme
et al., 2013). NO is a key anti-mycobacterial molecule, and it can
be converted into highly RNS such as NO3 and NO2 within Mtbinfected macrophages (Jamaati et al., 2017). In addition to its
microbicidal activity, NO also acts as a secondary messenger and
modulates the expression of genes involved in IFN-γ signaling
pathways during Mtb infection (Lee and Kornfeld, 2010; Herbst
et al., 2011). HIF-1α is an important factor for IFN-γ-mediated
control of Mtb infection (Braverman et al., 2016). NO positively
regulates HIF-1α expression and contributes to the protective
macrophage response against Mtb infection (Braverman and
Stanley, 2017). Furthermore, NO inhibits prolonged NFκB
activation in macrophages, and limits excessive inflammation
and tissue damage during Mtb infection (Braverman and Stanley,
2017). Thus, iNOS and its product NO exert direct antimicrobial
responses and also modulate IFN-γ-mediated anti-Mtb activities
and the inflammatory response during infection. In addition,
increased NO leads to nitrosylation of iron-sulfur proteins
present in the electron transport chain, inhibiting mitochondrial
respiration (Brown, 2001). Nitrosylation of cysteine residues
of enzymes involved in glycolysis, TCA cycle, and fatty acid
oxidation, alters their activity and modulates both glucose and
fatty acid metabolism in activated immune cells (Doulias et al.,
2013; Kelly and O’Neill, 2015). It has been shown that NO
production in LPS-activated macrophages and DCs is associated
with mitochondrial dysfunction and a shift toward increased
glycolysis (Everts et al., 2012). Overall, NO produced during
infection causes nitrosylation of enzymes involved in glucose
and fatty acid metabolism, which modulates the host immune
response to infection.
Sphingolipids
The mucus secreted by lung alveolar epithelial cells acts as the
first line of defense against microbial infections (Sharma and
Prakash, 2017). One of the major components of these surfactants
are sphingolipids, which play a crucial role in protecting the
host against invasion of macrophages by Mtb (Garg et al.,
2004). Sphingolipids are regulated by the de novo sphingolipid
biosynthesis pathway and the sphingomyelin catabolic pathway
(Gault et al., 2010). Specific sphingolipids associated with
inflammatory and metabolic diseases are sphingomyelin (SM),
ceramide (Cer), ceramide-1 phosphate (C1P), sphingosine (Sph),
sphingosine-1 phosphate (S1P), and lactosylceramide (LacCer).
All metabolites of sphingolipid biosynthesis are metabolically
associated with each other to maintain a state of equilibrium
within the innate immune cells and cope with the lipid
Frontiers in Molecular Biosciences | www.frontiersin.org
EPIGENETIC REGULATION OF
IMMUNOMETABOLISM
Epigenetic modifications can be induced by nutritional states
of cells, which drive the inflammatory response accompanying
metabolic disease (Barres et al., 2013). Mechanisms by
which epigenetic modulations occur, include (I) Genomic
DNA methylation by DNA methyltransferases including
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Kumar et al.
Immunometabolism and Innate Immunity in Tuberculosis
non-tail arginine of H3 to alter the antigen presentation of
macrophages (Yaseen et al., 2015). In a recent study, it was
observed that Mtb infection in DCs led to induction of stable
DNA demethylation at enhancers elements across the genome
(Pacis et al., 2019).
DNMT1, DNMT3A, and DNMT3B, which generally results in
transcriptional repression, (II) histone modifications including
acetylation, methylation, phosphorylation, ubiquitylation and
sumoylation (Bannister and Kouzarides, 2011; Raghuraman
et al., 2016). Immune regulation through methylation changes
is reported in TNF-α, UBASH3B (Ubiquitin-associated and
SH3 domain-containing protein B) and TRIM3 (Tripartite
motif-containing-3) genes (Wang et al., 2010; Hermsdorff et al.,
2013). Role of altered DNA methylation in regulating immune
function of T cells and macrophages is well documented in
metabolic disorders, including obesity and T2DM (Barres et al.,
2013; Raghuraman et al., 2016). Macrophage differentiation
from monocytes is associated with various histone-modifying
components involving H3K4me1, H3K4me3, and H3K27ac at
promoter and enhancer regions (Saeed et al., 2014). Besides,
cytokine production by macrophages is induced by H3K4me3
and demethylation of H3K27 (Takeuch and Akira, 2011). Also,
HDAC3 regulates inflammatory genes in macrophages, while
HDAC2 resolves inflammation by suppressing IL-6 (Chen et al.,
2014; Zhang et al., 2015). The role of H3 acetylation in regulating
inflammatory genes in LPS stimulated monocytes has also been
reported (Iglesias et al., 2012).
Increased glycolysis and β-oxidation lead to accumulation
of acetyl CoA which is used as a group donor by histone
acetyltransferases (HAT) leading to relaxation of chromatin
structure resulting positive regulation of transcription (Laker and
Ryall, 2016). Similarly, NAD+ was found to control epigenetic
remodeling in monocytes through SIRT1 during acute systemic
inflammation (Davis and Gallagher, 2019). The chromatin
remodeling in BCG stimulated innate immune cells is primarily
due to histone modification (H3K4me3 and H3K9me3) in the
glycolysis genes leading to activation of AKT/mTOR/HIF1α
pathway, which induces a metabolic shift in host cells from
OXPHOS to aerobic glucose metabolism. This finding shows the
rewiring of cellular metabolism to facilitate increased production
of cytokines such as TNF-α and IL6 that promote mycobacterial
killing (Kleinnijenhuis et al., 2011; Arts et al., 2016).
Mtb tends to prevent the expression of immune regulatory
genes such as CIITA, CD64, and HLA DR through altering
chromatin dynamics and modifying histones at specific promoter
sites (Pattenden et al., 2002). In blood cells from patients
with pulmonary tuberculosis, DNA hypermethylation of CpG
sites in TLR2 promoter was observed (Chen et al., 2014). In
another study, using global histone acetylation (Ac)/methylation
(Me) in blood leukocytes of pulmonary tuberculosis patients
showed H3K14 hypoacetylation and H3K27 hypermethylation
played a role in developing active pulmonary tuberculosis (Chen
et al., 2017). Mtb (Rv1988) can interfere with the host genetic
remodeling also by inducing histone modifications (H3) of
CONCLUDING REMARKS
Recent advances in TB research, including investigations into
the role of metabolic reprogramming in different immune cells,
have expanded our understanding of the pathogenesis and
progression of the disease. It is now widely recognized that the
immune response and metabolic remodeling are interconnected.
Therefore, the net host response to Mtb infection is a result of
combined immunologic and metabolic activities of the immune
cells. However, much more work is needed to elucidate the
intricate interactions among various metabolic programming
pathways, which can tip the balance in the survival advantage
toward the host or Mtb. Similarly, the causal link between
immune response and metabolic remodeling needs further
exploration, including investigations on how Mtb interferes
with these host processes. A comprehensive understanding of
the immunometabolic processes will not only help in our
understanding of how pathogenic bacteria subvert immune
response in their favor, but will also aid in uncovering new
treatment/vaccination strategies to control TB more effectively.
In this regard, the components of glycolysis and oxidative
phosphorylation reactions associated with Mtb infection of
immune cells could be harnessed for designing host-directed
treatment strategies to enhance bacterial clearance and improve
treatment outcomes.
AUTHOR CONTRIBUTIONS
LS, SS, YB, and ST conceived the concept. RK, PS, AK, and
SS wrote the manuscript. PS and AK contributed equally. All
authors read, edited, and agreed to publish the manuscript.
FUNDING
The grant support to our immunometabolism research was
provided by NIAID/NIH (Grant number: AI127844 to LS
and SS).
ACKNOWLEDGMENTS
The authors like to acknowledge the NIAID/NIH for providing
grant support to immunometabolism research (Grant number:
AI127844 to LS and SS).
REFERENCES
Alcais, A., Fieschi, C., Abel, L., and Casanova, J. L. (2005). Tuberculosis in
children and adults: two distinct genetic diseases. J. Exp. Med. 202, 1617–1621.
doi: 10.1084/jem.20052302
Almeida, P. E., Carneiro, A. B., Silva, A. R., Bozza, P., et al. (2012).
PPARγ expression and function in mycobacterial infection: roles in lipid
metabolism, immunity, and bacterial killing. PPAR Res. 2012:383829.
doi: 10.1155/2012/383829
Abadie, V., Badell, E., Douillard, P., Ensergueix, D., Leenen, P. J., et al. (2005).
Neutrophils rapidly migrate via lymphatics after Mycobacterium bovis
BCG intradermal vaccination and shuttle live bacilli to the draining
lymph nodes. Blood 106, 1843–1850. doi: 10.1182/blood-2005-03-1
281
Frontiers in Molecular Biosciences | www.frontiersin.org
13
October 2019 | Volume 6 | Article 105
Kumar et al.
Immunometabolism and Innate Immunity in Tuberculosis
Brunn, G. J., Hudson, C. C., Sekulic, A., Williams, J. M., et al. (1997).
Phosphorylation of the translational repressor PHAS-I by the mammalian
target of rapamycin. Science 277, 99–101. doi: 10.1126/science.277.5322.99
Caceres, N., Tapia, G., Ojanguren, I., Altare, F., Gil, O., Pinto, S., et al. (2009).
Evolution of foamy macrophages in the pulmonary granulomas of experimental
tuberculosis models. Tuberculosis 89, 175–182. doi: 10.1016/j.tube.2008.11.001
Capuano, S. V. III, Croix, D. A., Pawar, S., Zinovik, A., Myers, A., Lin,
P., et al. (2003). Experimental Mycobacterium tuberculosis infection
of cynomolgus macaques closely resembles the various manifestations
of human M. tuberculosis infection. Infect. Immun. 71, 5831–5844.
doi: 10.1128/IAI.71.10.5831-5844.2003
Chen, Y. C., Chao, T. Y., Leung, S. Y., Chen, C., et al. (2017). Histone
H3K14 hypoacetylation and H3K27 hypermethylation along with HDAC1 upregulation and KDM6B down-regulation are associated with active pulmonary
tuberculosis disease. Am. J. Transl. Res. 9, 1943–1955.
Chen, Y. C., Hsiao, C. C., Chen, C. J., Chao, T., et al. (2014). Aberrant Toll-like
receptor 2 promoter methylation in blood cells from patients with pulmonary
tuberculosis. J. Infect. 69, 546–557. doi: 10.1016/j.jinf.2014.08.014
Cheng, C. Y., Gutierrez, N. M., Marzuki, M. B., Lu, X., et al. (2017). Host
sirtuin 1 regulates mycobacterial immunopathogenesis and represents
a therapeutic target against tuberculosis. Sci. Immunol. 2:eaaj1789.
doi: 10.1126/sciimmunol.aaj1789
Cooper, A. M., Segal, B. H., Frank, A. A., Holland, S., et al. (2000). Transient loss of
resistance to pulmonary tuberculosis in p47(phox-/-) mice. Infect. Immun. 68,
1231–1234. doi: 10.1128/IAI.68.3.1231-1234.2000
Corcoran, S. E., and O’Neill, L. A. (2016). HIF1α and metabolic reprogramming in
inflammation. J. Clin. Invest. 126, 3699–3707. doi: 10.1172/JCI84431
Cruz, D., Watson, A. D., Miller, C. S., Montoya, D., et al. (2008). Host-derived
oxidized phospholipids and HDL regulate innate immunity in human leprosy.
J. Clin. Invest. 118, 2917–2928. doi: 10.1172/JCI34189
Dang, C. V. (2011). Therapeutic targeting of Myc-reprogrammed cancer
cell metabolism. Cold Spring Harb. Symp. Quant. Biol. 76, 369–374.
doi: 10.1101/sqb.2011.76.011296
D’Avila, H., Melo, R. C., Parreira, G. G., Werneck-Barroso, E., et al.
(2006). Mycobacterium bovis bacillus Calmette-Guerin induces TLR2-mediated
formation of lipid bodies: intracellular domains for eicosanoid synthesis in vivo.
J. Immunol. 176, 3087–3097. doi: 10.4049/jimmunol.176.5.3087
Davis, F. M., and Gallagher, K. A. (2019). Epigenetic mechanisms in
monocytes/macrophages regulate inflammation in cardiometabolic
and vascular disease. Arterioscler. Thromb. Vasc. Biol. 39, 623–634.
doi: 10.1161/ATVBAHA.118.312135
Davis, J. M., and Ramakrishnan, L. (2009). The role of the granuloma in
expansion and dissemination of early tuberculous infection. Cell 136, 37–49.
doi: 10.1016/j.cell.2008.11.014
DeBerardinis, R. J., and Thompson, C. B. (2012). Cellular metabolism
and disease: what do metabolic outliers teach us? Cell 148, 1132–1144.
doi: 10.1016/j.cell.2012.02.032
Del Prete, A., Zaccagnino, P., Di Paola, M., Saltarella, M., Oliveros Celis, C.,
Nico, B., et al. (2008). Role of mitochondria and reactive oxygen species
in dendritic cell differentiation and functions. Free Radic. Biol. Med. 44,
1443–1451. doi: 10.1016/j.freeradbiomed.2007.12.037
Delgoffe, G. M., Pollizzi, K. N., Waickman, A. T., Heikamp, E., et al. (2011). The
kinase mTOR regulates the differentiation of helper T cells through the selective
activation of signaling by mTORC1 and mTORC2. Nat. Immunol. 12, 295–303.
doi: 10.1038/ni.2005
Diotallevi, M., Checconi, P., Palamara, A. T., Celestino, I., Coppo, L., et al. (2017).
Glutathione fine-tunes the innate immune response toward antiviral pathways
in a macrophage cell line independently of its antioxidant properties. Front.
Immunol. 8:1239. doi: 10.3389/fimmu.2017.01239
Donnelly, R. P., Loftus, R. M., Keating, S. E., Liou, K., et al. (2014). mTORC1dependent metabolic reprogramming is a prerequisite for NK cell effector
function. J. Immunol. 193, 4477–4484. doi: 10.4049/jimmunol.1401558
Dorrello, N. V., Peschiaroli, A., Guardavaccaro, D., Colburn, N. H., Sherman,
N., et al. (2006). S6K1- and betaTRCP-mediated degradation of PDCD4
promotes protein translation and cell growth. Science 314, 467–471.
doi: 10.1126/science.1130276
Doulias, P. T., Tenopoulou, M., Greene, J. L., Raju, K., and Ischiropoulos,
H. (2013). Nitric oxide regulates mitochondrial fatty acid metabolism
Almeida, P. E., Silva, A. R., Maya-Monteiro, C. M., Torocsik, D., et al.
(2009). Mycobacterium bovis bacillus Calmette-Guerin infection induces TLR2dependent peroxisome proliferator-activated receptor gamma expression and
activation: functions in inflammation, lipid metabolism, and pathogenesis. J.
Immunol. 183, 1337–1345. doi: 10.4049/jimmunol.0900365
Andersson, H., Andersson, B., Eklund, D., Ngoh, E., Persson, A., Svensson,
K., et al. (2014). Apoptotic neutrophils augment the inflammatory response
to Mycobacterium tuberculosis infection in human macrophages. PLoS ONE
9:e101514. doi: 10.1371/journal.pone.0101514
Anes, E., Kuhnel, M. P., Bos, E., Moniz-Pereira, J., Habermann, A., et al.
(2003). Selected lipids activate phagosome actin assembly and maturation
resulting in killing of pathogenic mycobacteria. Nat. Cell Biol. 5, 793–802.
doi: 10.1038/ncb1036
Appelberg, R., Moreira, D., Barreira-Silva, P., Borges, M., Silva, L., DinisOliveira, R., et al. (2015). The Warburg effect in mycobacterial granulomas is
dependent on the recruitment and activation of macrophages by interferon- γ.
Immunology 145, 498–507. doi: 10.1111/imm.12464
Arts, R. J. W., Joosten, L. A. B., and Netea, M. G. (2016). Immunometabolic
circuits in trained immunity. Semin. Immunol. 28, 425–430.
doi: 10.1016/j.smim.2016.09.002
Austyn, J. M., and Gordon, S. (1981). F4/80, a monoclonal antibody directed
specifically against the mouse macrophage. Eur. J. Immunol. 11, 805–815.
doi: 10.1002/eji.1830111013
Banaiee, N., Kincaid, E. Z., Buchwald, U., Jacobs, W. R., et al. (2006).
Potent inhibition of macrophage responses to IFN- γ by live virulent
Mycobacterium tuberculosis is independent of mature mycobacterial
lipoproteins but dependent on TLR2. J. Immunol. 176, 3019–3027.
doi: 10.4049/jimmunol.176.5.3019
Bannister, A. J., and Kouzarides, T. (2011). Regulation of chromatin by histone
modifications. Cell Res. 21, 381–395. doi: 10.1038/cr.2011.22
Barres, R., Kirchner, H., Rasmussen, M., Yan, J., Kantor, F. R., et al.
(2013). Weight loss after gastric bypass surgery in human obesity remodels
promoter methylation. Cell Rep. 3, 1020–1027. doi: 10.1016/j.celrep.2013.
03.018
Behar, S. M., Martin, C. J., Booty, M. G., Nishimura, T., et al. (2011). Apoptosis is
an innate defense function of macrophages against Mycobacterium tuberculosis.
Mucosal Immunol. 4, 279–287. doi: 10.1038/mi.2011.3
Belton, M., Brilha, S., Manavaki, R., Mauri, F., Nijran, K., Hong, Y., et al. (2016).
Hypoxia and tissue destruction in pulmonary TB. Thorax 71, 1145–1153.
doi: 10.1136/thoraxjnl-2015-207402
Ben-Sahra, I., Howell, J. J., Asara, J. M., Manning, B., et al. (2013). Stimulation of
de novo pyrimidine synthesis by growth signaling through mTOR and S6K1.
Science 339, 1323–1328. doi: 10.1126/science.1228792
Ben-Sahra, I., Hoxhaj, G., Ricoult, S. J. H., Asara, J. M., et al. (2016). mTORC1
induces purine synthesis through control of the mitochondrial tetrahydrofolate
cycle. Science 351, 728–733. doi: 10.1126/science.aad0489
Billig, S., Schneefeld, M., Huber, C., Grassl, G. A., Eisenreich, W., et al. (2017).
Lactate oxidation facilitates growth of Mycobacterium tuberculosis in human
macrophages. Sci. Rep. 7:6484. doi: 10.1038/s41598-017-05916-7
Blomgran, R., and Ernst, J. D. (2011). Lung neutrophils facilitate activation of naive
antigen-specific CD4+ T cells during Mycobacterium tuberculosis infection. J.
Immunol. 186, 7110–7119. doi: 10.4049/jimmunol.1100001
Bogdan, C. (2001). Nitric oxide and the immune response. Nat. Immunol. 2,
907–916. doi: 10.1038/ni1001-907
Bordbar, A., Lewis, N. E., Schellenberger, J., Palsson, B. O., et al. (2010). Insight
into human alveolar macrophage and M. tuberculosis interactions via metabolic
reconstructions. Mol. Syst. Biol. 6:422. doi: 10.1038/msb.2010.68
Braverman, J., Sogi, K. M., Benjamin, D., Nomura, D. K., et al. (2016). HIF-1α is
an essential mediator of IFN- γ -dependent immunity to Mycobacterium
tuberculosis. J. Immunol. 197, 1287–1297. doi: 10.4049/jimmunol.16
00266
Braverman, J., and Stanley, S. A. (2017). Nitric oxide modulates macrophage
responses to Mycobacterium tuberculosis infection through activation
of HIF-1α and repression of NF-κB. J. Immunol. 199, 1805–1816.
doi: 10.4049/jimmunol.1700515
Brown, G. C. (2001). Regulation of mitochondrial respiration by nitric oxide
inhibition of cytochrome c oxidase. Biochim. Biophys. Acta 1504, 46–57.
doi: 10.1016/S0005-2728(00)00238-3
Frontiers in Molecular Biosciences | www.frontiersin.org
14
October 2019 | Volume 6 | Article 105
Kumar et al.
Immunometabolism and Innate Immunity in Tuberculosis
aerobic glycolysis in human alveolar macrophages that is required for
control of intracellular bacillary replication. J. Immunol. 196, 2444–2449.
doi: 10.4049/jimmunol.1501612
Gogolak, P., Rethi, B., Szatmari, I., Lanyi, A., Dezso, B., Nagy, L., et al.
(2007). Differentiation of CD1a- and CD1a+ monocyte-derived dendritic
cells is biased by lipid environment and PPAR γ. Blood 109, 643–652.
doi: 10.1182/blood-2006-04-016840
Gordon, S. (2003). Alternative activation of macrophages. Nat. Rev. Immunol. 3,
23–35. doi: 10.1038/nri978
Gordon, S., and Taylor, P. R. (2005). Monocyte and macrophage heterogeneity.
Nat. Rev. Immunol. 5, 953–964. doi: 10.1038/nri1733
Guerrini, V., Prideaux, B., Blanc, L., Bruiners, N., Arrigucci, R., Singh, S., et al.
(2018). Storage lipid studies in tuberculosis reveal that foam cell biogenesis is
disease-specific. PLoS Pathog. 14:e1007223. doi: 10.1371/journal.ppat.1007223
Guirado, E., Schlesinger, L. S., and Kaplan, G. (2013). Macrophages
in tuberculosis: friend or foe. Semin. Immunopathol. 35, 563–583.
doi: 10.1007/s00281-013-0388-2
Gutierrez, M. G., Master, S. S., Singh, S. B., Taylor, G., et al. (2004). Autophagy
is a defense mechanism inhibiting BCG and Mycobacterium tuberculosis
survival in infected macrophages. Cell 119, 753–766. doi: 10.1016/j.cell.2004.
11.038
Hedlund, S., Persson, A., Vujic, A., Che, K. F., Stendahl, O., et al.
(2010). Dendritic cell activation by sensing Mycobacterium tuberculosisinduced apoptotic neutrophils via DC-SIGN. Hum. Immunol. 71, 535–540.
doi: 10.1016/j.humimm.2010.02.022
Herbst, S., Schaible, U. E., and Schneider, B. E. (2011). Interferon γ activated
macrophages kill mycobacteria by nitric oxide induced apoptosis. PLoS ONE
6:e19105. doi: 10.1371/journal.pone.0019105
Hermsdorff, H. H., Mansego, M. L., Campion, J., Milagro, F. I., et al. (2013).
TNF-α promoter methylation in peripheral white blood cells: relationship with
circulating TNFα, truncal fat and n-6 PUFA intake in young women. Cytokine
64, 265–271. doi: 10.1016/j.cyto.2013.05.028
Hinchey, J., Lee, S., Jeon, B. Y., Basaraba, R. J., et al. (2007). Enhanced priming of
adaptive immunity by a proapoptotic mutant of Mycobacterium tuberculosis. J.
Clin. Invest. 117, 2279–2288. doi: 10.1172/JCI31947
Holz, M. K., Ballif, B. A., Gygi, S. P., and Blenis, J. (2005). mTOR and S6K1
mediate assembly of the translation preinitiation complex through dynamic
protein interchange and ordered phosphorylation events. Cell 123, 569–580.
doi: 10.1016/j.cell.2005.10.024
Huang, L., Nazarova, E. V., Tan, S., Liu, Y., Russell, D., et al. (2018).
Growth of Mycobacterium tuberculosis in vivo segregates with host
macrophage metabolism and ontogeny. J. Exp. Med. 215, 1135–1152.
doi: 10.1084/jem.20172020
Huang, L. E., Gu, J., Schau, M., and Bunn, H. F. (1998). Regulation of hypoxiainducible factor 1α is mediated by an O2-dependent degradation domain via
the ubiquitin-proteasome pathway. Proc. Natl. Acad. Sci. U.S.A. 95, 7987–7992.
doi: 10.1073/pnas.95.14.7987
Humphreys, I. R., Stewart, G. R., Turner, D. J., Patel, J., et al. (2006). A role for
dendritic cells in the dissemination of mycobacterial infection. Microbes Infect.
8, 1339–1346. doi: 10.1016/j.micinf.2005.12.023
Ibrahim, J., Nguyen, A. H., Rehman, A., Ochi, A., Jamal, M., et al. (2012). Dendritic
cell populations with different concentrations of lipid regulate tolerance
and immunity in mouse and human liver. Gastroenterology 143, 1061–1072.
doi: 10.1053/j.gastro.2012.06.003
Iglesias, M. J., Reilly, S. J., Emanuelsson, O., Sennblad, B., Pirmoradian Najafabadi,
M., et al. (2012). Combined chromatin and expression analysis reveals specific
regulatory mechanisms within cytokine genes in the macrophage early immune
response. PLoS ONE 7:e32306. doi: 10.1371/journal.pone.0032306
Infantino, V., Convertini, P., Cucci, L., Panaro, M. A., Di Noia, M., et al. (2011).
The mitochondrial citrate carrier: a new player in inflammation. Biochem. J.
438, 433–436. doi: 10.1042/BJ20111275
Ishikawa, F., Niiro, H., Iino, T., Yoshida, S., Saito, N., Onohara, S., et al. (2007). The
developmental program of human dendritic cells is operated independently
of conventional myeloid and lymphoid pathways. Blood 110, 3591–3660.
doi: 10.1182/blood-2007-02-071613
Jamaati, H., Mortaz, E., Pajouhi, Z., Folkerts, G., Movassaghi, M., Moloudizargari,
M., et al. (2017). Nitric oxide in the pathogenesis and treatment of tuberculosis.
Front. Microbiol. 8:2008. doi: 10.3389/fmicb.2017.02008
through
reversible
protein
S-nitrosylation.
Sci.
Signal.
6:rs1.
doi: 10.1126/scisignal.2003252
Duque-Correa, M. A., Kuhl, A. A., Rodriguez, P. C., Zedler, U., et al. (2014).
Macrophage arginase-1 controls bacterial growth and pathology in hypoxic
tuberculosis granulomas. Proc. Natl. Acad. Sci. U.S.A. 111, E4024–E4032.
doi: 10.1073/pnas.1408839111
Ehrt, S., and Schnappinger, D. (2009). Mycobacterial survival strategies in the
phagosome: defence against host stresses. Cell. Microbiol. 11, 1170–1178.
doi: 10.1111/j.1462-5822.2009.01335.x
Eisenreich, W., Rudel, T., Heesemann, J., and Goebel, W. (2019). How viral
and intracellular bacterial pathogens reprogram the metabolism of host cells
to allow their intracellular replication. Front. Cell. Infect. Microbiol. 9:42.
doi: 10.3389/fcimb.2019.00042
Elks, P. M., Brizee, S. M., van der Vaart, Walmsley, S. R., van Eeden, F., et al. (2013).
Hypoxia inducible factor signaling modulates susceptibility to mycobacterial
infection via a nitric oxide dependent mechanism. PLoS Pathog. 9:e1003789.
doi: 10.1371/journal.ppat.1003789
Epelman, S., Lavine, K. J., Beaudin, A. E., Sojka, D., et al. (2014). Embryonic and
adult-derived resident cardiac macrophages are maintained through distinct
mechanisms at steady state and during inflammation. Immunity 40, 91–104.
doi: 10.1016/j.immuni.2013.11.019
Eruslanov, E. B., Lyadova, I. V., Kondratieva, T. K., Majorov, K., et al.
(2005). Neutrophil responses to Mycobacterium tuberculosis infection in
genetically susceptible and resistant mice. Infect. Immun. 73, 1744–1753.
doi: 10.1128/IAI.73.3.1744-1753.2005
Escoll, P., and Buchrieser, C. (2018). Metabolic reprogramming of host cells upon
bacterial infection: why shift to a Warburg-like metabolism? FEBS J. 285,
2146–2160. doi: 10.1111/febs.14446
Eum, S. Y., Kong, J. H., Hong, M. S., Lee, Y., et al. (2010). Neutrophils are the
predominant infected phagocytic cells in the airways of patients with active
pulmonary TB. Chest 137, 122–128. doi: 10.1378/chest.09-0903
Everts, B., Amiel, E. G. J., van der Windt, Freitas, T. C., Chott, R., et al. (2012).
Commitment to glycolysis sustains survival of NO-producing inflammatory
dendritic cells. Blood 120, 1422–1431. doi: 10.1182/blood-2012-03-41
9747
Fortune, S. M., Solache, A., Jaeger, A., Hill, P. J., Belisle, J., et al. (2004).
Mycobacterium tuberculosis inhibits macrophage responses to IFN- γ through
myeloid differentiation factor 88-dependent and -independent mechanisms. J.
Immunol. 172, 6272–6280. doi: 10.4049/jimmunol.172.10.6272
Fu, L. M. (2003). The potential of human neutrophil peptides in tuberculosis
therapy. Int. J. Tuberc. Lung Dis. 7, 1027–1032.
Gallegos, A. M., Pamer, E. G., and Glickman, M. S. (2008). Delayed protection by
ESAT-6-specific effector CD4+ T cells after airborne M. tuberculosis infection.
J. Exp. Med. 205, 2359–2368. doi: 10.1084/jem.20080353
Garg, S. K., Volpe, E., Palmieri, G., Mattei, M., Galati, D., Martino, A., et al. (2004).
Sphingosine 1-phosphate induces antimicrobial activity both in vitro and in
vivo. J. Infect. Dis. 189, 2129–2138. doi: 10.1086/386286
Gault, C. R., Obeid, L. M., and Hannun, Y. A. (2010). An overview of sphingolipid
metabolism: from synthesis to breakdown. Adv. Exp. Med. Biol. 688, 1–23.
doi: 10.1007/978-1-4419-6741-1_1
Gautam, U. S., Foreman, T. W., Bucsan, A. N., Veatch, A., et al. (2018). In vivo
inhibition of tryptophan catabolism reorganizes the tuberculoma and augments
immune-mediated control of Mycobacterium tuberculosis. Proc. Natl. Acad. Sci.
U.S.A. 115, E62–E71. doi: 10.1073/pnas.1711373114
Gerriets, V. A., Kishton, R. J., Nichols, A. G., Macintyre, A., et al. (2015). Metabolic
programming and PDHK1 control CD4+ T cell subsets and inflammation. J.
Clin. Invest. 125, 194–207. doi: 10.1172/JCI76012
Gibbings, S. L., Goyal, R., Desch, A. N., Leach, S. M., et al. (2015).
Transcriptome analysis highlights the conserved difference between
embryonic and postnatal-derived alveolar macrophages. Blood 126, 1357–1366.
doi: 10.1182/blood-2015-01-624809
Gideon, H. P., and Flynn, J. L. (2011). Latent tuberculosis: what the host sees?
Immunol. Res. 50, 202–212. doi: 10.1007/s12026-011-8229-7
Gingras, A. C., Gygi, S. P., Raught, B., Polakiewicz, R. D., et al. (1999). Regulation
of 4E-BP1 phosphorylation: a novel two-step mechanism. Genes Dev. 13,
1422–1437. doi: 10.1101/gad.13.11.1422
Gleeson, L. E., Sheedy, F. J. E. M., Palsson-McDermott, Triglia, D., O’Leary,
S., et al. (2016). Cutting edge: Mycobacterium tuberculosis induces
Frontiers in Molecular Biosciences | www.frontiersin.org
15
October 2019 | Volume 6 | Article 105
Kumar et al.
Immunometabolism and Innate Immunity in Tuberculosis
Krzywinska, E., and Stockmann, C. (2018). Hypoxia, metabolism and immune cell
function. Biomedicines 6:56. doi: 10.3390/biomedicines6020056
Lachmandas, E., Beigier-Bompadre, M., Cheng, S. C., Kumar, V., van Laarhoven,
A., et al. (2016a). Rewiring cellular metabolism via the AKT/mTOR pathway
contributes to host defence against Mycobacterium tuberculosis in human and
murine cells. Eur. J. Immunol. 46, 2574–2586. doi: 10.1002/eji.201546259
Lachmandas, E., Boutens, L., Ratter, J. M., Hijmans, A., Hooiveld, G., et al. (2016b).
Microbial stimulation of different Toll-like receptor signalling pathways
induces diverse metabolic programmes in human monocytes. Nat. Microbiol.
2:16246. doi: 10.1038/nmicrobiol.2016.246
Lagranderie, M., Abolhassani, M., Vanoirbeek, J. A., Lima, C., Balazuc, A.,
et al. (2010). Mycobacterium bovis bacillus Calmette-Guerin killed by
extended freeze-drying targets plasmacytoid dendritic cells to regulate lung
inflammation. J. Immunol. 184, 1062–1070. doi: 10.4049/jimmunol.0901822
Lai, R., Jeyanathan, M., Afkhami, S., Zganiacz, A., Hammill, J. A., et al.
(2018). CD11b(+) Dendritic cell-mediated anti-Mycobacterium tuberculosis
Th1 activation is counterregulated by CD103(+) dendritic cells via IL-10. J.
Immunol. 200, 1746–1760. doi: 10.4049/jimmunol.1701109
Laker, R. C., and Ryall, J. G. (2016). DNA methylation in skeletal muscle stem cell
specification, proliferation, and differentiation. Stem Cells Int. 2016:5725927.
doi: 10.1155/2016/5725927
Laplante, M., and Sabatini, D. M. (2012). mTOR signaling in growth control and
disease. Cell 149, 274–293. doi: 10.1016/j.cell.2012.03.017
Le Naour, F., Hohenkirk, L., Grolleau, A., Misek, D. E., Lescure, P., et al. (2001).
Profiling changes in gene expression during differentiation and maturation
of monocyte-derived dendritic cells using both oligonucleotide microarrays
and proteomics. J. Biol. Chem. 276, 17920–17931. doi: 10.1074/jbc.M10015
6200
Lee, J., and Kornfeld, H. (2010). Interferon-γ regulates the death of M.
tuberculosis-infected macrophages. J Cell Death 3: 1–11. doi: 10.4137/JCD.S
2822
Lee, W., VanderVen, B. C., Fahey, R. J., Russell, D., et al. (2013). Intracellular
Mycobacterium tuberculosis exploits host-derived fatty acids to limit metabolic
stress. J. Biol. Chem. 288, 6788–6800. doi: 10.1074/jbc.M112.445056
Lewis, N. D., Asim, M., Barry, D. P., de Sablet, T., Singh, K., et al. (2011). Immune
evasion by Helicobacter pylori is mediated by induction of macrophage arginase
II. J. Immunol. 186, 3632–3641. doi: 10.4049/jimmunol.1003431
Linke, M., Fritsch, S. D., Sukhbaatar, N., Hengstschlager, M., and Weichhart, T.
(2017). mTORC1 and mTORC2 as regulators of cell metabolism in immunity.
FEBS Lett. 591, 3089–3103. doi: 10.1002/1873-3468.12711
Liu, C. H., Liu, H., and Ge, B. (2017). Innate immunity in tuberculosis:
host defense vs pathogen evasion. Cell. Mol. Immunol. 14, 963–975.
doi: 10.1038/cmi.2017.88
Liu, G., Burns, S., Huang, G., Boyd, K., Proia, R. L., et al. (2009). The receptor S1P1
overrides regulatory T cell-mediated immune suppression through Akt-mTOR.
Nat. Immunol. 10, 769–777. doi: 10.1038/ni.1743
Liu, G., Yang, K., Burns, S., Shrestha, S., and Chi, H. (2010). The S1P(1)-mTOR axis
directs the reciprocal differentiation of T(H)1 and T(reg) cells. Nat. Immunol.
11, 1047–1056. doi: 10.1038/ni.1939
Liu, T. F., Vachharajani, V. T., Yoza, B. K., McCall, C., et al. (2012). NAD+dependent sirtuin 1 and 6 proteins coordinate a switch from glucose to fatty
acid oxidation during the acute inflammatory response. J. Biol. Chem. 287,
25758–25769. doi: 10.1074/jbc.M112.362343
Lowe, D. M., Redford, P. S., Wilkinson, R. J., O’Garra, A., et al. (2012).
Neutrophils in tuberculosis: friend or foe? Trends Immunol. 33, 14–25.
doi: 10.1016/j.it.2011.10.003
Lunt, S. Y., and Vander Heiden, M. G. (2011). Aerobic glycolysis: meeting the
metabolic requirements of cell proliferation. Annu. Rev. Cell Dev. Biol. 27,
441–464. doi: 10.1146/annurev-cellbio-092910-154237
Lyadova, I. V. (2017). Neutrophils in tuberculosis: heterogeneity shapes the Way?
Mediators Inflamm. 2017:8619307. doi: 10.1155/2017/8619307
MacMicking, J. D., North, R. J., LaCourse, R., Mudgett, J. S., et al. (1997).
Identification of nitric oxide synthase as a protective locus against tuberculosis.
Proc. Natl. Acad. Sci. USA. 94, 5243–5248. doi: 10.1073/pnas.94.10.5243
Madan-Lala, R., Sia, J. K., King, R., Adekambi, T., Monin, L., et al. (2014).
Mycobacterium tuberculosis impairs dendritic cell functions through the serine
hydrolase Hip1. J. Immunol. 192, 4263–4272. doi: 10.4049/jimmunol.1303185
Jantsch, J., Chakravortty, D., Turza, N., Prechtel, A. T., Buchholz, B., et al. (2008).
Hypoxia and hypoxia-inducible factor-1α modulate lipopolysaccharideinduced dendritic cell activation and function. J. Immunol. 180, 4697–4705.
doi: 10.4049/jimmunol.180.7.4697
Jellusova, J., and Rickert, R. C. (2017). A Brake for B Cell Proliferation: appropriate
responses to metabolic stress are crucial to maintain B cell viability and prevent
malignant outgrowth. Bioessays 39. doi: 10.1002/bies.201700079
Jha, A. K., Huang, S. C., Sergushichev, A., Lampropoulou, V., Ivanova, Y., et al.
(2015). Network integration of parallel metabolic and transcriptional data
reveals metabolic modules that regulate macrophage polarization. Immunity
42, 419–430. doi: 10.1016/j.immuni.2015.02.005
Kaplan, G., and Gaudernack, G. (1982). In vitro differentiation of human
monocytes. Differences in monocyte phenotypes induced by cultivation on
glass or on collagen. J. Exp. Med. 156, 1101–1114. doi: 10.1084/jem.156.4.1101
Kapsenberg, M. L. (2003). Dendritic-cell control of pathogen-driven T-cell
polarization. Nat. Rev. Immunol. 3, 984–993. doi: 10.1038/nri1246
Kauppinen, A., Suuronen, T., Ojala, J., Kaarniranta, K., and Salminen, A.
(2013). Antagonistic crosstalk between NF-κB and SIRT1 in the regulation
of inflammation and metabolic disorders. Cell. Signal. 25, 1939–1948.
doi: 10.1016/j.cellsig.2013.06.007
Keane, J., Gershon, S., Wise, R. P., Mirabile-Levens, E., Kasznica, J., et al.
(2001). Tuberculosis associated with infliximab, a tumor necrosis
factor alpha-neutralizing agent. N. Engl. J. Med. 345, 1098–1104.
doi: 10.1056/NEJMoa011110
Kelly, B., and O’Neill, L. A. (2015). Metabolic reprogramming in
macrophages and dendritic cells in innate immunity. Cell Res. 25, 771–784.
doi: 10.1038/cr.2015.68
Kersten, S. (2014). Integrated physiology and systems biology of PPARα. Mol.
Metab. 3, 354–371. doi: 10.1016/j.molmet.2014.02.002
Khader, S. A., Partida-Sanchez, S., Bell, G., Jelley-Gibbs, D. M., Swain, S., et al.
(2006). Interleukin 12p40 is required for dendritic cell migration and T
cell priming after Mycobacterium tuberculosis infection. J. Exp. Med. 203,
1805–1815. doi: 10.1084/jem.20052545
Killick, K. E., Ni Cheallaigh, C., O’Farrelly, C., Hokamp, K., MacHugh, D. E.,
et al. (2013). Receptor-mediated recognition of mycobacterial pathogens. Cell.
Microbiol. 15, 1484–1495. doi: 10.1111/cmi.12161
Kim, J., Kundu, M., Viollet, B., and Guan, K. L. (2011). AMPK and mTOR regulate
autophagy through direct phosphorylation of Ulk1. Nat. Cell Biol. 13, 132–141.
doi: 10.1038/ncb2152
Kim, M. J., Wainwright, H. C., Locketz, M., Bekker, L. G., et al. (2010). Caseation of
human tuberculosis granulomas correlates with elevated host lipid metabolism.
EMBO Mol. Med. 2, 258–274. doi: 10.1002/emmm.201000079
Kim, Y. S., Lee, H. M., Kim, J. K., Yang, C., et al. (2017). PPAR-α Activation
mediates innate host defense through induction of TFEB and lipid catabolism.
J. Immunol. 198, 3283–3295. doi: 10.4049/jimmunol.1601920
Kleinnijenhuis, J., Oosting, M., Joosten, L. A., Netea, M. G., et al. (2011). Innate
immune recognition of Mycobacterium tuberculosis. Clin. Dev. Immunol.
2011:405310. doi: 10.1155/2011/405310
Kolter, T., and Sandhoff, K. (2005). Principles of lysosomal membrane digestion:
stimulation of sphingolipid degradation by sphingolipid activator proteins
and anionic lysosomal lipids. Annu. Rev. Cell Dev. Biol. 21, 81–103.
doi: 10.1146/annurev.cellbio.21.122303.120013
Kolter, T., and Sandhoff, K. (2006). Sphingolipid metabolism diseases. Biochim.
Biophys. Acta 1758, 2057–2079. doi: 10.1016/j.bbamem.2006.05.027
Koo, M. S., Subbian, S., and Kaplan, G. (2012). Strain specific transcriptional
response in Mycobacterium tuberculosis infected macrophages. Cell Commun.
Signal. 10:2. doi: 10.1186/1478-811X-10-2
Kota, B. P., Huang, T. H., and Roufogalis, B. D. (2005). An overview
on biological mechanisms of PPARs. Pharmacol. Res. 51, 85–94.
doi: 10.1016/j.phrs.2004.07.012
Kratchmarov, R., Viragova, S., Kim, M. J., Rothman, N. J., et al. (2018). Metabolic
control of cell fate bifurcations in a hematopoietic progenitor population.
Immunol. Cell Biol. 96, 863–871. doi: 10.1111/imcb.12040
Krawczyk, C. M., Holowka, T., Sun, J., Blagih, J., Amiel, E., DeBerardinis,
R., et al. (2010). Toll-like receptor-induced changes in glycolytic
metabolism regulate dendritic cell activation. Blood 115, 4742–4749.
doi: 10.1182/blood-2009-10-249540
Frontiers in Molecular Biosciences | www.frontiersin.org
16
October 2019 | Volume 6 | Article 105
Kumar et al.
Immunometabolism and Innate Immunity in Tuberculosis
Murphy, D. J. (2001). The biogenesis and functions of lipid bodies in
animals, plants and microorganisms. Prog. Lipid Res. 40, 325–438.
doi: 10.1016/S0163-7827(01)00013-3
Nagao, A., Kobayashi, M., Koyasu, S., Chow, C. C. T., et al. (2019). HIF-1dependent reprogramming of glucose metabolic pathway of cancer cells and
its therapeutic significance. Int. J. Mol. Sci. 20:238. doi: 10.3390/ijms2002
0238
Nazarova, E. V., Montague, C. R., La, T., Wilburn, K. M., et al. (2017).
Rv3723/LucA coordinates fatty acid and cholesterol uptake in Mycobacterium
tuberculosis. Elife 6:e26969. doi: 10.7554/eLife.26969
Nencioni, A., Grunebach, F., Zobywlaski, A., Denzlinger, C., Brugger, W.,
and Brossart, P. (2002). Dendritic cell immunogenicity is regulated
by peroxisome proliferator-activated receptor gamma. J. Immunol. 169,
1228–1235. doi: 10.4049/jimmunol.169.3.1228
Newsholme, P., Curi, R., Gordon, S., and Newsholme, E. A. (1986). Metabolism
of glucose, glutamine, long-chain fatty acids and ketone bodies by murine
macrophages. Biochem. J. 239, 121–125. doi: 10.1042/bj2390121
Nizet, V., and Johnson, R. S. (2009). Interdependence of hypoxic and innate
immune responses. Nat. Rev. Immunol. 9, 609–617. doi: 10.1038/nri2607
North, R. J., and Jung, Y. J. (2004). Immunity to tuberculosis. Annu. Rev. Immunol.
22: 599–623. doi: 10.1146/annurev.immunol.22.012703.104635
Obach, M., Navarro-Sabate, A., Caro, J., Kong, X., Duran, J., Gomez, M., et al.
(2004). 6-Phosphofructo-2-kinase (pfkfb3) gene promoter contains hypoxiainducible factor-1 binding sites necessary for transactivation in response to
hypoxia. J. Biol. Chem. 279, 53562–53570. doi: 10.1074/jbc.M406096200
O’Brien, A., Loftus, R. M., Pisarska, M. M., Tobin, L., et al. (2019). Obesity
reduces mTORC1 activity in mucosal-associated invariant T cells, driving
defective metabolic and functional responses. J. Immunol. 202, 3404–3411.
doi: 10.4049/jimmunol.1801600
Ohanian, J., and Ohanian, V. (2001). Sphingolipids in mammalian cell signalling.
Cell. Mol. Life Sci. 58, 2053–2068. doi: 10.1007/PL00000836
Olakanmi, O., Schlesinger, L. S., Ahmed, A., and Britigan, B. E. (2002).
Intraphagosomal Mycobacterium tuberculosis acquires iron from
both extracellular transferrin and intracellular iron pools. Impact of
interferon-γ and hemochromatosis. J. Biol. Chem. 277, 49727–49734.
doi: 10.1074/jbc.M209768200
O’Neill, L. A., and Pearce, E. J. (2016). Immunometabolism governs dendritic cell
and macrophage function. J. Exp. Med. 213, 15–23. doi: 10.1084/jem.20151570
Ong, C. W. M., Fox, K., Ettorre, A., Elkington, P. T., Friedland, J.,
et al. (2018). Hypoxia increases neutrophil-driven matrix destruction
after exposure to Mycobacterium tuberculosis. Sci. Rep. 8:11475.
doi: 10.1038/s41598-018-29659-1
Ordway, D., Henao-Tamayo, M., Orme, I. M., and Gonzalez-Juarrero, M.
(2005). Foamy macrophages within lung granulomas of mice infected with
Mycobacterium tuberculosis express molecules characteristic of dendritic cells
and antiapoptotic markers of the TNF receptor-associated factor family. J.
Immunol. 175, 3873–3881. doi: 10.4049/jimmunol.175.6.3873
Pacis, A., Mailhot-Leonard, F., Tailleux, L., Randolph, H. E., Yotova, V., et al.
(2019). Gene activation precedes DNA demethylation in response to infection
in human dendritic cells. Proc. Natl. Acad. Sci. U.S.A. 116, 6938–6943.
doi: 10.1073/pnas.1814700116
Pathak, S. K., Basu, S., Basu, K. K., Banerjee, A., Pathak, S., et al. (2007).
Direct extracellular interaction between the early secreted antigen ESAT-6 of
Mycobacterium tuberculosis and TLR2 inhibits TLR signaling in macrophages.
Nat. Immunol. 8, 610–618. doi: 10.1038/ni1468
Patsoukis, N., Weaver, J. D., Strauss, L., Herbel, C., Seth, P., et al.
(2017). Immunometabolic regulations mediated by coinhibitory receptors
and their impact on T cell immune responses. Front. Immunol. 8:330.
doi: 10.3389/fimmu.2017.00330
Pattenden, S. G., Klose, R., Karaskov, E., and Bremner, R. (2002). Interferon-γ induced chromatin remodeling at the CIITA locus is BRG1 dependent. EMBO
J. 21, 1978–1986. doi: 10.1093/emboj/21.8.1978
Pearce, E. J., and Everts, B. (2015). Dendritic cell metabolism. Nat. Rev. Immunol.
15, 18–29. doi: 10.1038/nri3771
Petrofsky, M., and Bermudez, L. E. (1999). Neutrophils from Mycobacterium
avium-infected mice produce TNF-α, IL-12, and IL-1β and have a
putative role in early host response. Clin. Immunol. 91, 354–358.
doi: 10.1006/clim.1999.4709
Mahajan, S., Dkhar, H. K., Chandra, V., Dave, S., Nanduri, R., et al. (2012).
Mycobacterium tuberculosis modulates macrophage lipid-sensing nuclear
receptors PPARγ and TR4 for survival. J. Immunol. 188, 5593–5603.
doi: 10.4049/jimmunol.1103038
Mak, T. W., Grusdat, M., Duncan, G. S., Dostert, C., Nonnenmacher, Y., et al.
(2017). Glutathione primes T cell metabolism for inflammation. Immunity 46,
675–689. doi: 10.1016/j.immuni.2017.03.019
Malik, Z. A., Thompson, C. R., Hashimi, S., Porter, B., Iyer, S., et al. (2003). Cutting
edge: Mycobacterium tuberculosis blocks Ca2+ signaling and phagosome
maturation in human macrophages via specific inhibition of sphingosine
kinase. J. Immunol. 170, 2811–2815. doi: 10.4049/jimmunol.170.6.2811
Mandard, S., Muller, M., and Kersten, S. (2004). Peroxisome proliferatoractivated receptor alpha target genes. Cell. Mol. Life Sci. 61, 393–416.
doi: 10.1007/s00018-003-3216-3
Mantovani, A., Cassatella, M. A., Costantini, C., and Jaillon, S. (2011). Neutrophils
in the activation and regulation of innate and adaptive immunity. Nat. Rev.
Immunol. 11, 519–531. doi: 10.1038/nri3024
Marakalala, M. J., and Ndlovu, H. (2017). Signaling C-type lectin
receptors in antimycobacterial immunity. PLoS Pathog. 13:e1006333.
doi: 10.1371/journal.ppat.1006333
Martin, S., and Parton, R. G. (2006). Lipid droplets: a unified view of a dynamic
organelle. Nat. Rev. Mol. Cell Biol. 7, 373–378. doi: 10.1038/nrm1912
Mathis, D., and Shoelson, S. E. (2011). Immunometabolism: an emerging frontier.
Nat. Rev. Immunol. 11:81. doi: 10.1038/nri2922
Matta, S. K., and Kumar, D. (2016). Hypoxia and classical activation limits
Mycobacterium tuberculosis survival by Akt-dependent glycolytic shift in
macrophages. Cell Death Discov. 2:16022. doi: 10.1038/cddiscovery.2016.22
Mattila, J. T., Ojo, O. O., Kepka-Lenhart, D., Marino, S., Kim, J., et al. (2013).
Microenvironments in tuberculous granulomas are delineated by distinct
populations of macrophage subsets and expression of nitric oxide synthase and
arginase isoforms. J. Immunol. 191, 773–784. doi: 10.4049/jimmunol.1300113
Mbongue, J. C., Nicholas, D. A., Torrez, T. W., Kim, N., et al. (2015). The role
of indoleamine 2, 3-dioxygenase in immune suppression and autoimmunity.
Vaccines (Basel) 3, 703–729. doi: 10.3390/vaccines3030703
McClean, C. M., and Tobin, D. M. (2016). Macrophage form, function, and
phenotype in mycobacterial infection: lessons from tuberculosis and other
diseases. Pathog. Dis. 74:ftw068. doi: 10.1093/femspd/ftw068
Mehra, S., Alvarez, X., Didier, P. J., Doyle, L. A., et al. (2013). Granuloma
correlates of protection against tuberculosis and mechanisms of immune
modulation by Mycobacterium tuberculosis. J. Infect. Dis. 207, 1115–1127.
doi: 10.1093/infdis/jis778
Mellman, I., and Steinman, R. M. (2001). Dendritic cells: specialized
and regulated antigen processing machines. Cell 106, 255–258.
doi: 10.1016/S0092-8674(01)00449-4
Melo, R. C., and Dvorak, A. M. (2012). Lipid body-phagosome interaction in
macrophages during infectious diseases: host defense or pathogen survival
strategy? PLoS Pathog. 8:e1002729. doi: 10.1371/journal.ppat.1002729
Meyer, N., and Penn, L. Z. (2008). Reflecting on 25 years with MYC. Nat. Rev.
Cancer 8, 976–990. doi: 10.1038/nrc2231
Miyamoto, S., Murphy, A. N., and Brown, J. H. (2008). Akt mediates mitochondrial
protection in cardiomyocytes through phosphorylation of mitochondrial
hexokinase-II. Cell Death Differ. 15, 521–529. doi: 10.1038/sj.cdd.44
02285
Mori, M. (2007). Regulation of nitric oxide synthesis and apoptosis by arginase and
arginine recycling. J Nutr. 137, 1616S−1620S. doi: 10.1093/jn/137.6.1616S
Morris, D., Gonzalez, B., Khurasany, M., Kassissa, C., Luong, J., Kasko, S., et al.
(2013a). Characterization of dendritic cell and regulatory T cell functions
against Mycobacterium tuberculosis infection. Biomed Res. Int. 2013:402827.
doi: 10.1155/2013/402827
Morris, D., Nguyen, T., Kim, J., Kassissa, C., Khurasany, M., Luong,
J., et al. (2013b). An elucidation of neutrophil functions against
Mycobacterium tuberculosis infection. Clin. Dev. Immunol. 2013:959650.
doi: 10.1155/2013/959650
Mortaz, E., Adcock, I. M., Tabarsi, P., Masjedi, M. R., et al. (2015). Interaction
of pattern recognition receptors with Mycobacterium Tuberculosis. J. Clin.
Immunol. 35, 1–10. doi: 10.1007/s10875-014-0103-7
Mosser, D. M. (2003). The many faces of macrophage activation. J. Leukoc. Biol. 73,
209–212. doi: 10.1189/jlb.0602325
Frontiers in Molecular Biosciences | www.frontiersin.org
17
October 2019 | Volume 6 | Article 105
Kumar et al.
Immunometabolism and Innate Immunity in Tuberculosis
Sanchez, D., Rojas, M., Hernandez, I., Radzioch, D., Garcia, L. F., et al.
(2010). Role of TLR2- and TLR4-mediated signaling in Mycobacterium
tuberculosis-induced macrophage death. Cell. Immunol. 260, 128–136.
doi: 10.1016/j.cellimm.2009.10.007
Sanchez, T., and Hla, T. (2004). Structural and functional characteristics of S1P
receptors. J. Cell. Biochem. 92, 913–922. doi: 10.1002/jcb.20127
Sarbassov, D. D., Guertin, D. A., Ali, S. M., Sabatini, D., et al. (2005).
Phosphorylation and regulation of Akt/PKB by the rictor-mTOR complex.
Science 307, 1098–1101. doi: 10.1126/science.1106148
Sauve, A. A., and Youn, D. Y. (2012). Sirtuins: NAD(+)-dependent deacetylase
mechanism and regulation. Curr. Opin. Chem. Biol. 16, 535–543.
doi: 10.1016/j.cbpa.2012.10.003
Sawai, H., and Hannun, Y. A. (1999). Ceramide and sphingomyelinases
in the regulation of stress responses. Chem. Phys. Lipids 102, 141–147.
doi: 10.1016/S0009-3084(99)00082-1
Saxton, R. A., and Sabatini, D. M. (2017). mTOR signaling in growth, metabolism,
and disease. Cell 168, 960–976. doi: 10.1016/j.cell.2017.02.004
Schlesinger, L. S. (1996). Entry of Mycobacterium tuberculosis into
mononuclear phagocytes. Curr. Top. Microbiol. Immunol. 215, 71–96.
doi: 10.1007/978-3-642-80166-2_4
Schluger, N. W., and Rom, W. N. (1998). The host immune response
to tuberculosis. Am. J. Respir. Crit. Care Med. 157, 679–691.
doi: 10.1164/ajrccm.157.3.9708002
Seiler, P., Aichele, P., Bandermann, S., Hauser, A. E., Lu, B., et al. (2003). Early
granuloma formation after aerosol Mycobacterium tuberculosis infection is
regulated by neutrophils via CXCR3-signaling chemokines. Eur. J. Immunol.
33, 2676–2686. doi: 10.1002/eji.200323956
Semenza, G. L. (2000). HIF-1: mediator of physiological and
pathophysiological responses to hypoxia. J. Appl. Physiol. 88, 1474–1480.
doi: 10.1152/jappl.2000.88.4.1474
Semenza, G. L. (2001). HIF-1, O(2), and the 3 PHDs: how animal cells signal
hypoxia to the nucleus. Cell 107, 1–3. doi: 10.1016/S0092-8674(01)00518-9
Sharma, L., and Prakash, H. (2017). Sphingolipids are dual specific drug targets for
the management of pulmonary infections: perspective. Front. Immunol. 8:378.
doi: 10.3389/fimmu.2017.00378
Shi, L., Eugenin, E. A., and Subbian, S. (2016). Immunometabolism in tuberculosis.
Front. Immunol. 7:150. doi: 10.3389/fimmu.2016.00150
Shi, L., Jiang, Q., Bushkin, Y., Subbian, S., and Tyagi, S. (2019). Biphasic dynamics
of macrophage immunometabolism during Mycobacterium tuberculosis
infection. MBio 10:e02550–18. doi: 10.1128/mBio.02550-18
Shi, L., Salamon, H., Eugenin, E. A., Pine, R., Cooper, A., et al. (2015). Infection
with Mycobacterium tuberculosis induces the Warburg effect in mouse lungs.
Sci. Rep. 5:18176. doi: 10.1038/srep18176
Shin, J. H., Yang, J. Y., Jeon, B. Y., Yoon, Y., et al. (2011). (1)H NMR-based
metabolomic profiling in mice infected with Mycobacterium tuberculosis. J.
Proteome Res. 10, 2238–2247. doi: 10.1021/pr101054m
Singh, P., and Subbian, S. (2018). Harnessing the mTOR pathway for tuberculosis
treatment. Front. Microbiol. 9:70. doi: 10.3389/fmicb.2018.00070
Singh, R., and Cuervo, A. M. (2012). Lipophagy: connecting autophagy and lipid
metabolism. Int. J. Cell Biol. 2012:282041. doi: 10.1155/2012/282041
Singh, V., Jamwal, S., Jain, R., Verma, P., Gokhale, R., Rao, K., et al. (2012).
Mycobacterium tuberculosis-driven targeted recalibration of macrophage lipid
homeostasis promotes the foamy phenotype. Cell Host Microbe 12, 669–681.
doi: 10.1016/j.chom.2012.09.012
Singh, V., Kaur, C., Chaudhary, V. K., Rao, K. V., et al. (2015). M. tuberculosis
secretory protein ESAT-6 induces metabolic flux perturbations to drive foamy
macrophage differentiation. Sci. Rep. 5:12906. doi: 10.1038/srep12906
Sociali, G., Magnone, M., Ravera, S., Damonte, P., Vigliarolo, T., Von
Holtey, M., et al. (2017). Pharmacological Sirt6 inhibition improves glucose
tolerance in a type 2 diabetes mouse model. FASEB J. 31, 3138–3149.
doi: 10.1096/fj.201601294R
Somashekar, B. S., Amin, A. G., Rithner, C. D., Troudt, J., et al. (2011). Metabolic
profiling of lung granuloma in Mycobacterium tuberculosis infected guinea pigs:
ex vivo 1H magic angle spinning NMR studies. J. Proteome Res. 10, 4186–4195.
doi: 10.1021/pr2003352
Speer, A., Sun, J., Danilchanka, O., Meikle, V., Rowland, J. L., et al.
(2015). Surface hydrolysis of sphingomyelin by the outer membrane
protein Rv0888 supports replication of Mycobacterium tuberculosis
Podinovskaia, M., Lee, W., Caldwell, S., and Russell, D. G. (2013). Infection of
macrophages with Mycobacterium tuberculosis induces global modifications to
phagosomal function. Cell. Microbiol. 15, 843–859. doi: 10.1111/cmi.12092
Porstmann, T., Santos, C. R., Griffiths, B., Cully, M., Wu, M., et al. (2008). SREBP
activity is regulated by mTORC1 and contributes to Akt-dependent cell growth.
Cell Metab. 8, 224–236. doi: 10.1016/j.cmet.2008.07.007
Prusinkiewicz, M. A., and Mymryk, J. S. (2019). Metabolic reprogramming
of the host cell by human adenovirus infection. Viruses 11:E141.
doi: 10.3390/v11020141
Qualls, J. E., and Murray, P. J. (2016). Immunometabolism within the
tuberculosis granuloma: amino acids, hypoxia, and cellular respiration. Semin.
Immunopathol. 38, 139–152. doi: 10.1007/s00281-015-0534-0
Queval, C. J., Brosch, R., and Simeone, R. (2017). The macrophage: a disputed
fortress in the battle against Mycobacterium tuberculosis. Front. Microbiol.
8:2284. doi: 10.3389/fmicb.2017.02284
Raghuraman, S., Donkin, I., Versteyhe, S., Barres, R., and Simar, D. (2016). The
emerging role of epigenetics in inflammation and immunometabolism.
Trends Endocrinol. Metab. 27, 782–795. doi: 10.1016/j.tem.2016.0
6.008
Rajaram, M. V., Brooks, M. N., Morris, J. D., Torrelles, J., et al. (2010).
Mycobacterium tuberculosis activates human macrophage peroxisome
proliferator-activated receptor gamma linking mannose receptor
recognition to regulation of immune responses. J. Immunol. 185, 929–942.
doi: 10.4049/jimmunol.1000866
Rakhshandehroo, M., Knoch, B., Muller, M., and Kersten, S. (2010). Peroxisome
proliferator-activated receptor alpha target genes. PPAR Res. 2010:612089.
doi: 10.1155/2010/612089
Ramakrishnan, L. (2012). Revisiting the role of the granuloma in tuberculosis. Nat.
Rev. Immunol. 12, 352–366. doi: 10.1038/nri3211
Reed, M. B., Domenech, P., Manca, C., Su, H., Barczak, A. K., et al. (2004). A
glycolipid of hypervirulent tuberculosis strains that inhibits the innate immune
response. Nature 431, 84–87. doi: 10.1038/nature02837
Rehman, A., Hemmert, K. C., Ochi, A., Jamal, M., Henning, J., et al. (2013). Role of
fatty-acid synthesis in dendritic cell generation and function. J. Immunol. 190,
4640–4649. doi: 10.4049/jimmunol.1202312
Reiley, W. W., Calayag, M. D., Wittmer, S. T., Huntington, J., et al. (2008). ESAT6-specific CD4 T cell responses to aerosol Mycobacterium tuberculosis infection
are initiated in the mediastinal lymph nodes. Proc. Natl. Acad. Sci. U.S.A. 105,
10961–10966. doi: 10.1073/pnas.0801496105
Riddle, S. R., Ahmad, A., Ahmad, S., Deeb, S. S., Malkki, M., et al.
(2000). Hypoxia induces hexokinase II gene expression in human lung
cell line A549. Am. J. Physiol. Lung Cell. Mol. Physiol. 278, L407–416.
doi: 10.1152/ajplung.2000.278.2.L407
Riquelme, P., Tomiuk, S., Kammler, A., Fandrich, F., Schlitt, H. J., et al. (2013).
IFN-γ-induced iNOS expression in mouse regulatory macrophages prolongs
allograft survival in fully immunocompetent recipients. Mol. Ther. 21, 409–422.
doi: 10.1038/mt.2012.168
Rius, J., Guma, M., Schachtrup, C., Akassoglou, K., Zinkernagel, A. S., et al. (2008).
NF-κB links innate immunity to the hypoxic response through transcriptional
regulation of HIF-1α. Nature 453, 807–811. doi: 10.1038/nature06905
Robitaille, A. M., Christen, S., Shimobayashi, M., Cornu, M., Fava, L. L., et al.
(2013). Quantitative phosphoproteomics reveal mTORC1 activates de novo
pyrimidine synthesis. Science 339, 1320–1323. doi: 10.1126/science.1228771
Russell, D. G. (2011). Mycobacterium tuberculosis and the intimate
discourse of a chronic infection. Immunol. Rev. 240, 252–268.
doi: 10.1111/j.1600-065X.2010.00984.x
Russell, D. G., Cardona, P. J., Kim, M. J., Allain, S., et al. (2009). Foamy
macrophages and the progression of the human tuberculosis granuloma. Nat.
Immunol. 10, 943–948. doi: 10.1038/ni.1781
Saeed, S., Quintin, J., Kerstens, H. H., Rao, N. A., et al. (2014). Epigenetic
programming of monocyte-to-macrophage differentiation and trained innate
immunity. Science 345:1251086. doi: 10.1126/science.1251086
Saka, H. A., and Valdivia, R. (2012). Emerging roles for lipid droplets in immunity
and host-pathogen interactions. Annu. Rev. Cell Dev. Biol. 28, 411–437.
doi: 10.1146/annurev-cellbio-092910-153958
Salamon, H., Bruiners, N., Lakehal, K., Shi, L., Ravi, J., Yamaguchi, K., et al.
(2014). Cutting edge: vitamin D regulates lipid metabolism in Mycobacterium
tuberculosis infection. J. Immunol. 193, 30–34. doi: 10.4049/jimmunol.1400736
Frontiers in Molecular Biosciences | www.frontiersin.org
18
October 2019 | Volume 6 | Article 105
Kumar et al.
Immunometabolism and Innate Immunity in Tuberculosis
VanderVen, B. C., Fahey, R. J., Lee, W., Liu, Y., Abramovitch, R., et al. (2015).
Novel inhibitors of cholesterol degradation in Mycobacterium tuberculosis
reveal how the bacterium’s metabolism is constrained by the intracellular
environment. PLoS Pathog. 11:e1004679. doi: 10.1371/journal.ppat.10
04679
Volkman, H. E., Pozos, T. C., Zheng, J., Davis, J. M., et al. (2010).
Tuberculous granuloma induction via interaction of a bacterial secreted
protein with host epithelium. Science 327, 466–469. doi: 10.1126/science.11
79663
Vynnycky, E., and Fine, P. E. (2000). Lifetime risks, incubation period,
and serial interval of tuberculosis. Am. J. Epidemiol. 152, 247–263.
doi: 10.1093/aje/152.3.247
Wahl, D. R., Byersdorfer, C. A., Ferrara, J. L., Opipari, A., et al. (2012).
Distinct metabolic programs in activated T cells: opportunities
for selective immunomodulation. Immunol. Rev. 249, 104–115.
doi: 10.1111/j.1600-065X.2012.01148.x
Walmsley, S. R., Chilvers, E. R., Thompson, A. A., Vaughan, K., et al.
(2011). Prolyl hydroxylase 3 (PHD3) is essential for hypoxic regulation of
neutrophilic inflammation in humans and mice. J. Clin. Invest. 121, 1053–1063.
doi: 10.1172/JCI43273
Wang, S., Liu, R., Yu, Q., Dong, L., Bi, Y., and Liu, G. (2019). Metabolic
reprogramming of macrophages during infections and cancer. Cancer Lett. 452,
14–22. doi: 10.1016/j.canlet.2019.03.015
Wang, X., Zhu, H., Snieder, H., Su, S., Munn, D., Harshfield, G., et al. (2010).
Obesity related methylation changes in DNA of peripheral blood leukocytes.
BMC Med. 8:87. doi: 10.1186/1741-7015-8-87
Warburg, O. (1956). On the origin of cancer cells. Science 123, 309–314.
doi: 10.1126/science.123.3191.309
Welin, A., Eklund, D., Stendahl, O., and Lerm, M. (2011). Human macrophages
infected with a high burden of ESAT-6-expressing M. tuberculosis undergo
caspase-1- and cathepsin B-independent necrosis. PLoS ONE 6:e20302.
doi: 10.1371/journal.pone.0020302
WHO (2018). Global Tuberculosis Report. WHO.
Wolf, A. J., Desvignes, L., Linas, B., Banaiee, N., Tamura, T., Takatsu,
K., et al. (2008). Initiation of the adaptive immune response to
Mycobacterium tuberculosis depends on antigen production in the local
lymph node, not the lungs. J. Exp. Med. 205, 105–115. doi: 10.1084/jem.200
71367
Wolf, A. J., Linas, B., Trevejo-Nunez, G. J., Kincaid, E., Tamura, T.,
et al. (2007). Mycobacterium tuberculosis infects dendritic cells with high
frequency and impairs their function in vivo. J. Immunol. 179, 2509–2519.
doi: 10.4049/jimmunol.179.4.2509
Wong, K. W., and Jacobs, W. R., Jr (2011). Critical role for NLRP3 in necrotic
death triggered by Mycobacterium tuberculosis. Cell. Microbiol. 13, 1371–1384.
doi: 10.1111/j.1462-5822.2011.01625.x
Yang, Z., and Ming, X. F. (2014). Functions of arginase isoforms in
macrophage inflammatory responses: impact on cardiovascular diseases
and metabolic disorders. Front. Immunol. 5:533. doi: 10.3389/fimmu.2014.
00533
Yaseen, I., Kaur, P., Nandicoori, V. K., and Khosla, S. (2015). Mycobacteria
modulate host epigenetic machinery by Rv1988 methylation of a nontail arginine of histone H3. Nat. Commun. 6:8922. doi: 10.1038/ncomms
9922
Yecies, J. L., and Manning, B. D. (2011). Transcriptional control of
cellular metabolism by mTOR signaling. Cancer Res. 71, 2815–2820.
doi: 10.1158/0008-5472.CAN-10-4158
Yim, H. C., Li, J. C., Pong, J. C., Lau, A., et al. (2011). A role for c-Myc in regulating
anti-mycobacterial responses. Proc. Natl. Acad. Sci. U.S.A. 108, 17749–17754.
doi: 10.1073/pnas.1104892108
Zaccagnino, P., Saltarella, M., Maiorano, S., Gaballo, A., Santoro, G., Nico,
B., et al. (2012). An active mitochondrial biogenesis occurs during
dendritic cell differentiation. Int. J. Biochem. Cell Biol. 44, 1962–1969.
doi: 10.1016/j.biocel.2012.07.024
Zhai, W., Wu, F., Zhang, Y., Fu, Y., and Liu, Z. (2019). The immune
escape mechanisms of Mycobacterium Tuberculosis. Int. J. Mol. Sci. 20:340.
doi: 10.3390/ijms20020340
in macrophages. Mol. Microbiol. 97, 881–897. doi: 10.1111/mmi.1
3073
Stine, Z. E., Walton, Z. E., Altman, B. J., Hsieh, A., et al. (2015). MYC, metabolism,
and cancer. Cancer Discov. 5, 1024–1039. doi: 10.1158/2159-8290.CD-1
5-0507
Sturgill-Koszycki, S., Schlesinger, P. H., Chakraborty, P., Haddix, P. L., et al.
(1994). Lack of acidification in Mycobacterium phagosomes produced
by exclusion of the vesicular proton-ATPase. Science 263, 678–681.
doi: 10.1126/science.8303277
Subbian, S., O’Brien, P., Kushner, N. L., Yang, G., Tsenova, L., et al.
(2013). Molecular immunologic correlates of spontaneous latency in a
rabbit model of pulmonary tuberculosis. Cell Commun. Signal. 11:16.
doi: 10.1186/1478-811X-11-16
Subbian, S., Tsenova, L., Yang, G., O’Brien, P., Parsons, S., Peixoto, B., et al. (2011).
Chronic pulmonary cavitary tuberculosis in rabbits: a failed host immune
response. Open Biol. 1:110016. doi: 10.1098/rsob.110016
Sutherland, J. S., Jeffries, D. J., Donkor, S., Walther, B., Hill, P., et al. (2009).
High granulocyte/lymphocyte ratio and paucity of NKT cells defines TB disease
in a TB-endemic setting. Tuberculosis 89, 398–404. doi: 10.1016/j.tube.2009.0
7.004
Szatmari, I., Gogolak, P., Im, J. S., Dezso, B., Rajnavolgyi, E., et al.
(2004). Activation of PPARγ specifies a dendritic cell subtype capable
of enhanced induction of iNKT cell expansion. Immunity 21, 95–106.
doi: 10.1016/j.immuni.2004.06.003
Szatmari, I., Torocsik, D., Agostini, M., Nagy, T., Gurnell, M., Barta,
E., et al. (2007). PPARγ regulates the function of human dendritic
cells primarily by altering lipid metabolism. Blood 110, 3271–3280.
doi: 10.1182/blood-2007-06-096222
Takeuch, O., and Akira, S. (2011). Epigenetic control of macrophage polarization.
Eur. J. Immunol. 41, 2490–2493. doi: 10.1002/eji.201141792
Tannahill, G. M., Curtis, A. M., Adamik, J. E. M., Palsson-McDermott, McGettrick,
A., et al. (2013). Succinate is an inflammatory signal that induces IL-1β through
HIF-1α. Nature 496, 238–242. doi: 10.1038/nature11986
Tascon, R. E., Soares, C. S., Ragno, S., Stavropoulos, E., Hirst, E.,
et al. (2000). Mycobacterium tuberculosis-activated dendritic cells
induce protective immunity in mice. Immunology 99, 473–480.
doi: 10.1046/j.1365-2567.2000.00963.x
Theocharis, S., Margeli, A., Vielh, P., and Kouraklis, G. (2004).
Peroxisome proliferator-activated receptor-gamma ligands as cell-cycle
modulators. Cancer Treat. Rev. 30, 545–554. doi: 10.1016/j.ctrv.2004.
04.004
Thwe, P. M., Pelgrom, L. R., Cooper, R., Beauchamp, S., Reisz, J., et al. (2017).
Cell-intrinsic glycogen metabolism supports early glycolytic reprogramming
required for dendritic cell immune responses. Cell Metab. 26, 558–567 e555.
doi: 10.1016/j.cmet.2017.08.012
Tian, T., Woodworth, J., Skold, M., and Behar, S. M. (2005). In vivo depletion of
CD11c+ cells delays the CD4+ T cell response to Mycobacterium tuberculosis
and exacerbates the outcome of infection. J. Immunol. 175, 3268–3272.
doi: 10.4049/jimmunol.175.5.3268
Ting, L. M., Kim, A. C., Cattamanchi, A., and Ernst, J. D. (1999). Mycobacterium
tuberculosis inhibits IFN-γ transcriptional responses without inhibiting
activation of STAT1. J. Immunol. 163, 3898–3906.
Vachharajani, V. T., Liu, T., Wang, X., Hoth, J. J., Yoza, B., et al. (2016).
Sirtuins link inflammation and metabolism. J. Immunol. Res. 2016:8167273.
doi: 10.1155/2016/8167273
van Crevel, R., Ottenhoff, T. H., and van der Meer, J. W. (2002). Innate
immunity to Mycobacterium tuberculosis. Clin. Microbiol. Rev. 15, 294–309.
doi: 10.1128/CMR.15.2.294-309.2002
van de Laar, L., Saelens, W., De Prijck, S., Martens, L., Scott, C. L., et al. (2016).
Yolk sac macrophages, fetal liver, and adult monocytes can colonize an empty
niche and develop into functional tissue-resident macrophages. Immunity 44,
755–768. doi: 10.1016/j.immuni.2016.02.017
van der Windt, G. J., Everts, B., Chang, C. H., Curtis, J. D., et al. (2012).
Mitochondrial respiratory capacity is a critical regulator of CD8+ T cell
memory development. Immunity 36, 68–78. doi: 10.1016/j.immuni.2011.
12.007
Frontiers in Molecular Biosciences | www.frontiersin.org
19
October 2019 | Volume 6 | Article 105
Kumar et al.
Immunometabolism and Innate Immunity in Tuberculosis
Zhang, Q., Zhao, K., Shen, Q., Han, Y., Gu, Y., Li, X., et al. (2015). Tet2 is required
to resolve inflammation by recruiting Hdac2 to specifically repress IL-6. Nature
525, 389–393. doi: 10.1038/nature15252
Zhang, W., Petrovic, J. M., Callaghan, D., Jones, A., Cui, H., et al. (2006). Evidence
that hypoxia-inducible factor-1 (HIF-1) mediates transcriptional activation
of interleukin-1β (IL-1β) in astrocyte cultures. J. Neuroimmunol. 174:63–73.
doi: 10.1016/j.jneuroim.2006.01.014
Zou, Z., Chen, J., Liu, A., Zhou, X., Song, Q., Jia, C., et al. (2015).
mTORC2 promotes cell survival through c-Myc-dependent upregulation of E2F1. J. Cell Biol. 211, 105–122. doi: 10.1083/jcb.20141
1128
Frontiers in Molecular Biosciences | www.frontiersin.org
Conflict of Interest: The authors declare that the research was conducted in the
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