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Infect Genet Evol. Author manuscript; available in PMC 2021 July 01.
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Published in final edited form as:

Infect Genet Evol. 2020 July ; 81: 104204. doi:10.1016/j.meegid.2020.104204.
Genetics and evolution of tuberculosis pathogenesis: New

perspectives and approaches
Michael L. McHenry1, Scott M. Williams1,2,*, Catherine M. Stein1,3
1Department of Population and Quantitative Health Sciences; Case Western Reserve University,
Cleveland OH
2Department of Genetics and Genome Sciences; Case Western Reserve University, Cleveland
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OH
3Division
of Infectious Diseases and HIV Medicine, Department of Medicine; Case Western
Reserve University, Cleveland OH
Abstract
Tuberculosis is the most lethal infectious disease globally, but the vast majority of people who are
exposed to the primary causative pathogen, Mycobacterium tuberculosis (MTB), do not develop
active disease. Most people do, however, show signs of infection that remain throughout their
lifetimes. In this review, we develop of framework that describes several possible transitions from
pathogen exposure to TB disease and reflect on the genetics studies to address many of these. The
evidence strongly supports a human genetic component for both infection and active disease, but
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many of the existing studies, including some of our own, do not clearly delineate what transition(s)
is being explicitly examined. This can make interpretation difficult in terms of why only some
people develop active disease. Nonetheless, both linkage peaks and associations with either active
disease or latent infection have been identified. For transition to active disease, pathways defined
as active TB altered T and B cell signaling in rheumatoid arthritis and T helper cell differentiation
are significantly associated. Pathways that affect transition from exposure to infection are less
clear-cut, as studies of this phenotype are less common, and a primary response, if it exists, is not
yet well defined. Lastly, we discuss the role that interaction between the MTB lineage and human
genetics can play in TB disease, especially severity. Severity of TB is at present the only way to
study putative co-evolution between MTB and humans as it is impossible in the absence of disease
to know the MTB lineage(s) to which an individual has been exposed. In addition, even though
severity has been defined in multiple heterogeneous ways, it appears that MTB-human co-
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evolution may shape pathogenicity. Further analysis of co-evolution, requiring careful analysis of
paired samples, may be the best way to completely assess the genetic basis of TB.
*
Corresponding author: 10900 Euclid Avenue, Department of Population and Quantitative Health Sciences, Case Western Reserve
University, Cleveland, OH 44106, smw154@case.edu.
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McHenry et al. Page 2
Keywords
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Tuberculosis; Genetics of pathogenicity; Host-pathogen co-evolution
1. Introduction
Pulmonary tuberculosis (TB) is a major public health problem, as it causes more deaths than
any other pathogen[1]. It is also the leading cause of death among people infected with
human immunodeficiency virus (HIV)[2]. In Sub-Saharan Africa and Southeast Asia TB is a
re-emerging disease, even though incidence is decreasing globally[1]. The bacterium,
Mycobacterium tuberculosis (MTB), causes most TB, and is transmitted via airborne
droplets from coughing and sneezing by people with active disease, meaning that it can be a
very mobile pathogen in the age of frequent global travel; hence global exposure is high with
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between one fourth and one third of the entire global population being infected. However,
most people exposed to MTB do not develop active disease. In 2017, only 10 million people
developed active disease and 1.6 million people died[1]. These numbers are of interest
because they demonstrate that the vast majority of people have resistance to TB.
Additionally, some people do not even show signs of having been infected. Examining
patterns of resistance to either disease or infection can be extremely useful in developing
policies to prevent TB and may be elucidated by understanding the long and complex history
of MTB and humans.
Host genetic factors can affect TB risk, and may influence other outcomes that occur
between exposure to MTB and development of active TB disease (Figure 1). Following
exposure to MTB, a necessary cause of TB, several outcomes or clinical trajectories exist
that can be detected using different means (Figure 1). For example, infected individuals are
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identified with tuberculin skin tests (TST) using purified protein derivative (PPD) and/or
interferon-γ release assays (IGRA) (eg. Quantiferon (QFT)). Most exposed individuals will
exhibit signs of infection (latent MTB infection or LTBI), but not active disease. However,
some individuals never even develop LTBI, even in the face of prolonged and persistent
exposure to an infectious TB case and hence MTB[3, 4]. These latter individuals are
described as resistant to MTB infection, and have been termed resisters (RSTRs)[5].
Prevalence of RSTR varies as a function of follow-up time and use of TST and/or IGRA, so
current estimates of the prevalence of RSTR in high-exposure settings range from 7–25%
[5–7]. The path an individual traverses post-exposure is related to differences in immune
response and this can have a strong genetic component driven by the long evolutionary co-
existence of MTB and humans.
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2. Overview from infection to TB

TB is the outward manifestation of the immune response to MTB, and in understanding
genetic factors as potential markers and/or therapeutic targets of disease, it is important to
understand the natural course from exposure to TB. The progression can manifest via
multiple paths. Post exposure to MTB some people exhibit signs of infection (arrow A),
while others never become infected (arrow B). Following infection, there is an innate
response by the immune system that, in a small number of people, may lead to early
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clearance of the bacteria (arrow E)[6, 8, 9]. However, in most people, the bacteria persist,
and stimulate an adaptive response to control the bacteria. At this point, mycobacterial
antigens are presented, and T and B cells are recruited and utilized to control the
infection[10]. In some people, mostly young children or those with immunodeficiencies,
primary active disease can develop (arrow C)[11]. If the infection is controlled, a granuloma
is formed and the host enters a stage of latent infection (arrow D), with bacteria persisting
inside macrophages. If the infection remains in this state, there are neither symptoms nor
transmission (as far as is currently understood). If the host immune system is unable to
control the bacteria after the primary infection, then the host progresses from LTBI to active
TB (arrow F), at which time he/she will experience symptoms and potentially transmit the
infection[12]. Those in a state of latent infection can live their entire life in latency or have
an activation of disease later in life. However, transition from LTBI to active TB is more
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likely to occur in the presence of immunosuppression or other stressors on the immune

system; this is why HIV co-infection is so perilous. In this review we use this transition map
to understand the current genetic literature of host genetics of TB and how it can influence
each stage of pathogenesis. We also discuss the pieces of the overall picture that are still
missing.
3. Exposure to infection: Who is resistant?

The first process of interest is the transition from exposure to infection. While only a
minority of people resist infection (Figure 1, arrow B), studying them is of particular interest
as they may be especially useful in elucidating the natural history of TB and knowing their
genetic constitutions may be useful in developing prevention and/or treatment strategies.
Genetic influences on resistance to infection have been studied in two ways. Some studies
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have examined LTBI as the trait of interest, using cross-sectional study design, without any
long-term follow-up. Other studies have conducted longitudinal follow-up to identify
individuals who started as uninfected (TST or IGRA negative), but eventually converted to
TST/IGRA positive or LTBI. We contend that RSTRs cannot be defined based on a single
assessment without longitudinal follow-up, as conversion to test positivity may occur later
[4–7].
It remains to be seen to what extent resistance to infection is driven by genetics. However,

PPD reactivity is correlated among siblings, but not among unrelated children who live in
the same household who have similar exposures to TB[13]. Such data are indicative of a
genetic component for RSTR. In addition, linkage analyses, candidate gene studies, and
genome-wide association studies (GWAS) have added to the evidence that genetic variation
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associates with MTB infection. A genome-wide linkage analysis in Uganda suggested that
regions on 2q21–2q24 and on 5p13–5q22 were linked to the RSTR phenotype[14]. The
chromosome 2 locus was later fine-mapped to two potential candidate genes, GTDC1 and
ZEB2 [15]; the locus identified on chromosome 5 was later fine-mapped to a gene,
SLC6A3[16], and this result was replicated in a candidate gene study of RSTR [17]. A
genome-wide linkage study of PPD reactivity as a binary (cross-sectional) trait in South
Africa found a locus at 11p14, termed TST1[16]. This locus was found in a later study to be
identical to a QTL controlling TNF expression and production[18]. When PPD reactivity
was analyzed as a quantitative outcome in the same cross-sectional study, another locus
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termed TST2 on 5p15 was identified that is thought to modulate T cell responses[18].
Finally, a genome-wide association study of TST reactivity among HIV-infected individuals
from Tanzania and Uganda, defining the trait both as binary and quantitative phenotypes,
identified a region on chromosome 5q31 that included the IL9 gene [19]. This latter study is
interesting because in the Tanzanian population, the phenotype was defined cross-
sectionally, while in the Ugandan population, the longitudinally-characterized RSTR
definition was used. Since this association was replicated across different phenotype
definitions, the association with chromosome 5q31 was robust to phenotype definition. This
study also examined association with the previously identified loci described above (5p15,
11p14, 2q21-q24, and 5p13–5q22) and observed replication at the p<0.001 level with all
these loci.
One study in Ghana found a haplotype that associated with low levels of circulating IL-10
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with an increased likelihood of PPD positivity (but not with pulmonary disease)[20].
Another study focused on ULK1, a gene thought to be important in signal transduction of
autophagy effectors, and showed an association with LTBI risk[21, 22]. Autophagy
pathways, which are responsible for the destruction of infected cells, are thought to be the
most influential host factors in restricting intracellular growth of MTB in macrophages and
regulation of the maturation of the mycobacterial phagosome [23].
While the role of antibodies in many infectious diseases is well documented, the role of this
response in TB remains unclear. There is likely a role for B cells in susceptibility to MTB
infection, but it is likely that the effects go beyond their direct antibody-mediated effector
functions[5]. This conclusion is based on the idea that passive transfer of antibodies has not
been associated with protection against TB and IgG levels do not appear to be consistently
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associated with control of bacterial infection. Instead, depletion of B cells is associated with
a higher bacterial burden. Furthermore, antibodies, plasma cells, and anti-responsive innate
immune cells are found in MTB granulomas[24, 25]. There is even evidence that IgG can
“cure” infected macrophages if presented at the right time [26]. A recent study has shown
that RSTRs show immunological evidence of exposure to MTB (shown by IgM, class-
switched IgG, and non IFN-γ T cell responses to MTB specific proteins) and that these
RSTRs show enhanced antibody avidity and IgG Fc profiles specific to MTB. This result
indicates that there is an adaptive immune response to MTB exposure that involves
antibodies[27]. Overall, these results point to a number of genes and their downstream
products that may influence the initial response to MTB exposure and potentially prevent
infection.
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4. Primary Active Disease

While the vast majority of healthy individuals who become infected enter a state of latent
infection, a small portion of people (~5%) develop active tuberculosis either right away or
after a relatively brief period of latency[11](Figure 1, arrow C). This state is known as
primary active tuberculosis and is most common in adults with immunodeficiencies or
children, especially those who are very young (less than 2 years old) and/or have inherited a
primary immunodeficiency (such as chronic granulomatous disease or Mendelian
susceptibility to mycobacterial disease)[28]. These children often manifest a severe

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disseminated form of TB that can infect the central nervous system and is extremely life-
threatening. Prior to the widespread use of the BCG vaccine and increased availability of
antibiotics, this form of TB was common among children in endemic areas[28, 29]. While
these advances have decreased mortality, 230,000 children died from TB in 2018 (including
those infected with HIV) and there remains a strong correlation between younger age and
death from TB[1, 30].
There are different types of evidence pointing to the influence of host genetics on
susceptibility to TB, and these genetic influences may affect timing of transition to active
TB. Twin and Mendelian Susceptibility to Mycobacterial Disease (MSMD) studies together
support the conclusion that TB susceptibility is influenced by genetic variation. MSMD is an
immunodeficiency disorder in children characterized by mutations in the IFN-γ and IL-12
signaling pathways[31–33]. Children with MSMD are extremely vulnerable to weakly
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virulent mycobacterial species and can even get sick from the BCG vaccine. These children
often suffer from a number of other bacterial infections as well[34]. MSMD associates with
a number of different genotypes, including mutations in seven autosomal and two X-linked
genes (IFNGR1/2, STAT1, IRF8, CYBB, IL12B, IL12RB1, NEMO, and ISH15 genes), all
of which lead to impairment of IFN-γ immune function. [28, 34, 35]. However, these loci
only account for about half of known MSMD cases. Many siblings of children with MSMD
often get severe primary TB (but are not susceptible to weak environmental mycobacteria).
Defects in the IFN-γ response have also been shown to be present in the siblings, but the
most common characteristic is a complete IL-12Rβ1 deficiency[36, 37]. Taken together,
these deficiencies point to the importance of the IFN-γ response in controlling the initial TB
infection and leading to a state of latency, rather than a severe primary disease. The response
appears to be affected by multiple genes.
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Genetic association studies of children with active TB have not been common, but there are
some associations reported in the literature. There have been two studies, one in China and
one in the USA, that have associated variants in SLC11A1 with pediatric disease[38, 39].
Another study in Turkey found that TLR8 polymorphisms are associated with pediatric
TB[40]. Two studies have also examined the association between genetic variants and BCG
vaccine induced production of cytokines that are known to be an important part of the
response to BCG vaccination. One study found that SIGLEC14 variants were associated
with increased BCG-induced IL-2 and IL-17 production in South African children[41]. The
other found that variants in HSP90B1 (a chaperone protein for multiple toll-like receptors)
were associated with higher BCG-induced IL-2 production in South African children[42].
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4.1 Delayed transition from latent infection to active TB

Most people infected with MTB enter a state of latency. However, a portion of these people
(~5–10%) will go on to develop active pulmonary tuberculosis later in life. This transition
can happen many decades later, but likelihood of transition to TB decreases the longer a
person remains in a latent state [11, 28]. States of immunodeficiency have been observed to
trigger reactivation, such as HIV or the use of immunosuppressant drugs (especially anti-
TNF drugs), but reactivation can also happen in people without known immunodeficiency.
The transition in seemingly healthy individuals is not well understood but it is generally
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thought to be distinct from that of children who have severe primary TB[43]. As many
healthy adults who develop active TB and are included in genetic epidemiology studies will
likely have been latently infected prior to activation, most case-control studies on
susceptibility probably capture host genetic variation related to reactivation of TB.
Unfortunately, based on the design of current TB susceptibility studies that usually do not
explicitly test for LTBI, we have not been able to say with certainty which variants are
related directly to progression from LTBI to TB as opposed to primary active disease.
5. Studies of Susceptibility to Pulmonary TB

Susceptibility to TB is distinct from resistance to MTB infection and is central in
understanding genetic factors underlying TB pathogenesis. From a design standpoint, there
are problems with the approach taken in many case-control studies of active TB. Not all
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studies have ensured that exposure status is similar between cases and controls, and in some
studies controls could contain the unexposed, the exposed and infected (LTBI), and
RSTRs[44, 45]. Assuming the study participants are adults, most cases probably were latent
prior to active disease in endemic areas. In the context of Figure 1 and our understanding of
TB pathogenesis, susceptibility studies do not neatly fit into a single biological process. The
number of potential steps and paths to active TB may affect our ability to detect meaningful
results, as we often do not determine a priori which of the steps we are assessing in a given
study. Nonetheless, the most likely scenario of the progression to active disease in adults is
that they have had a (re)activation of latent infection. Confirming this scenario may
substantially improve power to detect genetic actors in TB risk, if studied explicitly.
Hundreds of candidate gene studies have been published focusing on pulmonary TB as the
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phenotype. A recent review summarized 15 genes with robust, replicable associations,

although many other variants have been reported[19]. The majority of these 15 genes
variants code for human leukocyte antigen (HLA) (with variants in HLA-DRB1 especially
well represented), but multiple studies have also reported associations for variants in IFNG,
IFNGR1, IL10, MBL2, MCP1, SLC11A1, TLR2, TLR4, TLR9, TNF, and VDR[19].
Pathway analysis of these genes revealed multiple canonical pathways to be significantly
associated with TB susceptibility. The most significant pathway was in altered T and B cell
signaling in rheumatoid arthritis and T helper cell differentiation[19]. Other pathways
include the innate and adaptive immune responses, and helper T cell cytokine responses.
Since the vast majority of candidate gene studies have examined one gene at a time, and
often only a few variants within each gene, pathway analysis may provide clearer insight
into the biological mechanisms underlying TB risk. Considering most candidate genes were
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studied due to their suspected role in the immunological response, it can help us better
match our understanding of genetic variation in susceptibility studies to the pathophysiology
of TB, if we discuss these 15 results (which are also found in Table 1 of Stein et al. [19]) in
the context of their role within the immunological response to TB and the rest of this section
will focus on the genes listed in this paragraph.
HLA is an important type of protein for recognition of both foreign and host cells by the
immune system and represents the major system by which “self” is distinguished from
“other” in the human body. As stated above, many variants related to TB susceptibility are
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associated with polymorphisms in various HLA genes and these have a wide-ranging impact
on regulating the immune system and host response to infection[46].
VDR codes for the vitamin D receptor and MBL2 codes for mannose binding lectin 2, both
are which found throughout cells of the innate immune system. The MBL2 protein functions
by binding to sugars found on the surface of many pathogens. This serves as a signal to
activate the complement system, which is a host immune response that can destroy invading
pathogens and trigger inflammation[47]. The role of vitamin D in infection is still being
examined but it is known that vitamin D can activate transcription and studies have indicated
that it can regulate the expression of many genes in the immune system, including genes
coding for important components of the innate immune response[48].
When MTB enters the lung, it must contend with the resident alveolar macrophages. And as
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stated above, LTBI is an intracellular infection of macrophages and active TB disease can
occur when macrophages do not adequately contain the mycobacterium. Thus, macrophage
related variants are thought to be important in TB risk. There have been a number of
associations reported that pertain to this response (including those above), which is part of
the innate immune system (the initial response to infection) and variants pertaining to the
macrophage response may contribute to resistance and susceptibility. MCP1 (also known as
CCL2) codes for monocyte chemoattractant protein 1 (known as CCL2), and functions to
recruit immune cells to a site of infection (such as MTB in the lungs). The immune cells
recruited to the site of the infection including monocytes, precursor cells that may eventually
become macrophages[49]. TNF codes for tumor necrosis factor, a cytokine that is a key
driver of the inflammatory response, which is important to fighting a myriad of pathogens
and is chiefly produced by activated macrophages.
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SLC11A1 (previously called NRAMP1), is one of the most well studied genes for
association with pulmonary TB susceptibility and a large number of studies have found
associations between SLC11A1 and susceptibility[19]. It is an important regulator of
macrophage responses to MTB [19, 50, 51]. SLC11A1 functions within macrophages,
regulating changes in iron transport and the transport of other cations in response to
infection, thus depriving MTB of the iron it needs to replicate and spread within the body
[50–53].
One of the most well studied pathways in genetic susceptibility to TB in humans is that of
toll-like receptors (TLRs). TLRs are part of the innate immune system, found primarily on
macrophages and other antigen presenting cells such as dendritic cells, and function to
recognize conserved ligands in microbes. In essence, they help mount a proper immune
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response to specific microbes, including MTB. There are a number of polymorphisms that
have associated with TB susceptibility in the pathways for toll-like receptors (TLRs) and
other genes that affect TLR function[22, 54–60]. Unfortunately, with the exception of TLR2,
TLR4, and TLR9 (as reported above and in Table 1 of Stein et al. [19]), not all of these
polymorphisms have an obvious functional role and some lack adequate replication in the
literature[5]. However, toll-like receptors, as a family, show a clear role in both
immunological and genetic studies of TB.
Autophagy is the process by which the immune system clears out infected cells (including
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macrophages). Although polymorphisms in autophagy pathways are not included in the 15

robust associations described above, immunological studies have strongly suggested a role
for autophagy variants in the host response to MTB infection and TB disease. And
polymorphisms in ATG5 and IRGM, both of which are involved in autophagy, have been
associated with TB susceptibility [61–64].
T cells also play an important role in regulating the host response to infection by MTB. HIV-
positive individuals (who have low CD4+ cell counts) are more likely to progress to active
disease than those without HIV. Consistent with this observation, mouse studies have shown
that IFN-γ production by T-cells is important in controlling MTB replication, survival, and
the formation of the granulomas that sustain latency[65–73]. Several of the robust
associations are key players in the IFN-γ response (e.g., IFNG and IFNGR1). There may
also be IFN-γ independent T cell responses that play a role in TB pathogenesis; for example
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SNPs in IL10 that have shown strong association with TB [5, 19, 27]. Another important T-
cell response associated with TB is the recognition of non-protein mycobacterial antigens.
CD1 and MR1 proteins function in this capacity and the genes coding for these (CD1 and
MR1) both have polymorphisms that may be associated with TB susceptibility, although
these findings are not considered as robust as some other genes [74, 75].
In addition to candidate gene studies, six linkage studies have identified loci that influence
TB susceptibility (Table 2). These studies, performed in Southeast Asia, South America and
both West and East Africa, identified several putatively linked loci, but the linkage regions
differed across studies. One study in Thailand identified suggestive evidence of linkage at
loci on chromosomes 5q23.2–31.3, 17p13.3–13.1, and 20p13–12.3 [76]. A study in West
Africans found evidence of putative linkage with TB on 6p21–23 and 20q13.31–33 that
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were later mapped to the CTSZ and MC3R [77]. A study of TB in Brazilians identified loci
on chromosomes 10q26.13, 11q12.3, and 20p12[78]. A different study of TB in Brazil found
a cluster of four genes (NOS2A, CCL18, CCL4, and STAT5B) on 17q11–21 that showed
linkage with TB[79]. This chromosome 17 region was chosen as the syntenic region in mice
had been shown to affect intra-macrophage infections in mice[79]. A study performed in
The Gambia and South Africa provided evidence of linkage with TB on chromosome 15q
and Xq[80]. Finally, a study in Uganda identified linkage with TB on 7p22–21, and nominal
linkage for IL1 and IL12A[14]. Of note, these linkage signals generally differ among
populations leaving many unanswered questions about universal versus population specific
effects. One limitation of interpreting these studies is that linkage peaks are wide, and in
most cases these significantly linked chromosomal regions do not contain any established
TB candidate genes.
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Genome-wide association studies (GWAS) studies have also yielded valuable insights into
TB susceptibility, with 9 case-control studies finding associations with pulmonary TB[19]
(Table 2). WT1 was originally identified on chromosome 18q11.2 and found to be associated
with susceptibility in a cohort of Ghanaians, Gambians, and Malawians[81]. It was then
replicated in Russians, Indonesians, admixed South Africans, and a different cohort of
Gambians [82, 83]. The study in South Africa also identified loci on chromosomes 14q24.2
and 11q21–22[82]. Loci on chromosomes 11 and 18 were found in a Russian cohort that
replicated the locus on chromosome 11 but not 18. This study did, however, identify a novel
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gene, ASAP1 [84]. When researchers examining a Moroccan cohort attempted to replicate
the results on chromosomes 11 and 18, they failed to do so at a level of genome-wide
significance (but did so at a nominal significance, p=0.05)[85]. HLA variants showed
associations in Russian, Icelandic, and Croation cohorts, but these same studies did not
replicate the aforementioned loci on chromosomes 11 and 18[86]. A study of a Japanese
cohort identified a locus on chromosome 20q12 that was significantly associated with
younger age of TB onset[87]. A cohort of HIV-positive subjects showed a significant
association at 5q33.3 and a subsequent haplotype analysis was consistent with this
association being caused by variation in IL12B [88]. In summary, GWAS studies have
yielded a number of insights. These are in need of replication and may differ with respect to
populations, which may be due to different frequencies of certain polymorphisms in these
populations[19] (Table 2). Furthermore, none of the linkage peaks or associating loci
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replicated with genome-significance across studies. However, in at least one GWAS it was
shown that 8 of 22 previously associating candidate genes did replicate at a nominal p-value
(p < 0.05)[84]. This is unlikely to have occurred by chance alone.
Gene expression studies have also yielded insights into host genomics of TB. Most of these
studies have focused on transcripts that are unique to TB cases and found in peripheral blood
[89–96]. However, one study used cells stimulated with MTB after isolation from circulating
blood[97]. These studies varied greatly with respect to control groups and the transcripts
they studied, making it difficult to draw generalizable conclusions [19]. Some studies
reported differential expression of type I and II interferon pathways in TB cases [90, 94, 95].
One study showed differential expression for CCL1[96]. Interestingly, the transcriptomic
signatures in some of these studies normalized during or after treatment, indicating that
these signatures may be specific to active disease[90, 95, 96].
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6. Genetics of Severity of TB disease

Studies examining severity are less common than those studying association or linkage with
disease. And those that do study TB severity use a wide variety of severity definitions,
making comparisons difficult. Phenotypes utilized include TBscore (a validated outcome
based on 11 clinically relevant symptoms), disease progression, cavitary disease, lung
lesions, bacterial load, or parenchymal involvement as markers of severity [98–109] (Table
3). In these studies of phenotypes related to clinical severity, the MCP-1/MMP-1/PAR-1
pathway was associated with more severe disease based on the Bandim TBscore[99]. A
recent study also found an association between SNPs in IL12B and the Bandim
TBscore[109]. Variants in TLR4 were correlated with bacillary load and lung involvement
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on radiological examination[105], TLR8 variants were associated with bacterial load in one
study[98]. One study found a CTLA4 haplotype was less common in patients with larger
chest opacities[108]. HLA-DRB1 variants associated with more advanced lung lesions[102].
Variants in both SLC11A1 and IL23R have been associated with cavitary disease[100, 106].
In transcriptomic studies, greater expression of genes in the SOCS family were associated
with more lung parenchymal involvement upon radiological examination[104]. Higher
expression of IL17 and IFNG in peripheral blood was associated with radiological and
clinical parameters that describe disease severity in patients with active disease compared to
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healthy BCG-vaccinated controls[101].
In summary, severity as a phenotype is understudied, and it is not obvious how the different
phenotype definitions are related. Notably, some of the severity associating genes (i.e.,
IFNG, SLC11A1, MCP1, TLR variants, and HLA variants) are similar or identical to those
implicated in previous studies of susceptibility or resistance to TB. How TB risk and
severity relate will require more work to better define how the genetics of risk and
progression do or do not correlate across severity definitions. This will be useful in
understanding functional aspects TB genetics.
7. MTB Lineage, Human Disease, and Co-evolution

There are seven currently described lineages of MTB that cause disease in humans. Two are
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ancient and 5 are modern. In addition, there are numerous sub-lineages that are often highly
limited in their geographical distribution, some to a single country. Many of these sub-
lineages are thought to be recently diverged and many of them are thought to have come
from lineage, L4, that is the most widespread lineage of MTB. L4 was originally found in
Europe, and potentially moved to other continents with Europeans [110]. Studies have
indicated that MTB lineage can affect the probability of developing TB disease [111–114].
However, two studies in Uganda have shown no association between an MTB sub-lineage
unique to Uganda and severity of disease, as measured by presence of cavitary disease and
extent of lung involvement[115, 116]. A major question arises when trying to assess the
diversity of MTB, namely, whether pathogenicity or virulence is a function of the host,
MTB, or both. This is especially pertinent to TB, as most infections do not cause disease.
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7.1 Human-MTB interaction and TB

Although it is clear that both human and MTB genetic variants can affect TB risk, it is also
possible that combinations of the two impact risk. Such a model posits that human-MTB co-
evolution exists and that risk and/or severity is determined by the exact combination of
human genes and MTB genes[117]. Studies examining possible interaction between host
genotype and MTB lineage are sparse. It is especially difficult for the study of TB
susceptibility as it is virtually impossible to know what MTB lineages a specific host has
been exposed to prior to enrollment in a study. One way to circumvent this problem is to
study how interaction affects disease severity.
TB severity in the context of co-evolution is especially important as evolutionary theories

hypothesize that long-term coexistence between the human genome and MTB lineage may
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decrease risk of developing active TB or minimize the severity of disease, if disease is

present[117]. This concept is referred to as co-evolution. Co-evolution implies concordant
genetic variation of both MTB lineages and human variation as a product of long term
coexistence that promotes mutual adaptation and thereby modulates the effects of infection.
Co-evolution has been hypothesized to lead to prudent exploitation or covert infection, such
that exposure and latent infection does not necessarily lead to active disease and will cause
less virulent disease, when present[118, 119]. A pathogen that is prudently exploiting the
human host would be evolutionarily incentivized to persist and be transmitted, but not cause
disease severe enough to cause rapid death that could lead to the extinction of the host
Author Manuscript
population and ultimately the MTB population. [120]. Under the co-evolution model, a
newly divergent MTB lineage that did not historically co-exist with the human population in
question is more likely be associated with disease and also more likely to cause severe
disease [121]. In practice, only the latter can be explicitly studied as exposure histories are
impossible to know in the absence of disease. Consistent with this possibility and the
conditions that could lead to co-evolution, humans and MTB have a very long history and
most people exposed to MTB do not progress to active disease, making MTB a likely
prudent exploiter [122].
The potential for human-MTB co-evolution has been explored in human and model systems,
but studies have not yet identified a clear effect at the population level[111, 114, 123–127].
Studying co-evolution in TB risk can be problematic because even within a household the
strain to which an individual is predominantly exposed may not match that of the index case,
Author Manuscript
since community exposure can be the major source of exposure[128]. Thus, due to the idea
that co-existence would decrease severity over time and prolong the co-existence of the two
species, one way to approach possible co-evolution is to study TB severity. Another limit to
studying people with only TB compared to LTBI is that those who are latently infected
cannot usually be examined for MTB strain. Hence, all existing studies of host-MTB
genome interaction have been case-only studies that at best examine association between
lineage and host genotypes, but not explicit interactions [53, 124, 126, 129]. However, a
recent study of ours has shown that interaction between host variants in SLC11A1 and MTB
lineage can affect severity of TB, measured by the Bandim TBscore[109]. Specifically, we
found that the recently diverged Ugandan L4 sub-lineage caused more severe disease, but
only in individuals with an ancestral SLC11A1 genotype; those with the ancestral genotype
and the older MTB lineages did not have as severe disease. In general, the combinations of
Author Manuscript
host genotype and MTB lineage that had co-existed longer had less severe disease, lending
support to the model of co-evolution and prudent exploitation of humans by MTB. Relevant
to SLC11A1, this gene has bene a well-studied candidate gene for TB susceptibility but not
all studies found an association. It is possible that failure to replicate was a function of MTB
lineage among those with disease. Given how lineage can affect the relationship between
host genotype and TB, and that interactions between the two genomes may drive disease
processes, it will be important to improve our understanding of the role that the MTB
lineage - human genome interaction plays.
Beyond examination of MTB genetics classified by lineage, it will be important to

understand how the MTB genome and specific variants can affect severity and susceptibility
in humans. Some work has indicated that there may genetic diversity of MTB within a given
Author Manuscript
host and that MTB can evolve within the host it has infected, affecting both transmission and
drug resistance[130]. Elucidating the evolutionary process of MTB both within a host and on
a population level will allow for a deeper biological understanding of the interaction
between the host and MTB than examining lineages or human genomes alone. Future work
should be done in this area as it may elucidate what makes MTB pathogenic.
8. Conclusions
Author Manuscript
Previous study of human genetics in the context of TB has been extensive, but there are still
important gaps in the existing literature. Resistance to MTB infection has great relevance for
TB research, but has been relatively understudied with respect to human genetic influences.
Susceptibility has been the most extensively studied phenotype and there are a number of
robust associations reported. However, there is still variation between populations and
inconsistency in many results, with many associations not replicating across distinct study
populations. Severity is a field of study with little to no consistency in phenotype and only a
few studies in the context of genetics. We are beginning to recognize and understand the role
of MTB lineage and MTB genotypes but there is a need for population level studies looking
at the interaction between human genetic variants and the lineage and/or genotype of MTB.
This will at present need to be assessed in the context of severity. All of these factors are
important considerations and should help us better understand TB pathogenesis in a way that
Author Manuscript
helps to control disease or improve treatment.
Acknowledgements:
Funding for this work was provided by the Tuberculosis Research Unit (grant N01-AI95383 and
HHSN266200700022C/ N01-AI70022 from the NIAID) and R56 AI130947 from the National Institutes of Health.
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Highlights
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• Tuberculosis usually requires several steps from exposure to disease
• Human genetic variation associates with most transitions among TB related

phenotypes
• Mycobacterium-human coevolution can affect TB severity and likely risk

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Figure 1. Tuberculosis Disease Progression.

Possible paths from exposure to disease. A: Transition from Exposure to Infection (usually
leading to LTBI); B: RSTRs or those who never become infected (a minority of those
exposed); C: Development of primary active disease (usually in children or individuals who
are immunocompromised, rare or non-existent in others); D: Transition from infection to a
state of latency (LTBI, presumably the most common transition post exposure and
infection); E: Early clearance of infection, manifested as reversion of TST/QFT; F: Re-
activation of disease following a period of latency. Arrow sizes are proportional to likelihood
of transition.
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Table 1.
Summary of findings for resistance to MTB infection, by phenotype definition and approach
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Type of study Gene/Locus Phenotype Population References

Candidate gene ULK1 TST positivity Seattle [21, 22]
SLC6A3 RSTR Uganda [17]
IL10 TST positivity Ghana [20]
Genome-wide 2q21-q24 (GTDC1 and ZEB2) 5p13-q22 RSTR (longitudinal) Uganda [14] [16] [15]
11p14 (TST1) TST positivity (cross-sectional) South Africa [16]
5p15 (TST2) Reactivity (quantitative) [18]
5q31 (including IL9) TST positivity and reactivity Tanzania and Uganda [19]
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Table 2.
Summary of findings from genome-wide scans of TB disease

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Approach Locus (nearby gene) Population References

Linkage
5q23.2–31.3, 17p13.3–13.1, 20p13–12.3 Thais [76]
6p21–23 and 20q13.31–33 West Africans [77]
15q and Xq Gambia and South Africa [80]
10q26.13, 11q12.3, and 20p12 Brazilians [78]
17q11–q21 Brazilians [79]
7p22–7p21 Uganda [14]
Association
*3 studies replicating 18q11.2 (WT1) Ghana, Gambia, Malawia, Indonesia, South Africa, [81] [82, 83]
same locus Russia
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14q24.2 11q21-q22 South Africa [82]
ASAP1 Russia [84]
HLA Variants Russia, Iceland, Croatia [86]
20q12 Japan (young onset TB) [87]
5q33.3 (IL12B) Uganda and Tanzania (HIV+) [88]

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Table 3.
Genes associated with severity

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Gene Definition of severity Population References

MCP1/MMP1/PAR1 Bandim TBscore Peru [99]
IL12B Bandim TBscore Uganda [109]
SOCS Parenchymal Involvement Pakistan [104]
IL17 & IFNG Radiological/Clinical Severity Argentina [101]
TLR4 Bacillary load & Lung Involvement India [105]
CTLA4 Chest opacity size Ghana [108]
HLA-DRB1 Advanced nature of lung lesions Korea [102]
IL23R Cavitary Disease China (Uygur) [100]
SLC11A1 Cavitary Disease East India [106]
TLR8 Bacterial Load Pakistan [98]

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Genetics and evolution of tuberculosis pathogenesis: New

Tuberculosis; Genetics of pathogenicity; Host-pathogen co-evolution

2. Overview from infection to TB

likely to occur in the presence of immunosuppression or other stressors on the immune

3. Exposure to infection: Who is resistant?

It remains to be seen to what extent resistance to infection is driven by genetics. However,

4. Primary Active Disease

susceptibility to mycobacterial disease)[28]. These children often manifest a severe

4.1 Delayed transition from latent infection to active TB

5. Studies of Susceptibility to Pulmonary TB

phenotype. A recent review summarized 15 genes with robust, replicable associations,

macrophages). Although polymorphisms in autophagy pathways are not included in the 15

6. Genetics of Severity of TB disease

healthy BCG-vaccinated controls[101].

7. MTB Lineage, Human Disease, and Co-evolution

7.1 Human-MTB interaction and TB

TB severity in the context of co-evolution is especially important as evolutionary theories

decrease risk of developing active TB or minimize the severity of disease, if disease is

Beyond examination of MTB genetics classified by lineage, it will be important to

helps to control disease or improve treatment.

8. Nemes E, Geldenhuys H, Rozot V, Rutkowski KT, Ratangee F, Bilek N, et al. Prevention of M.

10.1111/imr.12274. [PubMed: 25703553]

14. Epub 2012/06/23. doi: 10.1016/j.ajpath.2012.05.009. [PubMed: 22721647]

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2003;171(9):4689–99. Epub 2003/10/22. doi: 10.4049/jimmunol.171.9.4689.

2014;15(3):195–8. Epub 2014/02/07. doi: 10.1038/gene.2014.5. [PubMed: 24500401]

cluster of genes on chromosome 17q11–q21 controlling susceptibility to tuberculosis and leprosy

84. Curtis J, Luo Y, Zenner HL, Cuchet-Lourenco D, Wu C, Lo K, et al. Susceptibility to tuberculosis

2012;7(10):e46191. doi: 10.1371/journal.pone.0046191.

one. 2012;7(9):e45839. Epub 2012/10/03. doi: 10.1371/journal.pone.0045839.

i. Epub 2011/10/20. doi: 10.5588/ijtld.11.0089. [PubMed: 22008758]

111. Coscolla M, Gagneux S. Consequences of genomic diversity in Mycobacterium tuberculosis.

10.1186/1471-2334-13-484. [PubMed: 24134504]

Infect Dis. 2018;18(3):e64–e75. Epub 2017/11/08. doi: 10.1016/s1473-3099(17)30623-0.

• Tuberculosis usually requires several steps from exposure to disease

• Human genetic variation associates with most transitions among TB related

• Mycobacterium-human coevolution can affect TB severity and likely risk

Figure 1. Tuberculosis Disease Progression.

Type of study Gene/Locus Phenotype Population References

SLC6A3 RSTR Uganda [17]

IL10 TST positivity Ghana [20]

11p14 (TST1) TST positivity (cross-sectional) South Africa [16]

5p15 (TST2) Reactivity (quantitative) [18]

Summary of findings from genome-wide scans of TB disease

Approach Locus (nearby gene) Population References

5q23.2–31.3, 17p13.3–13.1, 20p13–12.3 Thais [76]

6p21–23 and 20q13.31–33 West Africans [77]

15q and Xq Gambia and South Africa [80]

10q26.13, 11q12.3, and 20p12 Brazilians [78]

17q11–q21 Brazilians [79]

7p22–7p21 Uganda [14]

14q24.2 11q21-q22 South Africa [82]

ASAP1 Russia [84]

HLA Variants Russia, Iceland, Croatia [86]

20q12 Japan (young onset TB) [87]