Acquired immunodeficiencies and tuberculosis: focus on HIV/AIDS and diabetes mellitus

Katharina Ronacher Simone A. Joosten Reinout van Crevel Hazel M. Dockrell Gerhard Walzl Tom H. M. Ottenhoff Acquired immunodeficiencies and tuberculosis: focus on HIV/AIDS and diabetes mellitus Authors’ addresses Katharina Ronacher1*, Simone A. Joosten2*, Reinout van Crevel3, Hazel M. Dockrell4, Gerhard Walzl1#, Tom H. M. Ottenhoff2# 1 DST/NRF Centre of Excellence for Biomedical Tuberculosis Research and MRC Centre for Tuberculosis Research, Division of Molecular Biology and Human Genetics, Faculty of Medicine and Health Sciences, Stellenbosch University, Cape Town, South Africa. 2 Department of Infectious Diseases, Leiden University Medical Centre, Leiden, The Netherlands. 3 Department of Medicine, Radboud University Medical Center, Nijmegen, The Netherlands. 4 Immunology and Infection Department, Faculty of Infectious and Tropical Diseases, London School of Hygiene and Tropical Medicine, London, UK. Summary: The spread of human immunodeficiency virus (HIV) infection within Africa led to marked increases in numbers of cases of tuberculosis (TB), and although the epidemic peaked in 2006, there were still 1.8 million new cases in 2013, with 29.2 million prevalent cases. Half of all TB cases in Africa are in those with HIV co-infection. A brief review of the well-documented main immunological mechanisms of HIV-associated increased susceptibility to TB is presented. However, a new threat is facing TB control, which presents itself in the form of a rapid increase in the number of people living with type II diabetes mellitus (T2DM), particularly in areas that are already hardest hit by the TB epidemic. T2DM increases susceptibility to TB threefold, and the TB burden attributable to T2DM is 15%. This review addresses the much smaller body of research information available on T2DM-TB, compared to HIV-TB comorbidity. We discuss the altered clinical presentation of TB in the context of T2DM comorbidity, changes in innate and adaptive immune responses, including lymphocyte subsets and T-cell phenotypes, the effect of treatment of the different comorbidities, changes in biomarker expression and genetic predisposition to the respective morbidities, and other factors affecting the comorbidity. Although significant gains have been made in improving our understanding of the underlying mechanisms of T2DM-associated increased susceptibility, knowledge gaps still exist that require urgent attention. *These authors contributed equally. These authors contributed equally. # Correspondence to: Gerhard Walzl Stellenbosch University Biomedical Sciences Faculty of Medicine and Health Sciences PO Box 19063 Tygerberg Cape Town, Western Cape 7505, South Africa Tel.: +27219389158 e-mail: gwalzl@exchange.sun.ac.za This article is part of a series of reviews covering Tuberculosis appearing in Volume 264 of Immunological Reviews. Video podcast available Go to www.immunologicalreviews.com to watch an interview with Guest Editor Carl Nathan. Immunological Reviews 2015 Vol. 264: 121–137 © 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd Immunological Reviews 0105-2896 Keywords: type II diabetes mellitus, tuberculosis, HIV TB, HIV/AIDS, and diabetes: overview of rapidly emerging co-epidemics Tuberculosis (TB) remains an enormous public health challenge. Despite drug therapy that is effective in most individuals, improved diagnostic tools, and much research toward the development of new vaccines, TB continues to be difficult to control, an issue that is further compounded by the rising frequencies of drug resistant Mycobacterium tuberculosis (Mtb) strains (1). Susceptibility to developing active TB is influenced by many host factors, including concomitant infections and non-communicable diseases. Human immunodeficiency virus (HIV) infection and type 2 diabetes mellitus (T2DM) are prime examples of concomitant conditions that are known to significantly impact immunity against TB. As the associations between HIV and TB have been the sub- © 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd Immunological Reviews 264/2015 121 Ronacher et al
HIV, diabetes mellitus, TB comorbidity Acknowledgements This study described has received funding from the European Union’s Seventh Programme for Research, Technological Development and Demonstration under grant agreements TANDEM 305279, IDEA 241642, ADITEC 280873, NEWTBVAC HEALTH.F3.2009 241745. We also gratefully acknowledge the support of the Netherlands Organization of Scientific Research (NWO) and The Bill & Melinda Gates Foundation Grand Challenges in Global Health, grant 37772 and OPP1065330. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. The authors have no conflicts of interest to declare. ject of extensive research in recent decades, this review only covers pertinent highlights from the literature. The literature on the immune responses in patients with TB and T2DM comorbidity is considerably smaller, and two recent reviews have provided a timely summary of the key areas (2, 3). Here we concentrate on recent developments and approaches that may bring further insights. The epidemiological evidence that HIV markedly increases susceptibility to infection with and disease caused by M. tuberculosis has been evident since the 1980s. The spread of HIV infection within Africa led to marked increases in numbers of cases of TB, and although the HIV epidemic peaked in 2006, there were still 1.8 million new cases in 2013, with 29.2 million prevalent cases (4). There were 7.5 million incident cases of TB in 2013, although the annualized rates of change became negative after 2000. In several African settings, as many as half of all TB cases are in patients with HIV co-infection. Perhaps tellingly, some Mtb infections are not apparent until HIV patients are started on anti-retroviral therapy, illustrating that for TB, it is the immune response causing immunopathology that produces the symptoms of TB (5). Diabetes is another important risk factor for TB. The association between TB and diabetes was well known in the first half of the 20th century, but somewhat forgotten with the advent of widely available treatment for both diseases (6). In the last decades, with the current global growth of diabetes, the link between TB and DM is re-emerging. Currently, there are an estimated 350 million diabetes patients (7). Approximately 90% of these cases are T2DM, and due to urbanization, increased living standards and poor diets, the number of individuals with T2DM is expected to rise by more than 50% in the coming 20 years, with the largest increase expected in Africa. T2DM is associated with an approximately threefold increased risk of active TB (8), and as a result, it is estimated that 15% of the TB burden world- 122 wide is now attributable to T2DM (9). Surprisingly, little is known about the link between TB, HIV infection, and T2DM. HIV negative but not HIV-positive individuals with diabetes in Tanzania were found to have an increased risk of TB, suggesting that the effect of HIV over-rides the risk from T2DM. However, HIV infection as well as its treatment can lead to insulin resistance and T2DM, even at normal body weight (10, 11). Clearly, more research is needed on the combination and interaction of the three diseases (12), including their treatment. TB in HIV-infected individuals and in diabetes patients: clinical manifestations and treatment The presentation of TB in HIV-infected individuals may be atypical, especially in those with advanced disease characterized by low numbers of circulating CD4+ T cells. These patients more often present with extrapulmonary and disseminated (i.e. miliary) TB disease. Pulmonary TB may present without typical lung cavities, and some patients may only have enlarged lymph nodes or even normal chest X-rays. Treatment of concurrent HIV and TB can be challenging, due to overlapping side effects and drug toxicity, adherence issues and drug–drug interactions, especially between rifampicin and various HIV drugs. TB treatment outcome in HIV-infected individuals is also less favorable, with more treatment failures, relapses, and deaths. Anti-retroviral treatment not only reduces the risk of TB but also improves TB treatment outcome. In contrast to HIV, T2DM seems to have more subtle effects on TB presentation. There is no convincing evidence suggesting that T2DM leads to more extrapulmonary or disseminated TB, and from two systematic reviews, it appears that the radiographic presentation of TB is not different in patients with concurrent diabetes (6, 13). A recent case series, the largest so far, found that TB patients with T2DM were more likely to have opacities in lower lung fields, any © 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd Immunological Reviews 264/2015 Ronacher et al
HIV, diabetes mellitus, TB comorbidity and multiple cavitation and extensive parenchymal lesions, especially in those patients with poorer glycemic control (14). With regard to treatment, it is known that T2DM is associated with increased TB treatment failure, relapse, and death (3). However, it is uncertain if optimal glucose control can completely (or partly) reverse these effects. Also, lower plasma concentrations of TB drugs have been found in T2DM patients (15). Diabetes patients have a higher body weight, and this is probably associated with decreased rifampicin exposure. However, it is not known if higher dosages will improve treatment outcome or whether treatment duration should be prolonged. Glycemic control in patients treated for TB can be challenging. TB often leads to decreased appetite, body mass, and physical activity, all of which may influence glucose homeostasis. Inflammation associated with active TB induces insulin resistance, and rifampicin decreases the effectiveness of most oral diabetes drugs (15). TB patients who have T2DM may also require more frequent monitoring of liver and kidney function. Unlike for HIV, immune reconstitution and its distinct pathology are not associated with diabetes. Immunology of HIV-TB co-infection Despite the essential role of CD4+ T cells and type-1 cytokines in host defense to mycobacteria, this body of knowledge has proved insufficient to fully explain host resistance and to provide correlates of protection. The well known association between TB and HIV accompanied by reduced CD4+ T-cell numbers and function illustrates the central role of CD4+ T cells in protection against TB, but protection appears to be of greater complexity. New insights are emerging, as discussed below. Cellular immunity against Mtb Mtb predominantly infects host macrophages, particularly alveolar macrophages. Mycobacteria are phagocytosed following ligation to specific cell surface receptors and are taken up into phagosomes, which then partially mature and acidify, followed by processing and presentation of mycobacterial antigens by human leukocyte antigen (HLA) class I and II molecules to CD8+ and CD4+ T cells, respectively (16). Besides ‘direct’ antigen presentation, ‘indirect’ antigen presentation or ‘cross presentation’ can take place, particularly via HLA class I on dendritic cells that have either taken up Mtb antigens released by dead cells or are loaded with antigens actively shuttled from live, infected cells via a not © 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd Immunological Reviews 264/2015 fully uncovered mechanism, which, however, is distinct from exosomes or apoptosis (17). Although T-cell immunity is well known to be crucial in the control of Mtb infection, the precise cells, including the exact T-cell subsets and T-cell functions, which are indispensable for protective immunity remain incompletely identified. As mentioned, epidemiological studies of concomitant TB and HIV infection have demonstrated that the risk of developing active pulmonary TB increases dramatically when CD4+ T-cell numbers decrease as a consequence of HIV infection (18). HIV infects CD4+ T cells, including those specific for Mtb, and the resulting depletion of these helper T cells significantly impairs immune control of Mtb, demonstrating that CD4+ T cells are required for controlling Mtb infection. CD4+ T cells can produce multiple key cytokines, including IFN-c, IL-2, and TNF-a. TNF-a is particularly important in the formation and maintenance of mycobacterial granulomas, and it seems to be a critical component of the immune response to Mtb, as TB re-activation occurred relatively frequently in patients treated with anti-TNF antibodies as therapy for inflammatory disorders like rheumatoid arthritis or inflammatory bowel disease, before they were routinely screened and treated for latent TB (19, 20). IFN-c is considered another key cytokine in anti-mycobacterial immunity and is frequently used as a biomarker in diagnostic assays. Mice defective in IFN-c signaling show increased Mtb outgrowth and cannot control infection (21). More importantly, rare patients with genetic or acquired (neutralizing anti-cytokine autoantibodies) deficiencies in the IL12/IL23IFN-c cytokine signaling pathway display enhanced susceptibility to non-tuberculous as well as tuberculous mycobacterial infections (22), pointing to a critical role of IFN-c in the host response toward mycobacteria. Recent findings suggest that certain CD4+ Th1 cells can control Mtb infection also via IFN-c and TNF-a independent mechanisms (23), at least in a mouse model, although it remains to be seen whether such cells also contribute to Mtb control in humans. Due to its central role in the immune response to TB, induction of IFN-c by mycobacterial antigens has been utilized in commercial immunodiagnostic assays such as Quantiferon-TB Gold and T-SPOT.TB. In addition, IFN-c is often used as an indicator cytokine of vaccine-induced responses in clinical vaccine studies (24, 25). However, it has been demonstrated that the frequency of CD4+ or CD8+ T cells producing IFN-c fails to correlate with protection against TB (26–30). Also, although MVA85A booster vaccination fol- 123 Ronacher et al
HIV, diabetes mellitus, TB comorbidity lowing previously administered BCG in South African infants was clearly immunogenic as reflected by enhanced frequencies of IFN-c producing T cells, no additive protective efficacy could be demonstrated in a recent large-scale phase IIb efficacy study (26, 27). It has also been proposed that protective immunity against TB might be associated with multifunctional T cells producing IFN-c, TNF-a, and IL-2, and in animal studies such cells were associated with vaccineinduced protection and proposed as a correlate of protection (28, 29, 31–36). However, although such multifunctional CD4+ T cells can be induced by vaccination [both in animals (31–33) and in humans (30, 31, 34–36)], the proportions of these cells do not correlate with protection (30), and they are also abundantly present in the blood of patients with active pulmonary TB (37, 38). Thus, multifunctional CD4+ T cells may be part of the host protective response trying to limit infection, but they are not a useful correlate of protection in TB. Instead, the magnitude of T-helper 1 (Th1) and Th17 responses, including multifunctional T cells, has been reported to correlate with disease activity and might reflect bacterial load rather than protective immunity (38, 39). As mentioned, HIV co-infection is associated with increased incidence rates of TB in sub-Saharan Africa (40), which is thought to be the result of impaired T-cell immunity (40), due to the depletion of CD4+ T cells. In situ in patients with TB alone, Mtb granulomas differ in architecture from that in patients with advanced HIV infection and decreased CD4+ T-cell counts, often having multi-bacillary and necrotic characteristics, increased numbers of granulocytes, and high levels of TNF-a compared to lesions from TB patients without HIV (41–43). T-cell responses to Mtbderived PPD in chronically HIV-infected individuals were lower than in non-HIV infected persons, and in TB patients with active disease, PPD stimulated IFN-c production was lower in those affected by HIV co-infection (18). In latently Mtb-infected individuals, there was no correlation between absolute CD4+ T-cell counts and the magnitude of the IFN-c response, neither in HIV-infected nor in HIV-uninfected individuals (18). Deletion of Mtb-specific T cells occurs early during HIV infection, possibly due to the high levels of CCR5 expressed by Mtb-specific T cells (18). Since CCR5 is one of the receptors utilized by HIV to enter T cells, Mtb induced increased levels of CCR5 may increase the susceptibility of Mtb-specific T cells to HIV infection and their subsequent depletion. In addition, the high levels of IL-2 produced by Mtb-specific T cells on a per cell basis, which promotes T-cell proliferation further enhance their suscepti- 124 bility to HIV infection (40). Data on multifunctional T cells in TB patients with concomitant HIV infection remain subject of debate: while some studies reported multifunctional CD4+ T cells in these patients at the time of TB diagnosis (44), others only detected such cells following anti-retroviral therapy (45). Mycobacterial antigen-specific multifunctional T cells (producing IFN-c, TNF-a, and IL-2) were impaired, both in infants and in BAL cells from adult HIV patients in a TB high endemic area but in the absence of disease (46, 47). Inflammatory immunopathology: immune reconstitution inflammatory syndrome (IRIS) The initiation of anti-retroviral therapy can result in immune reconstitution inflammatory syndrome (IRIS), a strong inflammatory response associated with rapidly normalizing CD4+ T cells and myeloid cells that are triggered to respond to earlier (partially treated or yet undiagnosed) infections. IRIS is characterized by unbalanced inflammatory responses, yet its etiology and pathogenesis remain poorly understood. IRIS occurs in 10–40% of HIV-infected patients starting on anti-retroviral treatment with low CD4+ T-cell counts and is correlated with the bacterial burden (48). In TB-HIV, two types of IRIS can occur following initiation of anti-retroviral therapy: inflammatory TB pathology occurring despite anti-TB chemotherapy is called ‘paradoxical TB-IRIS’, whereas acute inflammatory TB pathology in the absence of a previous TB diagnosis is called ‘unmasking TB-IRIS’ (5). The initial reconstitution of CD4+ T cells is mostly by CD4+ memory T cells, suggesting rapid redistribution from lymphoid sites, while secondary reconstitution also includes naive CD4+ T cells (40). Anti-retroviral therapy induced immune reconstitution does not restore full functionality of T-cell subsets, as the capacity to produce IFN-c in response to Mtb remains low compared to healthy donors (40). Although for a long time T cells have been considered to be the primary affected population during HIV infection and IRIS, recently emerging evidence also demonstrates altered innate immune responses during HIV infection. Following initiation of ART, not only do numbers of circulating T cells rise but also those of myeloid cells, in particular dendritic cells (48–50). This may result in temporal increases in myeloid derived cytokines and subsequent immune activation, potentially contributing to IRIS. Current data are not unambiguous, but evidence suggests an effect of HIV directly on (alveolar) macrophage function, resulting in increased Mtb outgrowth, impaired levels of TNF-a, and decreased macrophage survival (40, 51). Better insights into the © 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd Immunological Reviews 264/2015 Ronacher et al
HIV, diabetes mellitus, TB comorbidity immunological mechanisms underlying IRIS are needed, including the precise contribution of T-cell subsets, innate immune responses, and other risk factors, to allow better prevention and treatment strategies of TB-IRIS. Immuneregulation and Th17 immunity in TB Besides activating effector immunity, mycobacteria also activate regulatory T cells (Tregs), which typically dampen inflammation and limit tissue damage. The proper balancing of Tregs versus effector T-cell activity is critical, since an imbalance may result in either hyper inflammation accompanied by extensive host tissue damage, or hypo inflammation and downregulation of effector immunity, allowing Mtb to escape from immune control and to multiply. Mtb is capable of inducing various Treg populations in patients and infected individuals (52–56). In humans, CD8+ Tregs appear to contribute significantly to the reservoir of Mtbinduced Tregs (56–59). Tregs have been found at the site of TB disease, both in mycobacterium-induced granulomas (56, 60) and in broncho-alveolar lavage (BAL) (54, 61), and their in vitro depletion enhanced human effector immunity against Mtb (62). In animals Treg depletion during Mtb infection reduced pathology and bacterial burden, while the reverse was seen following adoptive transfer of Tregs (63, 64), suggesting that these cells contribute significantly to the regulation of bacterial containment in vivo. Acquired immunodeficiencies due to HIV or impaired immunity due to T2DM may alter the balance between effector and regulatory T cells (65–70). Th17 cells are characterized by production of IL-17A/F and IL-22, have strong pro-inflammatory capacities, and play a significant role in mucosal immunity. In animal models of TB, the presence of Th17 cells was associated with protection, and removal of IL-17-producing cells enhanced recruitment of Th1 cells to the lung (71). A recent study by the same group highlighted the essential role of IL-17 in protective immunity against hyper-virulent Mtb strains (72). In addition, the magnitude of the Th17 response was found to be important, since mice repeatedly exposed to Mtb and BCG developed strong IL-23-induced Th17 cell responses that became pathogenic rather than protective, with an IL-17/macrophage inflammatory protein-2 (MIP-2) dependent influx of neutrophils and induction of lung pathology rather than containment of infection (73). Thus, balanced induction of Th1 and Th17 responses is essential to protective as opposed to pathologic immunity to TB, at least in mouse models. Similarly, in a monkey model of BCG-induced pro© 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd Immunological Reviews 264/2015 tection, balanced induction of Th1 and Th17 cells was observed in Mtb controllers and considered a correlate of protection (74). In TB patients, Th17 cells are present in the circulation during disease, with a phenotype of long-lived memory cells, constituting a considerable proportion of cytokine producing cells (75), although at the site of disease IL-17 was poorly detectable, while IL-22 was abundantly present (76). While the essential role of CD4+ T cells in TB is undisputed, other cells contribute importantly to effector immunity and immune regulation. Following the advent of HLA class I tetramer and bioinformatics technologies, CD8+ T-cell responses against Mtb could be characterized in more detail and epitopes and (multifunctional) cytokine profiles identified (77, 78). Most CD8+ T cells are considered to recognize Mtb antigens presented by classical HLA class Ia molecules, and these cells can produce multiple cytokines (78). In TB patients, IFN-c-producing Mtb-specific CD8+ T cells decreased rapidly during treatment in one study (79), while in another the frequency of Mtb peptide/HLA class Ia tetramer positive CD8+ T cells increased during the course of treatment (80). The reason for this discrepancy is not clear, but one possible interpretation is that Mtb-specific CD8+ T cells may not necessarily be fully functional in controlling infection or may not recover their functional capacities completely following successful chemotherapy of TB (81). Animal models have suggested that the magnitude of CD8+ T-cell responses may reflect the bacterial burden (82– 84) and that CD8+ T-cell-derived IFN-c and perforin are required for protection against disease (82–84). Non-classical T-cell immunity In addition to classical HLA class Ia molecules, Mtb antigens can also be presented to CD8+ T cells via non-classical, HLA class Ib molecules, such as CD1, HLA-E, and MR1. Mycobacterial lipid antigens can be presented by the CD1 family of antigen presentation molecules (85). T cells restricted by CD1a,b,c molecules are considered as adaptive T-cell responses, while CD1d-restricted type II NKT or iNKT cells are considered as innate T-cell responses. Mtb lipids presented by CD1 molecules are recognized by CD4+ T cells and induce cytokine production and cytolytic activity toward infected target cells (86). At present, it is unknown whether CD1 presentation of mycobacterial lipids is affected by comorbidities such as HIV or T2DM. However, increased frequencies of natural killer T (NKT) cells have been described in patients with TB-T2DM, suggesting that increased bacte- 125 Ronacher et al
HIV, diabetes mellitus, TB comorbidity rial loads in TB-T2DM may be reflected by enhanced NKT activation (87). Human CD8+ T cells that recognize Mtb peptides in the context of HLA-E can have cytolytic or regulatory capacities (59). Although not yet formally investigated, antigen presentation through HLA-E may not be affected by concomitant HIV infection as much as HLA class Ia presentation, since HIV-nef cannot bind to the HLA-E intracellular domain, which is required for downregulation of HLA class Ia molecules (88). Other non-classically restricted CD8+ T-cell subsets include T cells restricted by the MHC-related molecule 1 (MR1), called MAIT cells (mucosal associated invariant T cells), that are characterized by the expression of the semi-invariant Va7.2 T-cell receptor (89). Intriguingly, MAIT cells possess anti-microbial activity and can be activated by many different bacteria, including mycobacteria and yeast but not viruses (90). MR1 presents vitamin metabolites, mostly vitamin B products, from vitamin biosynthetic pathways that are unique to bacteria and yeast, and MAIT cells seem to utilize these metabolites to detect infected cells (91). The frequency of MAIT cells decreased during active TB disease, possibly due to their migration to the site of disease (89, 90). Specific MAIT cells can be activated by Mtb-infected lung epithelial cells (92), an interaction that appears to be ligand-specific due to selected TCR usage (93). Specific analysis of MAIT cells using the lineage marker CD161HI has suggested that these cells are decreased in patients infected with HIV, in the absence or presence of Mtb (94). MAIT cells have not yet been studied in T2DM or in TB-T2DM co-infection settings. B cells and myeloid cells Beyond T cells and macrophages, many other cells take part in the host response to TB. Recent global microarray studies from blood samples of TB cases have identified robust signatures associated with myeloid cell activation, B-cell functions, and complement signals (95, 96). Indeed, B cells are important components of TB granulomas and locally secrete immunoglobulins, which may facilitate phagocytosis of Mtb (97–99). In addition to antibody-producing B cells, immunoregulatory B cells (Bregs) have been described, producing IL-10 and IL-35 (100, 101). Bregs are critical regulators of IL-17 production, which guides neutrophil recruitment (100–102), a prerequisite for the development of appropriate effector immunity but also a major component of TB immunopathology (103). Moreover, B cells in the absence of antibody production can modulate macrophages and thereby host effector immunity (104). Together, these data 126 indicate that B cells and Bregs may be more important regulators of the immune response to TB than hitherto appreciated, not necessarily only through secretion of antibodies but also through interacting with other immune cells. Macrophage infection by HIV attenuates IL-10 production, contributing to Mtb pathogenesis and to HIV virus propagation (105). In addition, HIV may perturb pH regulation of Mtb containing vacuoles within macrophages, possibly facilitating intracellular Mtb survival (40). Macrophage apoptosis is regulated by a number of different processes, including TNF-a concentration, which in TB-HIV is a critical regulator of macrophage apoptosis, and expression of HIV-nef which can inhibit macrophage apoptosis via inhibiting the TNF-a promotor region (106). In addition, HIV proteins may also interfere with autophagy, promoting initial stages but inhibiting maturation of phagolysosomes (107). Immunology of TB-T2DM comorbidity There seems to be a fundamental difference between the enhanced susceptibility of HIV patients and T2DM patients to TB. Although HIV-infected individuals are more prone to developing extrapulmonary TB (108), most studies have failed to show this for T2DM (6, 109). In contrast to HIV/ AIDS, the immunological basis for increased susceptibility of T2DM patients is still largely unknown, although some recent evidence exists that innate as well as adaptive immune responses are affected in T2DM patients. Dysregulation of the inflammasome and chronic inflammation, a immunological characteristic common to obesity and T2DM, may be involved in this increased susceptibility to TB (110). In relation to metabolic disorders and obesity, it has been shown that Mtb can also reside and persist in adipose tissues in a non-replicating state, evading recognition by the hostimmune system, and forming a reservoir for possible reactivation (111). Innate immune responses to Mtb during T2DM In Mtb-naive individuals, there is a growing body of evidence that macrophage function is altered during T2DM. These alterations range from decreased phagocytic and chemotactic activity to polarization toward alternatively activated macrophages (112–115). To assess innate responses to Mtb antigens in patients with T2DM, Restrepo et al. (116) collected monocytes from Mtb-naive T2DM patients and found reduced binding or phagocytosis of Mtb when compared to monocytes from healthy controls. This reduced © 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd Immunological Reviews 264/2015 Ronacher et al
HIV, diabetes mellitus, TB comorbidity association only occurred, however, at high concentrations of autologous serum and only with serum that had not been heat-inactivated, pointing toward a role for the serum opsonins C3b/iC3b. In a follow-up study, the same authors (117) showed that phagocytosis of Mtb via FccRs or complement receptors was reduced in T2DM patients with high levels of circulating HbA1c and that this was mediated by a functional defect in phagocytosis, rather than by a change in cell surface expression of FccRs or complement receptors. The authors speculated that this reduced phagocytosis was involved in delayed innate immune responses, which would also delay the onset of adaptive immune responses, and thus could contribute to enhanced susceptibility for TB in T2DM patients. The reduced binding of Mtb to T2DM monocytes (116) is consistent with the defective sentinel hypothesis postulated by Martinez and Kornfeld (2), who formulated two hypotheses, namely that during T2DM the Mtb-infected alveolar macrophages are either (i) impaired in sending signals for recruitment of lymphocytes (defective sentinel hypothesis) and/or (ii) that despite adequate signals a barrier for leukocyte transmigration into the airspace exist in patients with T2DM (2). In line with the increased inflammatory state of patients with metabolic syndromes, circulating concentrations of IL-18 are increased in T2DM patients and obese individuals. However, IL-18-dependent stimulation of monocytes from these individuals resulted in defective IFN-c production (118), suggesting the acquisition of partial IL-18 resistance. This could be explained by a significant reduction in the cell surface expression of the IL-18 receptor a and b chains by monocytes, which also resulted in reduced IFN-c production in response to microbial components (118). Although until now, no studies have systematically investigated innate immune responses to Mtb in latently infected individuals with and without T2DM, several studies have assessed monocyte/macrophage phenotype and function in active TB-T2DM comorbidity. The proportion of blood monocyte subtypes, notably classical (CD14++ CD16 ), and non-classical intermediate (CD14++ CD16+) + + (CD14 CD16 ) monocytes, did not differ between TB patients with and without T2DM, but T2DM patients’ monocytes expressed higher levels of CCR2 (119). This chemokine receptor plays an important role in migration of mononuclear cells to the lung and since the ligand of CCR2 (MCP1) is increased in the circulation of patients with T2DM, these monocytes may be actively retained in the circulation rather than traffic to the site of disease (119). © 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd Immunological Reviews 264/2015 Also at the site of TB disease, the lung, differences in alveolar macrophage phenotypes have been described that correlated with T2DM status. In T2DM patients with active pulmonary TB, alveolar macrophages had suppressed activation states as determined by reduced expression of activation markers and lower ROS production when compared to cells from TB patients without T2DM (120). These results are in agreement with studies on alveolar macrophages of hyperglycemic rats (121). The potential impact of hyperglycemia and T2DM on innate cell types other than macrophages has not been investigated yet in the context of TB or Mtb infection. However, there is evidence that neutrophil function is compromised in T2DM, with reduced chemotaxis and phagocytosis as well as reduced anti-microbial activity (122, 123). In contrast to the suppressive effects of T2DM on macrophage and neutrophil functions, T2DM has been shown to increase myeloid dendritic cell activation (124, 125). Whether this also holds true during Mtb infection and TB disease remains to be established. Our own unpublished results show that T2DM patients have significantly lower numbers of circulating NK cells (CD16+ CD56+) compared to healthy controls. Similarly, T2DM patients suffering from TB have lower NK numbers than TB patients without T2DM comorbidity (Ronacher, Walzl and the TANDEM Consortium, unpublished data). Reduced numbers of NK cells could contribute to the increased susceptibility to Mtb infection as well as TB disease. Although there is substantial evidence that the initial interactions between Mtb and innate immune cells such as macrophages are critical in controlling infection, detailed knowledge on qualitative and quantitative alterations in these initial steps of host defense during infection and how these may be perturbed by comorbidities such as T2DM are extremely scarce. Future research is needed to understand innate immunity in the context of infection and host metabolic perturbation. Adaptive immune responses during T2DM comorbidity Although several studies have investigated adaptive immunity in active TB-T2DM comorbidity, few studies have examined alterations in adaptive immune responses to Mtb in T2DM patients with latent TB infection (LTBI). A recent study by Kumar et al. (126) found diminished type 1 and type 17 cytokine responses in individuals with LTBI and T2DM compared to healthy individuals with LTBI. These findings were surprising, as it is generally accepted that T2DM is characterized by an increase in production of 127 Ronacher et al
HIV, diabetes mellitus, TB comorbidity pro-inflammatory cytokines from adipose tissue and elevated circulating pro-inflammatory cytokines compared to healthy controls (127). As described below in more detail, the same authors found elevated type 1 and type 17 circulating cytokines in active TB patients with T2DM compared to TB patients without T2DM (128). Additional studies in latently infected T2DM patients are necessary to further investigate this discrepancy. During active TB disease, the induction of chronic hyperglycemia resulted in a delay in IFN-c production and in fewer Mtb antigen-specific T cells within the first month postinfection in a murine study (129). However, after 2 months the concentrations of pro-inflammatory cytokines were higher in the lungs of hyperglycemic mice, possibly as a result of the higher bacterial burdens at that point in time. This suggests that hyperglycemia leads to a delay in the initiation of the adaptive immune response and that the host attempts to compensate for the lack of initial immune control by increased production of pro-inflammatory cytokines in response to the increased bacterial loads. In diabetic guinea pigs, Mtb infection also resulted in more rapidly progressing TB disease, with severe pathology and a high bacterial load (130). The immune response of these guinea pigs was characterized by a strong pro-inflammatory response, including production of IFN-c, IL-17A, and TNF-a (130). Active TB-T2DM comorbidity is associated with elevated frequencies of Th1 and Th17 cells and cytokines in humans (65, 128, 131). Patients with TB and T2DM had highly elevated circulating levels of pro-inflammatory cytokines (IL-1b, IL-18), type 1 (IFN-c, TNF-a, IL-2), type 17 (IL-17A), as well as type 2 (IL-5, IL-10) cytokines but decreased circulating levels of IL-22 (128). Interestingly, IL-22 has recently been shown to inhibit growth of Mtb by mediating enhanced phago-lysosomal fusion (132), and Th22 cells have been implicated in protection against TB (75). Plasma concentrations of IFN-c, TNF-a, IL-17A, and IL-10 were highly correlated with HbA1c levels, in agreement with the notion that chronic inflammation in T2DM contributes to poor glycemic control (128). The same authors also measured antigen-specific cytokine production in supernatants of QuantiFERON-TB Gold In Tube (QFT) assays; the production of IFN-c, IL-1b, and IL17A was significantly higher in TB patients with T2DM compared to TB patients without T2DM. These results, however, are in contrast to a study by Gan et al. (133), who found no such differences in quantitative QFT IFN-c responses in TB patients with and without T2DM. The reasons for this discrepancy are currently unclear, but this illustrates the need for further studies into 128 the dysregulation of adaptive immune responses in TB-T2DM comorbidity. A cross-sectional study from Tanzania reported that T2DM was associated with lower levels of Mtb-specific IFNc responses as determined by QFT assay and that the validity of the QFT Gold assay is questionable in T2DM patients. This observation was made in both active TB patients as well as non-TB controls (134). Interestingly T2DM did not affect the non-specific mitogen response in this study. This report however contradicts other studies, which show that T2DM is not associated with decreased Mtb-specific responses (135) but is associated with decreased non-specific responses (136). In fact, in whole blood stimulation assays with the complex Mtb antigen PPD (purified protein derivative) T2DM patients with TB produced higher levels of IFNc compared to non-diabetic TB patients (137). Although this might appear counter-intuitive, as T2DM patients are more susceptible to TB, the increased IFN-c production might again reflect the increased bacterial burden, as was observed in the diabetic mouse model (129). The mouse study also showed an initial decrease followed by an increase in IFN-c production, and therefore the timing of sampling could play a major role in explain these inconsistent results. Restrepo et al. (137) have hypothesized that downstream signaling cascades of Th1 and innate immune response cytokines might be dysfunctional due to protein modification by advanced glycation end products. They found that not only IFN-c levels were increased in T2DM patients in response to PPD but also that higher concentrations of TNF-a, GMCSF, and IL-2 were associated with T2DM and high HbA1c values. Furthermore, elevated IL-1b levels were associated with high HbA1c values. The results from this study thus suggested that in patients with T2DM both innate and type 1 cytokines but not type 2 cytokines are upregulated in response to stimulation with PPD. The increased levels of pro-inflammatory cytokines such as IFNc in patients with TB-T2DM suggests that while antigen-specific T-cell responses in TB-T2DM may be quantitatively greater, they are functionally not more effective than those in non-diabetic TB patients (2), presumably because the net balance of protective versus detrimental responses in T2DM is perturbed toward the latter. In the circulation of patients with TB-T2DM, decreased numbers of natural Tregs have been described, which might be a contributing factor to the increase in Th1 and Th17 responses (65). In contrast, T cells with a Treg phenotype were increased at the site of disease in patients with concomitant TB and T2DM, which was accompanied by © 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd Immunological Reviews 264/2015 Ronacher et al
HIV, diabetes mellitus, TB comorbidity enhanced IL-10 production and diminished levels of IFN-c, compatible with compromised effector immunity in the lungs of patients with TB-T2DM (138). This result suggests there may be compartmentalization of Tregs at the site of disease in TB-T2DM comorbidity. A schematic diagram summarizing alterations in T-cell and macrophage interactions during TB in HIV and T2DM is shown in Fig. 1. Biomarkers of TB disease: the impact of HIV and T2DM A number of groups have investigated diagnostic biomarkers of active TB disease. Gene expression profiles were determined in patients with TB compared to healthy controls, controls with other infectious or inflammatory diseases, or longitudinally during treatment (96, 139–145). Prominent signatures of TB disease were found to be associated with type I interferon signaling, a pathway classically allied with early responses in viral infections. A first global analysis of data from the various studies revealed a role for genes associated with B cells, myeloid cells and inflammation in active TB (95). Other recent studies identified changes in gene expression patterns when TB patients were treated; the signatures identified included genes associated with complement components and again B cells, both of which were not previously recognized as important in TB (96). In subsequent studies, biomarker signatures were identified that performed almost equally well in TB patients with or without HIV co-infection, both in infants and in adults (146, 147). While these studies were very well-designed and validated across different populations, no such studies have been published in TB-T2DM comorbidity cohorts. The effects of T2DM on host TB biomarker expression thus remain unknown and require urgent investigation. It will be of interest to see whether similar gene expression changes occur in patients with TB and DM and whether gene expression analysis can identify those requiring extended or additional chemotherapy. Fig. 1. Alterations in T-cell-macrophage interaction in response to Mtb induced by HIV and T2DM. Macrophage and T-cell responses to Mtb infection are composed of several critical steps, many of which are altered during concomitant HIV infection or by metabolic changes associated with T2DM. The most critical steps are depicted in this schematic representation and alterations described in T2DM (red arrows) and HIV (green arrows) infected patients are indicated for each step. Opposing arrows indicate conflicting literature on this factor. AGE, advanced glycation end products; PRR, pattern recognition receptors; MF, macrophage; ROS, reactive oxygen species; GSH, glutathione (reduced); Mtb, M. tuberculosis; NK, natural killer. © 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd Immunological Reviews 264/2015 129 Ronacher et al
HIV, diabetes mellitus, TB comorbidity Possible role of host genetics in TB-T2DM comorbidity Genetic risk loci for combined TB and T2DM comorbidity have not yet been defined, but genome-wide association studies (GWAS) are underway to try to identify these (148). However, many studies have analyzed genetic loci associated with T2DM in different cohorts and a meta-analysis of the initial findings was recently performed (149). Several loci were found to harbor multiple independent T2DM association signals, indicating the likely regulation of several independent pathways. A total of 38 loci were identified to be associated with T2DM in a study published in 2010 (149). A future challenge is to relate these associated loci to causal genes and gene-products as well as to decipher underlying biology, particularly because most associated loci were located outside annotated genes and their possible effects on closely located genes yet have to be determined (loci are frequently named after the gene located closest to the associated locus, but these are not necessarily the genes affected). In particular cases, a combination of biology, phenotypic, and expression data suggested a subset of candidates to be the prime responsible target of the susceptibility effect (149). Candidate genes proposed included HNF1A, HMGA2, and KLF14; however, the specific variants will have to be characterized further. More recent meta-analyses of independent cohorts have yielded another eight loci associated with T2DM risk, most of them being directly linked to glucose or insulin metabolism (150). Another seven novel loci were associated with risk for T2DM independent of ancestry (151). SLC16A11 was also identified as a risk factor for T2DM; SLC16A11 is a solute carrier, transporting monocarboxylates across the plasma membrane and has been associated with lipid metabolism in the liver which might be a mechanism contributing to T2DM (152). A recent study in Greenland found a strong association between T2DM and a nonsense, hypo-functional variant of the gene TBC1D4 (153, 154). Several GWAS studies have been performed also in TB (155–159), because there is a genetic component to TB susceptibility (160, 161). Associations with TB have been reported for genes involved in innate immunity [e.g. SLC11A1/NRAMP, TNF, IL-10, IL-1-receptor antagonist, ALOX5, LTA4H (162), TLR8 (163), VDR, and IGRM (164)]. Moreover, associations with regions on chromosome 11p13 (156) and 18q11.2 (155) have been identified, but no clear association with specific genes or gene functions could thus far be ascribed to these genetic loci, 130 although the 11p13 locus is just downstream of the Wilms’ tumor-1 gene, a gene regulating the vitamin D receptor and IL10 pathways, both involved in the pathogenesis of TB and likely also T2DM (156, 161). Moreover, eight loci have been identified that are closely linked to genes involved in immune signaling (157). A number of candidate loci have been associated directly to T2DM or TB, but aside from the VDR, so far no shared loci have been identified. This could also be due to population confounding, as in general the populations studied for T2DM and TB susceptibility factors are geographically quite distinct. New cohorts therefore need to be built to study these important issues, which for example are being undertaken by the TANDEM consortium (148). These cohorts thus should be focused in regions where T2DM and TB are increasingly common, such as in several Asian and African countries. An important further issue will be the interactions between host and pathogen genetic determinants, for which some evidence has been presented recently (165, 166). It is hoped such studies will provide new insights that can improve our understanding of this enigmatic comorbidity, and could be translated into preventive or therapeutic interventions for these diseases. Other underlying factors contributing to susceptibility to TB The role of vitamin D A further intriguing link between TB, HIV, and T2DM is through the vitamin D pathway, which appears crucial in TB-HIV pathogenesis and is also important in TB-T2DM pathogenesis. HIV disease progression occurs more easily in the presence of low vitamin D levels, and HIV modulates vitamin D metabolism, resulting in decreased availability of vitamin D in vivo (167). Moreover, both TB and HIV treatment can interfere with vitamin D concentrations, and alter vitamin D metabolism in the context of TB-HIV co-infection (167). Conversely, vitamin D can promote autophagy and infection control during TB-HIV co-infection, further supporting a central role for vitamin D in the response to both pathogens (168). Vitamin D can also restore HIV-disturbed macrophage TNF-a production following Mtb infection, partly depending on the expression of CD14 on macrophages (51). Alveolar macrophages from HIV-infected individuals are deficient in Mtb stimulated TNF-a production, and BAL cells from HIV-infected individuals are severely vitamin D deficient, further indicating that vitamin D is critical for both innate and adaptive immunity to Mtb, particularly in TB-HIV co-infection (51). © 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd Immunological Reviews 264/2015 Ronacher et al
HIV, diabetes mellitus, TB comorbidity Interestingly vitamin D appears to be a common denominator between susceptibility to TB and T2DM. Low serum vitamin D levels are associated with insulin resistance and T2DM (169), and it is well known that vitamin D deficiency predisposes to TB. Lopez-Lopez et al. (170) have demonstrated that vitamin D supplementation promotes anti-mycobacterial activity in macrophages from T2DM patients. T-cell-derived IFN-c requires vitamin D to stimulate macrophage to exert autophagy, phagosome maturation, and anti-microbial activity (171). Thus, vitamin D is required for innate and adaptive immunity to drive macrophage dependent anti-microbial activity. At the same time, a novel role for vitamin D in regulation of host lipid metabolism has been described, whereby vitamin D abrogates Mtbinduced formation of lipid droplets required for Mtb growth in macrophages (172). Regulation of vitamin D receptor expression as well as circulating vitamin D levels are thus critical for efficient control of Mtb, but concomitant T2DM may further impair this pathway in TB by affecting receptor expression. Patients suffering from concomitant TB and T2DM may therefore display further reduced anti-microbial activity due to combined reduced receptor expression as well as reduced vitamin D levels. In depth analysis of vitamin D regulation and its downstream effector mechanisms should be performed in patients suffering from TB-T2DM comorbidity, to explore possible therapeutic options. Advanced glycation end products Prolonged poor glucose control leads to glycation on amino groups, resulting in the formation of highly glycated proteins. These excessive glycation end products can disrupt C-type lectin function via competitive inhibition of carbohydrate binding (173), thus possibly contributing to poor innate responses to mycobacterial infections. Glycated proteins can undergo further modification such as oxidation, leading to the formation of so-called advanced glycation end products (AGEs), which can then bind to the receptor for advanced glycation end products (RAGE). Although binding of AGE albumin to RAGE on neutrophils enhanced phagocytosis of Staphylococcus aureus it inhibited reactive oxygen production and killing (174), thus demonstrating that engagement of RAGE can impair neutrophil function. It has also been speculated that elevated glucose concentrations in human airway epithelial cells together with blood glucose could promote growth of S. aureus and therefore increase the susceptibility of T2DM patients to respiratory infections (173). © 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd Immunological Reviews 264/2015 Glutathione deficiency Glutathione, a major redox regulator, exists in a reduced (GSH) and an oxidized (GSSG) form. Patients with T2DM are characterized by a deficiency in intracellular GSH concentrations leading to impaired IL-12p70 and thus impaired IFN-c production in Burkholderia pseudomallei or Mtb-infected PBMCs (175). Production of other cytokines including TNFa, IL-1b, and IL-18 was not impaired in cells from T2DM patients. Gene expression profiles of both melioidosis (caused by Burkholderia pseudomallei) and TB patients were identical, implying shared host responses to both pathogens (176). Addition of GSH restored both IL-12p70 and IFN-c production and improved bacterial containment in B. pseudomallei and Mtb-infected cells (175). To establish a direct causal link between GSH deficiency and susceptibility to B. pseudomallei, the authors depleted GSH in infected mice, which resulted in increased susceptibility to experimental melioidosis (175). GSH supplementation has previously been shown to improve Mtb control in a mouse model via a direct cytolytic effect of GSH on the bacteria as well as enhanced NK cell and Th1 cell activation (177). These results suggest a protective role for glutathione in host defense to bacterial pathogens, which is impaired inT2DM. Diabetes drugs and anti-retroviral therapy Few studies have investigated whether medication for diabetes is in any way associated with impaired immune responses to pathogens. Glibenclamide is a commonly used anti-diabetic drug, which increases intracellular calcium and stimulates insulin release from b cells. However, this compound is also known to inhibit the assembly of the inflammasome (178). In a recent study, glibenclamide was shown to impair IL-1b and IL-8 production by polymorphonuclear cells (PMNs) infected with B. pseudomallei in a concentration-dependent manner (179). This effect was specific to pharmacological doses of Glibenclamide and did not occur if PMNs were stimulated with metformin. In fact, treatment of neutrophils with metformin improved phagocytosis and bacterial killing in vitro as well as eradication of bacteria in a mouse model of peritonitis-induced sepsis (180). A recent study (181) found that metformin treatment reduced inflammatory lung pathology and M.tuberculosis outgrowth in mice. This effect was dependent on metformin mediated AMPK activation. Metformin induced reactive oxygen species, enhanced phagolysome fusion and inhibited the production of pro-inflammatory cytokines. Moreover, the data suggested that pulmonary lesions were 131 Ronacher et al
HIV, diabetes mellitus, TB comorbidity less extensive in TB patients using metformin compared to other DM drugs. Drugs used for the treatment of HIV, including protease inhibitors and non-nucleoside reverse transcriptase inhibitors, may contribute to the induction of insulin resistance and dyslipidemia (12). The incidence and severity of TB may thus be influenced not only by co-infection with HIV or by concomitant T2DM but also by therapy, reflecting a more complex triangular relationship than hitherto anticipated, and one that requires further investigation (12). Recommendations for a research agenda to combat HIV, diabetes, and TB comorbidity For TB patients, the standard Directly Observed Therapy Short Course (DOTS) is less effective at treating TB in those with T2DM, with increased treatment failure, relapse, and death (182). This raises both pharmacokinetic and immunological questions. Are TB drug concentrations high enough in patients with T2DM? Do metabolic changes in T2DM or the drugs used to control T2DM affect the blood concentrations and metabolism of TB drugs? Little is known about the optimal management of patients diagnosed with both diseases. For instance, good glycemic control, which may be important for TB treatment outcome, is difficult to achieve in T2DM patients who also have TB, due to inflammation, drug–drug interactions, and other factors (15). As TB and T2DM show significant comorbidity, bi-directional screening should be performed. Although this has been recommended (9), it has not yet been implemented, in contrast to the situation with TB and HIV where clinical review and testing for both conditions is much more common. For TB and T2DM, the research agenda set by the International Union against Tuberculosis and Lung Diseases and WHO working group has been a key driver in raising awareness, particularly within the research community (183). The need to screen TB patients for T2DM and T2DM patients for TB is highlighted in the priorities identified by the Working Group (183). This absence of joint screening for TB and T2DM is a result of a number of factors but includes health systems issues (15). Implementing T2DM services in a TB clinic and vice versa is complicated by logistical and technical issues, but large studies in India (184) and China (185) have shown that such screening can be done. Ongoing multicenter studies in Indonesia, Peru, South Africa, and Romania through TANDEM (www.tandem-fp7. eu) will help define optimal screening algorithms (148). The cost effectiveness of introducing bi-directional screening also requires analysis, as highlighted in the publication by 132 Harries et al. (148), and the TANDEM Consortium is carrying out some cost effectiveness analysis in Indonesia, Peru, and Romania. Many immunologists working on infectious diseases have ignored the relation between metabolic processes and the immune response, and this has only been changing very recently with the advent of metabolomics (186). It is still unclear what exactly causes the impaired innate and adaptive immune responses in TB and T2DM comorbidity and whether these innate and adaptive immune perturbations mainly occur due to chronic hyperglycemia or involve other contributing factors, which also play a role in well-managed T2DM. The impaired innate immune responses further delay the initiation of the adaptive immunity allowing a build-up of increased Mtb bacterial mass following infection. The resulting imbalanced inflammation may contribute to this further. Taken the important role of vitamin D in both TB and T2DM into account, an in depth analysis of vitamin D regulation and its downstream effector mechanisms should be performed in patients suffering from TB-T2DM comorbidity to explore possible therapeutic options. The bi-directional links between innate and adaptive immunity are also receiving much more attention, with a greater appreciation of the complexities of inflammatory processes in TB (187). There is also greater appreciation of the metabolic reprogramming that occurs in lymphocytes upon activation (188, 189), and it has become evident that a combination of genetic and metabolic approaches are a useful tool to identify risk of T2DM (190). The reasons for the significant discrepancies in adaptive immune findings in TB-T2DM comorbidity are currently unclear. This illustrates the need for further carefully planned and harmonized studies into the dysregulation of adaptive immune responses in TB-T2DM comorbidity. Confounders such as sampling time or sample handling differences or other variations in immune assay-based protocols should be ruled out to allow cross-comparisons of the results in different settings. It is still largely unexplored whether the immune dysregulation associated with T2DM alters vaccine efficacy, as impaired antibody function has been reported for some vaccines (191, 192) but not others (193). Although HIV infection clearly enhances the risk of BCG-osis in infants, which resulted in a WHO recommendation to withhold BCG vaccination in such infants, T2DM obviously does not affect neonates or infants. However, booster vaccines with newly developed TB subunit vaccines administered later in life should take into account the impact of T2DM and metabolic © 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd Immunological Reviews 264/2015 Ronacher et al
HIV, diabetes mellitus, TB comorbidity alterations. Future TB vaccine trials in adult cohorts with significant T2DM prevalence should investigate the impact of glycemic control on vaccine immunogenicity and eventual efficacy. The delay in priming of the adaptive immune responses during T2DM due to delayed activation and migration of myeloid cells to the lung and draining lymph nodes (194) might be targeted specifically by novel vaccination strategies, e.g. through mucosal targeting vaccines that stimulate local cell migration and priming (16). It needs to be determined whether any putative TB biomarkers for diagnosis as well as treatment response, irrespective of whether these are host-immune markers or transcript signatures, are also applicable in a T2DM background, particularly since there is accumulating evidence that host pathogen interactions are altered during TB-T2DM comorbidity. The fact that signatures have been developed that are diagnostic for adult and pediatric TB in the presence or absence of HIV infection, however, give rise to optimism in this respect (147). HIV and T2DM impact negatively on gains made in the fight against TB, but they also give rise to the opportunity to improve our understanding of the multifaceted nature of protective immune responses against Mtb, especially as these conditions increase susceptibility to TB through different immunological mechanisms. Although HIV-TB comorbidity has rightly attracted substantial attention from the clinical and basic immunology research communities with significant and successful interventions implemented at health systems level, we cannot afford to neglect the new threat facing TB control, which presents itself in the form of a rapid increase in T2DM, particularly in areas that are already hardest hit by the TB epidemic. 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