Mycobacterium tuberculosis is a leading cause of mortality worldwide and establishes a long-lived latent infection in a substantial proportion of the human population. Multiple lines of evidence suggest that some individuals are resistant to latent M. tuberculosis infection despite long-term and intense exposure, and we term these individuals ‘resisters’. In this Review, we discuss the epidemiological and genetic data that support the existence of resisters and propose criteria to optimally define and characterize the resister phenotype. We review recent insights into the immune mechanisms of M. tuberculosis clearance, including responses mediated by macrophages, T cells and B cells. Understanding the cellular mechanisms that underlie resistance to M. tuberculosis infection may reveal immune correlates of protection that could be utilized for improved diagnostics, vaccine development and novel host-directed therapeutic strategies.
Through a long coevolutionary history with humans, Mycobacterium tuberculosis has developed into a highly successful pathogen that infects 23–32% of the world population1,2 and tuberculosis (TB) is the leading infectious cause of death3. Following aerosol exposure to M. tuberculosis, three potential clinical outcomes are possible, namely, resistance or early clearance of the bacillus, asymptomatic or latent M. tuberculosis infection (LTBI) that can persist for decades, or symptomatic ‘active tuberculosis’, which includes pulmonary disease that can result in further transmission. Recent whole-blood transcriptomic profiling4,5 and advanced lung imaging modalities6 have provided new insight into the transition from subclinical to active TB7,8. However, why some heavily exposed individuals never acquire, or perhaps immediately eliminate, infection is poorly understood.
No reliable test exists that directly detects the presence or absence of M. tuberculosis in asymptomatic individuals. The purified protein derivative (PPD) skin reactivity test measures delayed-type hypersensitivity to mycobacterial antigens and has been the gold standard for the diagnosis of LTBI for >100 years9,10. As PPD is enriched for protein antigens11 that are not necessarily specific to M. tuberculosis, prior immunization with Mycobacterium bovis Bacillus Calmette–Guérin (BCG) or exposure to non-tuberculous mycobacteria can yield false positive results. IFNγ release assays (IGRAs) were developed as a whole-blood diagnostic test that measures IFNγ release from M. tuberculosis-antigen-specific CD4+ T cells after stimulation with two to three specific M. tuberculosis antigens and thus avoids false positive results from prior BCG vaccination8. In the absence of a direct measure of infection, the best surrogates for initial infection are the PPD skin reactivity test and/or IGRA responses that convert from negative to positive (that is, incident positive) after M. tuberculosis exposure.
In endemic TB settings, some adults who are heavily and repeatedly exposed to M. tuberculosis remain negative for reactivity in the PPD test and the IGRA. These individuals, whom we term resisters, can be defined clinically as resistant to infection (Fig. 1). However, as this designation includes several assumptions about exposure and the stability of the results of these diagnostic tests, we propose the following enrolment criteria for studies of resisters (Box 1). First, a high level of exposure is crucial and should include indices of exposure intensity (for example, high bacillary load of a known index case and close proximity of contact, such as sharing a room or bed) as well as indices of exposure duration that capture cumulative exposure (for example, repeated household exposures or employment in settings of documented high M. tuberculosis transmission), all of which can be assessed using validated exposure risk scores12,13. Second, diagnosis of a resister requires a negative result for both the PPD skin reactivity test and the IGRA to avoid misclassification. Third, these diagnostic tests should be carried out serially following documented exposures to capture any conversions to LTBI (or TB). The resister phenotype is probably heterogeneous and might involve innate immunological mechanisms of early clearance of M. tuberculosis (innate resisters). Alternatively, protective immunity might also occur through adaptive immune responses (adaptive resisters), including IFNγ-independent responses that have been measured in preclinical models14,15,16, and thus a potential role for B cell or unconventional T cell responses in early clearance of M. tuberculosis should be considered. Longitudinal, rigorous epidemiological studies of resisters, together with data from genetic and immunological platforms, are providing new insights into human resistance to M. tuberculosis infection.
In this Review, we describe the epidemiology of the resister phenotype and discuss several caveats about the definition of a resister. Next, we review the genetic determinants of the resister phenotype and discuss potential effector mechanisms in macrophages, unconventional T cells and B cells. We examine immune factors that prevent or limit M. tuberculosis infection in innate resisters or adaptive resisters, which could be harnessed for the development of host-directed therapies or more effective vaccines and adjuvants.
Despite the absence of a direct microbiological measure of M. tuberculosis in latent infection, historical and rigorous modern epidemiological studies suggest that resisters exist, although their estimated frequency varies in different studies.
Historical case–contact studies
Strong epidemiological evidence suggests that some individuals are naturally resistant to infection, even after heavy exposure to M. tuberculosis in closed environments. In 1966, all enlisted personnel and officers aboard the destroyer U.S.S. Richard E. Byrd were enrolled in a study after a 5 cm pulmonary cavity was detected (by radiography) in a crew member who suffered progressive respiratory symptoms for the prior 6 months aboard the ship17. Of the 308 at-risk enlisted crew members, 7 developed active TB, 6 of whom shared the same berthing compartment as the index case. Most crew members in this ‘high-burden’ compartment showed evidence of new infection (either active TB or an incident positive PPD), whereas seven crew members (~10%) were negative for the PPD skin test during the initial study and remained so at follow-up. Other studies, including an evaluation of nursing students in the pre-antibiotic era, also showed evidence of PPD-negative responses despite intense exposure to patients with TB (Table 1). A systematic review of household contact studies detected heterogeneity in resistance to infection, with an average of 50% of close contacts remaining uninfected18. However, these studies reveal substantial variability in PPD-conversion rates, which is consistent with unmeasured exposure variables. Not surprisingly, proximity and duration of contact with the index case as well as the infectivity of the index case (that is, bacillary burden) were predictors of PPD conversion.
The results of most early studies in hyperendemic conditions suggest that a minority of the population (5–50%) has the resister phenotype, and this variability probably reflects exposure intensity and the duration of follow-up17,19,20. However, the results of some studies suggest that rates of resistance are higher (for example, up to 70% of exposed individuals are resisters), even after periods of high exposure (that is, sleeping in the same bed or room) to the index case21,22,23,24. Importantly, most of these studies either had a short duration of follow-up or contained data that were difficult to accurately review by modern epidemiological standards. Finally, the strain of M. tuberculosis probably differed among the various studies and thus might affect transmission rates. For example, increased virulence and transmission might be one of several factors that are involved in the increased range and incidence of the lineage 2/Beijing strains of M. tuberculosis25,26,27.
The results of these early studies suggest that a resister phenotype exists, but the epidemiological methods that were used could not ensure high exposure and adequate follow-up to confirm the presence of clinical resistance to M. tuberculosis infection.
Contemporary cohort studies
Population studies of individuals in hyperendemic TB settings in the past 5 years have provided opportunities to examine resistance to M. tuberculosis infection. For example, among South African gold miners, exposure to silica dust and the congregate working, living and social conditions that are associated with mining contribute to the high level of ongoing M. tuberculosis transmission28,29. Mathematical modelling suggests that the annual risk of infection (that is, conversion in the PPD skin test) among gold miners is as high as 20%30. The prevalence of LTBI in these gold miners was estimated at 89%, and 13% (15/115) of HIV-negative participants showed no evidence of M. tuberculosis infection (that is, induration = 0 mm in the PPD skin test)31. In this extremely high-burden environment, any gold miners who remain persistently uninfected are likely resisters. According to mathematical models, the likelihood that a 40-year-old gold miner without evidence of M. tuberculosis infection (induration = 0 mm in the PPD skin test) is a resister is 93%, compared with only 22% among the general community32. Two prospective studies in South Africa are currently being carried out to identify HIV-uninfected or HIV-infected resisters who have been mining for ≥15 years, are 33–60 years of age, do not have evidence of past or active TB or silicosis and have neither a history of treatment for LTBI nor any non-HIV immunosuppressive conditions.
Few longitudinal studies of conversion in the PPD skin reactivity test or the IGRA in hyperendemic settings have incorporated extended follow-up periods. Uganda is a high-burden TB setting with a 3% annual risk of M. tuberculosis infection, as determined by PPD skin test and/or IGRA conversion33. LTBI is considerably more prevalent among household contacts than among community members, and consequently, there is a risk difference of 30% among adults34. In Kampala, Uganda, household contacts of index cases with culture-confirmed TB were evaluated for active TB and underwent PPD skin testing35. The annual incidence of new cases of culture-positive TB in this study was 740 per 100,000 individuals, compared with country-wide estimates of 159 per 100,000 individuals33. If an individual was negative in the PPD skin reactivity test at baseline ( <10 mm induration for HIV-negative individuals >5 years old, <5 mm induration for HIV-negative individuals ≤5 years old or <5 mm induration for all HIV-positive individuals), repeated PPD skin tests were carried out at 3, 6, 12 and 24 months after enrolment. Among the entire study cohort, 11.7% of adult close household contacts remained persistently negative in the PPD skin test throughout the two year follow-up12,36. Both the South African and Ugandan cohorts described here provide an opportunity to rigorously define the resister phenotype and explore its underlying cellular mechanisms.
Complexities of the resister phenotype
Given that the definition of a resister relies on epidemiological data and utilizes an indirect, immunological measurement of M. tuberculosis infection, it is likely that some resisters are misclassified. Several alternative hypotheses may explain the resister phenotype.
Despite meeting enrolment criteria as a household contact, an individual with a negative result in the PPD skin reactivity test may simply have had insufficient exposure, either from a low intensity of exposure (that is, a low bacillary burden in the index case, minimal contact with the index case or good ventilation within the household) or a short duration of contact with an index case. In the Ugandan study, a published modified epidemiological exposure risk score13, consisting of characteristics of the TB index case and the intensity of the contact with the index case, did not differ between resisters and individuals with LTBI12. This result suggested that all household contacts were highly exposed to M. tuberculosis. Participants in the Ugandan household contact study were re-contacted 8–10 years after the original study and were tested multiple times with IGRAs (3 assays over 3 years) and once with a repeat PPD skin reactivity test. Although they were not necessarily re-exposed within the same household in the interval since their initial enrolment as a household contact, all these individuals continued to live in areas of Kampala with high TB prevalence in which community exposure to M. tuberculosis might be substantial37,38,39. These data will further clarify the durability of the resister phenotype.
An alternative explanation for the resister phenotype is that persistently negative results in PPD skin reactivity tests or IGRAs are false negative results owing to the inherent limitations of an immunological definition of a clinical phenotype. Both PPD skin test and IGRA responses are incomplete measures of anti-mycobacterial immunity for a number of reasons. As discussed later, these LTBI diagnostic tests fail to detect the response of T cells that are specific for non-protein mycobacterial antigens via MHC-independent pathways, and IGRAs do not detect the response of antigen-specific T cells with alternative (that is, IFNγ-independent) cytokine-producing profiles40,41,42. T cell anergy could also cause false negative results in the PPD skin test. In the Uganda study, HIV-negative individuals were not more likely to be PPD-negative than HIV-positive individuals, for whom a positive PPD test was defined as induration >5 mm (ref.12). Furthermore, in recent follow-up studies, all resisters demonstrated reactivity to the mitogen positive control that was included in the IGRA methodology (W.H.B. and C.M.S., unpublished observation), suggesting that generalized CD4+ T cell anergy or depletion alone does not explain the resister phenotype. This does not rule out a contribution of pathogen-specific anergy, which has been observed in human lepromatous leprosy43.
Resistance to M. tuberculosis probably has a threshold, above which relative resistance can be overcome by a sufficiently high exposure. For example, in two landmark studies in the 1930s and 1940s in Norway and at the Philadelphia General Hospital, USA, the prevalence of LTBI among nursing students at matriculation was 45.3% (668/1,453)44 and 57% (366/643)45, respectively. At 3-year follow-up, however, 100% of students that were initially negative for the PPD skin test in both studies converted, and the majority of these negative-to-positive conversions occurred during the early stages of training. Considering these data, together with those from the contemporary studies discussed earlier, it is possible that repeated testing (for example, serial testing every 4 months with 2 doses45) and the use of tuberculin of non-standardized purity (for example, the two early studies were carried out before large-scale standardized preparations of tuberculin, such as PPD-S, became available in 1941) effectively sensitized some individuals in the absence of natural infection. Non-tuberculous mycobacterial infections are also known to produce false positive results in the PPD skin test in some populations, a response that could potentially be boosted by serial PPD testing, as was seen with M. tuberculosis infection46. Furthermore, the induration thresholds that were used for each method (Mantoux or von Pirquet) were not described in these studies. Nonetheless, the results of these pre-antibiotic era studies suggest that absolute M. tuberculosis resistance occurred at a low frequency in these populations.
Relative resistance to M. tuberculosis disease might also be a function of the infectious dose. The classical work of Lange and Chaussé showed that small droplets carrying one bacillus or a few bacilli are the effectors of aerosol transmission and that the vast majority of individuals with TB show only a single Ghon complex47,48. In natural infections, the frequency of exposure to M. tuberculosis is the most parsimonious surrogate for infectious dose, but how consistency of exposure is linked to innate resistance mechanisms is not known.
The epidemiological studies discussed above suggest that some individuals are resistant to M. tuberculosis infection, as defined by a persistently negative result in the PPD skin test and/or the IGRA, despite sustained high-level exposures over extended periods of time. Furthermore, these individuals fail to develop active TB over an extended follow-up period. Future research to uncover the mechanisms that are involved in resistance to M. tuberculosis infection will require detailed assessments of exposure to the bacillus to define the resister phenotype (Box 1). The true prevalence of resisters among individuals who have been exposed to M. tuberculosis is not known, but evidence from studies that assessed exposure variables and included longitudinal sampling suggest that the prevalence is <10%.
The cellular mechanisms that mediate M. tuberculosis resistance are unknown, although multiple susceptibility loci have been linked to or associated with the resister phenotype in genome-wide analyses.
Genetic basis of resistance to other pathogens
Genetic studies indicate that polymorphisms and mutations exist that are associated with resistance to some infections. For example, a 32 bp deletion in CC–chemokine receptor 5 (CCR5) in CD4+ T cells results in relative resistance to infection with R5-tropic HIV-1 and delays disease progression49. Similarly, mutations in the gene encoding fucosyltransferase 2 (FUT2), which is required for the cell surface expression of histo-blood group antigens (HBGAs; the receptors for norovirus), results in decreased HBGA levels on mucosal surfaces and thus prevents virus uptake and entry into epithelial cells. Consequently, individuals with these FUT2 mutations are completely (100% penetrant) resistant to Norwalk and other norovirus genogroups50,51. Atypical chemokine receptor 1 (ACKR1; also known as DARC and CD234) is the receptor on erythrocytes for Plasmodium vivax. Most west African individuals are homozygous for a promoter mutation that ablates ACKR1 expression in erythrocytes and, consequently, are resistant to P. vivax infection52. Although these examples show Mendelian inheritance (for example, single-gene-inactivating mutations that result in highly penetrant resistance), it is likely that complex polygenic inheritance patterns are important for resistance to other pathogens, including M. tuberculosis.
Genetic studies of purified protein derivative skin reactivity
Numerous lines of evidence, including results from twin53,54, Mendelian primary immunodeficiency55, genome-wide linkage56,57,58 and candidate-gene studies59,60, suggest that host genetics influences susceptibility to TB. Mendelian Susceptibility to Mycobacterial Disease (MSMD) is an immunodeficiency disorder in young children who are susceptible to disseminated BCG and non-tuberculous mycobacteria and who have mutations in the IFNγ and IL-12 signalling pathways55. Several studies also suggest that host genetic factors modulate resistance to M. tuberculosis infection. For example, the intensity of tuberculin reactivity after exposure to household contacts is correlated among siblings but not among unrelated children of the same household61.
In a genome-wide linkage analysis of the Ugandan cohort, suggestive evidence for a linkage of regions on chromosome 2q21–2q24 and chromosome 5p13–5q22 to the resister phenotype was detected57. These regions are distinct from the regions that are linked to protection from TB, suggesting that the genetic underpinnings of these two ends of the TB spectrum (that is, asymptomatic infection and clinical disease) are unique. In a low endemicity setting, a candidate-gene association study of individuals with or without LTBI who had close contact with an index pulmonary TB case reported that polymorphisms in Toll-interacting protein (TOLLIP) and Unc51-like kinase 1 (ULK1) were associated with LTBI susceptibility62,63. The specific roles of these proteins in the resister phenotype are discussed later.
Another genome-wide analysis assessed PPD skin test reactivity in M. tuberculosis-exposed South African individuals. This cross-sectional study measured rates of PPD-positivity both as a binary trait (that is, PPD = 0 mm versus >0 mm) and as a quantitative trait by measurement of skin induration (in millimetres)64. As a binary trait, a significant linkage signal that met the stringent genome-wide linkage cut-off was found at the TST1 locus on chromosome 11p14. Strikingly, in a later study of the same families, the TST1 locus was found to be genetically indistinguishable (at a resolution of 2–14 Mb) from a major quantitative trait locus (QTL) that controls tumour necrosis factor (TNF) production following stimulation of whole blood with either BCG alone or BCG plus IFNγ65. These findings indicate that a genetic determinant linked to TNF secretion in response to BCG and IFNγ might also determine PPD negativity, perhaps through TNF-induced microbicidal pathways. However, the genomic resolution around the TST1 locus in these studies was low (2–14 Mb), and this locus includes other genes besides TNF. When reactivity in the PPD skin test was measured in the same study as a quantitative trait (that is, the size of skin induration in millimetres), significant linkage was found with a second locus, TST2, on chromosome 5p15 (ref.64). This region of chromosome 5 overlaps with the region that was associated with the resister phenotype in the Ugandan cohort57. Although the TST1 locus was strictly linked to resistance to M. tuberculosis infection and invokes mechanisms that precede T cell priming, the TST2 locus might modulate T cell responses that govern the intensity of the response in the PPD skin test.
HIV-infected resisters, who have an increased likelihood of having inadequate adaptive immune responses owing to CD4+ T cell depletion, might be particularly dependent on innate immune mechanisms for resistance to M. tuberculosis. As HIV and TB are co-prevalent in Uganda and Tanzania, this hypothesis was tested in a genome-wide association study of PPD reactivity in HIV-infected individuals, which found that a locus on chromosome 5q31.1 was significantly associated with both binary (positive or negative in the PPD skin test; P = 1.22 × 10–8) and quantitative (induration in millimetres; P = 1.45 × 10–8) responses in the PPD skin test66. This region contains four genes, including the gene encoding IL-9, which is expressed and secreted by mast cells and T helper 2 (TH2) cells and was previously associated with bronchial hyper-responsiveness. Interestingly, an inverse relationship between the incidence of asthma and TB was reported67,68, suggesting that IL-9 and its pleiotropic effects on lung inflammatory responses protect against M. tuberculosis infection. Although IL9 is an intriguing possible resistance gene, the other genes in the 5q31.1 region may also have a role in resistance to M. tuberculosis. The study also replicated associations in the regions previously identified in HIV-negative resisters (on chromosomes 2, 5 and 11; discussed previously), including susceptibility loci near TST1.
Together, these results suggest that the resister phenotype has polygenic variance; that is, many individual genetic variants each with small individual effects contribute additively to the phenotype. Although evidence to support broad epistatic effects on infectious disease susceptibility is lacking, gene pair interactions have been described in genome-wide analyses of susceptibility to TB69,70 and leprosy71. Nonetheless, the substantial overlap in the loci that are associated with the resister phenotype or in the results of PPD skin reactivity tests that was detected in independent analyses argues that evolutionary pressure has selected variants that protect against the initial M. tuberculosis infection, at least in geographical regions that are hyperendemic for TB.
After inhalation, aerosolized M. tuberculosis must navigate multiple intrinsic barriers in the upper airways, including airway mucins and ciliated epithelial cells. The bacterium then encounters resident alveolar macrophages, which exhibit pro-inflammatory and anti-inflammatory responses and are uniquely positioned to have a key role in mediating early clearance of M. tuberculosis72,73,74. The effector functions of alveolar macrophages might be modulated by neutrophils through, for example, their formation of neutrophil extracellular traps; however, the role of neutrophils in both microbicidal and immunopathological activities is complex and is reviewed elsewhere75,76. M. tuberculosis is recognized by multiple pattern recognition receptors (PRRs) at the cell surface or within the phagosome or by cytosolic PRRs after phagosomal rupture77,78. Subsequently, the outcome of infection depends on effective phagosome acidification, phagosome–lysosome fusion, 6 kDa early secretory antigenic target (ESAT6) secretion system 1 (ESX1)-dependent escape of M. tuberculosis from the phagosome79, activation of the inflammasome (resulting in maturation of pro-IL-1β and pro-IL-18)78, upregulation of host genes that are either required for intracellular killing mechanisms (for example, reactive oxygen species, nitric oxide (produced by inducible nitric oxide synthase), cathelicidin antimicrobial peptide (CAMP)80 and autophagy) or detrimental to the host (that is, IFNβ production following intracellular sensing of M. tuberculosis DNA by cyclic GMP–AMP synthase (cGAS)81,82) and, ultimately, the activation of host cell death pathways (for example, pyroptosis, apoptosis and necroptosis)83,84. Resistance alleles could modulate a number of these airway clearance functions or macrophage antimicrobial mechanisms (Fig. 2).
Inflammatory signalling pathways
Genetic regulation of inflammatory pathways is well described85,86,87,88, and some studies have associated susceptibility to mycobacterial infections with polymorphisms in Toll-like receptor (TLR) pathway components89,90,91,92,93,94,95,96, regulators of TLR function97,98, C-type lectin receptors99, autophagy proteins100,101 and other pathways for pro-inflammatory cytokine production102. However, only some of these studies define functional polymorphisms (that affect TLR expression or signalling, for example), and the identified associations with clinical phenotypes require replication in other populations. Interestingly, patients with Mendelian primary immunodeficiency of myeloid differentiation primary response 88 (MYD88) or IL-1 receptor-associated kinase 4 (IRAK4), which are central to most TLR signalling pathways, do not develop mycobacterial diseases103. Furthermore, few human genetic studies have found an association of resistance to M. tuberculosis infection (as opposed to susceptibility to disease) with polymorphisms in genes involved in any of these cellular pathways. A recently discovered single nucleotide polymorphism (rs5743854) in the promoter of the gene encoding TOLLIP is an expression QTL for which the G/G allele is associated with lower TOLLIP expression in monocytes and with increased risk of LTBI, pulmonary TB and meningeal TB63. Although the specific mechanisms through which high TOLLIP expression contributes to M. tuberculosis resistance as well as to protection from disease are not known, the known role of TOLLIP in directing autophagy and its negative regulation of TLR2, TLR4 and IL-1 receptor (IL-1R) suggest that these pathways are mechanisms of resistance. Although replication of the genetic association findings in independent cohorts is needed, the studies discussed above suggest that resistance alleles exist and may be relevant to the resister phenotype.
Autophagy limits intracellular survival of M. tuberculosis and maturation of the mycobacterial phagosome104,105. An in vitro genome-wide screen identified autophagy factors as the host factors that were most influential in restricting the intracellular growth of M. tuberculosis106. The M. tuberculosis ESX1 secretion system is required for autophagy initiation through cGAS–stimulator of interferon genes (STING)-triggered recruitment of microtubule-associated proteins 1A/1B light chain 3 (MAP1LC3) to autophagosomes82,107,108, but ESX1 may also be involved in the impairment of autophagosome maturation109. Whether autophagy is involved in host protection versus virulence in the mouse model is controversial. Genetic deletion of the key autophagy factor Atg5 in mice results in more severe disease that correlates with both uncontrolled M. tuberculosis growth and exacerbated lung immunopathology110. However, this severe disease was later suggested to result from increased neutrophil recruitment in the autophagy protein 5 (ATG5)-deficient animals and not from defective autophagy111. Genetic variants within the autophagy pathway have been associated with TB in candidate-gene association studies100,101, but whether similar variants control LTBI risk is poorly studied. A recent candidate-gene association study found that two polymorphisms in ULK1, which encodes a component of an upstream protein complex that transduces signals to central autophagy effectors, were associated with LTBI in Asian contacts of index cases62. After adjustment for clinical risk factors for LTBI, each of these ULK1 minor alleles was estimated to confer an 80% reduction in LTBI risk. This result might be due to an improvement in selective autophagy, decreased M. tuberculosis replication or increased TNF secretion in response to TLR ligands, as suggested from mechanistic studies using ULK1-deficient cells62.
Monocyte gene expression and histone deacetylase pathways
One hypothesis to explain the resistance to M. tuberculosis infection in the Uganda study12 is that following infection, the expression profiles of blood monocytes from individuals with LTBI and resisters are distinct. In a comparative transcriptional profiling study, monocytes from each clinical group were infected ex vivo with M. tuberculosis112, and the microarray data were analysed with Gene Set Enrichment Analysis (GSEA)113 to identify host pathways that are associated with each clinical phenotype (resister and LTBI) according to curated gene sets from transcriptional databases. The gene set that was most significantly associated with the resister group was from a previous study of sodium butyrate-stimulated cells114. Sodium butyrate is a short chain fatty acid that inhibits histone deacetylases (HDACs), which modify chromatin and regulate cellular function, including signalling pathways115,116. Interestingly, phenylbutyrate, a class I HDAC inhibitor that is known to synergize with vitamin D to induce CAMP production and inhibit M. tuberculosis growth in macrophages117, has been tested as a potential host-directed therapy for pulmonary TB118. Activated vitamin D (1α,25(OH)2D3) binds to the vitamin D3 receptor (VDR), which translocates to the nucleus to induce expression of CAMP and drive other host processes, including autophagy and autophagosome–lysosome fusion80. CAMP has direct antimicrobial activity against M. tuberculosis in the phagosomal compartment80. Together, these data suggest that monocytes from resisters and individuals with LTBI respond differently to ex vivo M. tuberculosis infection. Targeting HDACs with inhibitors might provide a novel therapeutic option for M. tuberculosis infections; however, the specific mechanisms by which HDAC-dependent pathways are altered in resisters, and whether epigenetic mechanisms or ‘trained immunity’ are involved, are unknown.
T cell-mediated resistance
Several lines of evidence from human studies and animal challenge models underscore the importance of T cells in controlling M. tuberculosis infection119,120,121. HIV-infected individuals with low CD4+ T cell counts have increased risk of progressing from LTBI to TB. In addition, patients with MSMD have defects in the IL-12–IFNγ pathway and increased susceptibility to disseminated mycobacterial infections55. Furthermore, mouse models of acute M. tuberculosis infection have demonstrated the importance of IFNγ production in controlling bacterial replication and survival122. However, the source of IFNγ remains controversial, as its production by CD4+ T cells may be dispensable for control of M. tuberculosis infection in some mouse models14,15,16, whereas IFNγ production is essential in other mouse models123. Furthermore, IFNγ-producing CD4+ T cells have not emerged as an immunological correlate of protection from infection in humans, which suggests that this profile is important but is not sufficient for protection against M. tuberculosis infection124,125. In individuals with LTBI, MHC-restricted αβ T cells recognize a broad repertoire of MHC class I-restricted and MHC class II-restricted M. tuberculosis peptides and exemplify a classical TH1 cell-like response. Implicit in their definition, resisters lack reactivity in the PPD skin test or secretion of IFNγ by T cells following antigen stimulation, although, hypothetically, these individuals might have IFNγ-independent T cell responses that mediate resistance to M. tuberculosis or its clearance.
IFNγ-independent T cell responses
IFNγ-independent T cell responses to mycobacterial antigens have been described (Fig. 3). For example, Cambodian patients with pulmonary TB who remained anergic to PPD following treatment completion displayed tuberculin antigen-specific T cell responses in vitro that were characterized by the production of IL-10 rather than IFNγ126,127. IL-10, which is known for its anti-inflammatory role in mitigating TH1 cell responses to minimize the potentially deleterious effects of TNF and IFNγ, is mostly implicated in the immune response to TB, and no evidence exists for a protective role of IL-10 in the early stages of M. tuberculosis infection128. However, a genotyping study in Ghana found that individuals with the IL10 promoter haplotype with the highest association with low circulating levels of IL-10 were more likely to have TB or be PPD-positive than to be PPD-negative129. Whether high IL-10 levels in these individuals truly confer resistance to infection, as opposed to PPD-specific anergy in the presence of LTBI, remains to be determined.
Additional CD4+ T cell subsets, including TH17 cells, could contribute to the resister phenotype through IFNγ-independent mechanisms. In mice, the production of IL-17A, one of several TH17-related cytokines, recruits neutrophils and other inflammatory cells to the lung and is involved in granuloma maturation130. Adoptive transfer of BCG-specific TH17 cells harvested from immunized IFNγ-deficient mice into recipient V(D)J recombination-activating protein (RAG)-deficient mice gave these recipient mice a survival advantage when challenged with M. tuberculosis, which was comparable to that seen with transfer of TH1 cells from IFNγ-competent mice131. This IFNγ-independent partial protection provided by TH17 cells against M. tuberculosis was also seen in another adoptive transfer model132. Unlike IL-10, IL-17 is not known to directly interfere with IFNγ production, and whether these IFNγ-independent TH17 activities are relevant to the resister phenotype is unknown. However, taken together, these examples illustrate that despite having persistent negative responses in PPD skin reactivity tests and IGRAs, it is possible that resisters have other mycobacteria-specific MHC class I-restricted or MHC class II-restricted T cell responses.
Unconventional T cell responses
In addition to mycobacterial protein antigens, T cells also recognize non-protein mycobacterial antigens (Fig. 3). For example, T cells are activated by mycobacterial cell wall lipids that are bound to CD1 proteins, which are homologous to MHC class I molecules but are functionally non-polymorphic40,133,134. The human CD1 locus encodes four proteins (CD1A–CD1D) that are localized at the cell surface and present lipid antigens to T cells. In a cross-sectional study of South African adolescents with or without LTBI, there were low intra-donor correlations between T cell responses to protein and lipid antigens135, indicating that T cell responses to lipid antigens are not redundant with those to protein antigens and that the responses to the different antigens could be complementary. Immunity to lipid antigens could be primed by exposure in early life to non-tuberculous mycobacteria, which could facilitate clearance of M. tuberculosis following infection, thus limiting the initiation of peptide-specific T cell responses that are mostly responsible for producing a positive result in the PPD skin test. In addition, lipid-specific T cells could also be primed by vaccination with BCG. Functionally, T cells specific for mycobacterial lipids have been shown to have a TH1 cell cytokine-producing profile ex vivo, supporting their role in the clearance of M. tuberculosis-infected cells136.
The MHC class I-related gene protein (MR1) antigen-presenting molecule presents small molecules instead of peptides or lipids to T cells137 and is important for the development of mucosal-associated invariant T (MAIT) cells138,139,140. MAIT cells can kill M. tuberculosis-infected cells in an MR1-dependent manner41, and Mr1-knockout mice have a higher lung burden of M. bovis BCG than wild-type mice141. Furthermore, in candidate-gene association studies, MR1 and CD1 polymorphisms were associated with susceptibility to TB142,143. Finally, γδ T cells are a T cell lineage that express a heterodimeric T cell receptor and are activated by phosphorylated prenyl metabolites144,145. Vγ9Vδ2 T cells are activated by BCG-infected cells and can lyse BCG-infected target cells146.
Thus, in PPD-negative individuals, the CD1-specific, MR1-specific and γδ T cell populations might provide cellular immunity against M. tuberculosis that is independent of the IFNγ production by PPD-specific CD4+ T cells that defines LTBI. Further study is required to determine whether these other populations of T cells protect against M. tuberculosis infection in resisters or, alternatively, whether these T cells prevent progression of LTBI in individuals who are unable to produce IFNγ in response to M. tuberculosis antigens.
B cell-mediated resistance
Antibodies are powerful mediators of protective immunity against many infectious diseases, and stimulating their production is the goal of vaccination strategies147,148. In M. tuberculosis infection and disease, however, the role of humoral immunity is probably complex and remains unclear149,150. Passive transfer of antibodies has not consistently conferred protection151,152,153,154, and immunoglobulin G (IgG)-deficient individuals do not exhibit reduced control of bacterial infections155. By contrast, a post hoc analysis of the MVA85A vaccine trial found that elevated Ag85A-specific IgG titres correlated with protection against TB156. In addition, depletion of B cells in a non-human primate model of M. tuberculosis infection resulted in increased lesional bacterial burden157. Furthermore, in patients with active TB, B cell function is initially abnormal but returns to normal after successful treatment158,159. These observations highlight the immunoregulatory role of B cells in controlling M. tuberculosis infections, which extends beyond their direct antibody-mediated effector functions (Fig. 4).
Antibodies and latent Mycobacterium tuberculosis infection
Antibodies, plasma cells and antibody-responsive innate immune cells that express crystallizable fragment (Fc) receptors are abundant in M. tuberculosis granulomas160,161, indicating that these innate immune cells are actively recruited and might potentially contribute to antimicrobial activity162,163. Distinct Fc effector profiles were observed in individuals with LTBI versus those with active disease. Individuals with LTBI had improved antibody functionality that was linked to elevated binding to the low-affinity immunoglobulin-γ Fc region receptor III-A (FcγR3A)164, which is highly expressed by natural killer cells, neutrophils, mature macrophages and dendritic cells163. Furthermore, these antibodies not only improved innate immune cell activity but also contributed to the restriction of intracellular survival of M. tuberculosis in previously infected primary macrophages. Interestingly, this differential functional activity was not related to altered subclass selection but was instead related to substantial changes in antibody glycosylation among the M. tuberculosis-infected individuals164.
Antibodies and the resister phenotype
It is unclear whether antibodies contribute to the resister phenotype, but it is plausible that at the time of repeated M. tuberculosis exposure that pre-existing antibodies might direct the antimicrobial activity of macrophages, neutrophils or dendritic cells to eliminate the bacteria more effectively. Although in vitro studies indicate a limited role for antibody-mediated opsonophagocytic prevention of macrophage infection by M. tuberculosis, the addition of pooled IgG derived from individuals with LTBI to previously infected healthy donor primary macrophages can drive bacterial elimination by a process that probably involves activation of the inflammasome164. These results suggest that, in addition to their minor role in limiting initial infection through opsonization, antibodies ‘cure’ infected macrophages if they are present at the right time and place. Although the majority of healthy donor macrophages restricted M. tuberculosis survival in the presence of pooled IgG from individuals with LTBI164, the level of restriction varied by macrophage donor, which suggests that antibody-mediated killing of M. tuberculosis is also dependent on factors that are intrinsic to innate immune cells.
Thus, whether natural or affinity-matured humoral immunity exists among resisters is unknown, but humoral immunity might provide an exciting novel immunological axis that links the adaptive and innate immune responses to target and eradicate M. tuberculosis after exposure and warrants further exploration.
Conclusions and outlook
Historically, significant breakthroughs in treating infectious diseases have been made by studying mechanisms of resistance rather than susceptibility to infections. The most notable historical example is the observation that milkmaids exposed to cowpox were resistant to smallpox165. A more contemporary example is the HIV resistance of individuals with a variant of CCR5, CCR5Δ32 (refs166,167). Both these observations led to transformative therapeutic interventions — the smallpox vaccine and CCR5 inhibitors, respectively168.
For much of the past century, many investigators have postulated that some individuals are naturally resistant to M. tuberculosis infection in the face of intense exposure. However, a number of challenges have impeded the elucidation of potential resistance mechanisms, including the limitations of using an indirect immunological test to define the resister phenotype and the need to incorporate measurements of exposure intensity in study designs. Despite this, contemporary epidemiological evidence supports the existence of resisters. Genome-wide association analysis of data from independent studies has identified loci that are associated with resistance to M. tuberculosis infection. The elucidation of immunological and genetic mechanisms of the resister phenotype is at an early stage, but these studies might reveal heterogeneous protective responses that are relevant to different types of resisters. For example, macrophage-dependent pathways that prevent bacterial uptake or rapidly clear M. tuberculosis before the development of an adaptive immune response define innate resisters. Alternatively, adaptive resisters are individuals in which T cell and B cell effector functions eliminate or restrict M. tuberculosis infections, either independently of IFNγ production or through priming by non-protein antigens. Further study is required to clarify whether adaptive resisters have greater resistance to progression to active TB than individuals with traditionally defined LTBI; however, these studies could identify novel correlates of immune protection or aid current prognostic efforts to stratify those individuals who are most at risk of disease progression4,5.
Looking ahead, integrated research approaches using advanced epidemiological, genetic and immunological tools will be required to dissect mechanisms of resistance. In future studies, features of an optimally defined resister should incorporate several variables outlined in Box 1, including, first, indices of exposure (both intensity and duration) using, at a minimum, validated epidemiological risk scoring12,13; second, the use of both the PPD skin reactivity test and the IGRA to avoid misclassification bias resulting from discordant immunological tests; and third, longitudinal sampling for serial LTBI testing.
Epidemiological risk scores must include an assessment of the nature of contact between the index case or cases and the exposed individual (that is, whether the index case is the primary caregiver and the frequency and proximity of contact) and some assessment of infectivity of the exposure environment (for example, whether the index case is coughing, whether their sputum is smear-positive for M. tuberculosis and whether there are multiple index cases within a household or employment setting). Although not yet ready for practical implementation, more advanced assessments of infectious risk, such as aerobiological environmental sampling where transmission risk has been correlated with the degree of ventilation and with the number of viable bacteria sampled from cough aerosols, could be incorporated in future studies37,169,170.
Even in areas of high TB endemicity, some level of discordance exists between the results of PPD skin reactivity tests and IGRAs171. Consequently, individuals with discordant results in the PPD skin reactivity test and the IGRA are not categorized as resisters, although retaining clinical samples from these individuals is important to facilitate studies to better understand the mechanistic basis of this discordance. As the resister category might encompass multiple biological phenotypes, at this early stage in their characterization, we favour more stringent criteria to avoid misclassification, which justifies the increased expense and logistical complexity of implementing multiple testing modalities (PPD skin reactivity tests and IGRAs) and serial testing. Longitudinal sampling should include, at a minimum, multiple LTBI diagnostic tests in the year following initial exposure, as most but not all conversions occur in the first 3 months following exposure36. In circumstances in which resisters remain in regions of high M. tuberculosis transmission, follow-up testing may be warranted to ensure that any new conversions owing to community exposures are detected.
Advances in the past decade have transformed genetic methods and platforms, which now include affordable and standardized genome-wide detection of polymorphisms. These tools provide assessment of polymorphisms that are annotated in public databases. Whole-genome sequencing is also more affordable and can be used to examine resisters for unidentified polymorphisms that are not annotated in public databases. To address limitations in the availability of patient samples, new advances in stem cell work (for example, induced pluripotent stem cells derived from peripheral blood mononuclear cells) have made possible the creation of permanent cell lines from individuals, which can be differentiated into different cell types that are more relevant for studying M. tuberculosis pathogenesis (for example, alveolar macrophages). Finally, if M. tuberculosis cultures from index cases are available, comparisons of strain type, host phenotype (resister versus LTBI versus TB) and host genotype, as well as determination of whether transmission events are sympatric or allopatric172, are exciting avenues of investigation.
The integration of rigorous epidemiological phenotyping with mechanistic studies that investigate global immune pathways in macrophages, T cells and B cells, and how these pathways might differ between resisters and individuals with LTBI, should provide further biological insight into the mechanisms of early clearance or prevention of infection by M. tuberculosis. These potential biological mechanisms should provide targets for drugs and vaccines that could improve specific immune functions and improve therapeutic options for treating TB.
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This work was supported by grants from the US National Institutes of Health grants R01AI124348 (to W.H.B., T.R.H., C.S., C.M.S. and H.M.-K.), U01AI115642 (to W.H.B., T.R.H., C.S., C.M.S. and H.M.-K.), R01AI124349 (to E.S.) and T32AI007044 (to J.D.S.) and contract number NO1AI70022 (to W.H.B., C.M.S., T.R.H. and H.M.-K.); the Bill and Melinda Gates Foundation grant OPP1151836 (to T.R.H., W.H.B., C.S., C.M.S., H.M.-K., G.C. and R.S.W.) and grant OPP1151840 (to G.A. and S.F.); the Canadian Institutes of Health Research grant FDN143332 (to E.S.); and the South African Medical Research Council grant ACT4TB/HIV (to G.C. and R.S.W.). G.C. is also affiliated with the School of Public Health, University of Witwatersrand, Johannesburg, South Africa, and the Advancing Care and Treatment for TB/HIV, South African Medical Research Council, Johannesburg, South Africa. E.S. is also affiliated with the McGill International TB Centre, McGill University, Montreal, Quebec, Canada.
The authors declare no competing interests.
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- Purified protein derivative (PPD) skin reactivity test
A delayed-type hypersensitivity test that measures induration at the site of an intradermal injection of peptide extract from mycobacterial culture filtrate. A positive result reflects a pre-specified minimal diameter of skin induration and suggests the presence of latent Mycobacterium tuberculosis infection but may also result from non-M. tuberculosis sensitization, including prior vaccination with Mycobacterium bovis Bacillus Calmette–Guérin. Also known as the Mantoux tuberculin skin test (TST).
- Bacillus Calmette–Guérin
(BCG). A culture-adapted, attenuated Mycobacterium bovis strain that is used for vaccination against Mycobacterium tuberculosis.
- IFNγ release assays
(IGRAs). Whole-blood immune assays in which a patient’s blood is cultured in the presence of select antigens specific to Mycobacterium tuberculosis and the secretion of IFNγ is quantified. Positive results are independent of prior Bacillus Calmette–Guérin vaccination and negative results ensure a sufficient response to a mitogen positive control.
An individual who remains negative for the purified protein derivative skin reactivity test and the IFNγ release assay throughout serial testing despite heavy exposure to Mycobacterium tuberculosis.
- Innate resisters
Conceptually, resisters who immediately clear Mycobacterium tuberculosis following exposure to the bacterium and before priming of any adaptive immune responses.
- Adaptive resisters
Conceptually, resisters who clear or contain Mycobacterium tuberculosis infection via T cell and B cell mechanisms but who remain negative for the purified protein derivative skin reactivity test and the IFNγ release assay.
- Household contact
An individual who resides within the same domicile as an index case (patient with tuberculosis) for a pre-specified amount of time.
- Hyperendemic conditions
Regions in which ongoing Mycobacterium tuberculosis transmission is unusually high owing to an elevated prevalence of tuberculosis.
An occupational pulmonary disease that is prevalent among gold miners owing to protracted inhalation of silicate dust, which leads to scarring and increased Mycobacterium tuberculosis infection.
- Relative resistance
A threshold phenomenon in which mechanisms of host resistance to Mycobacterium tuberculosis infection may be overcome owing to frequent or lengthy exposure to contacts with a high bacillary burden.
- Ghon complex
The focus of primary Mycobacterium tuberculosis infection in the lung parenchyma that histologically corresponds to a granuloma and radiographically is recognized by its associated lymphadenopathy and calcification.
- Quantitative trait locus
(QTL). A genomic region containing polymorphisms that are associated with a quantifiable phenotype, such as the extent of induration (in millimetres) in the purified protein derivative skin reactivity test. When variation at these loci affect the expression levels of specific genes, they are referred to as expression QTLs.
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Simmons, J.D., Stein, C.M., Seshadri, C. et al. Immunological mechanisms of human resistance to persistent Mycobacterium tuberculosis infection. Nat Rev Immunol 18, 575–589 (2018). https://doi.org/10.1038/s41577-018-0025-3
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