Review Article | Published:

Immunological mechanisms of human resistance to persistent Mycobacterium tuberculosis infection

Nature Reviews Immunology (2018) | Download Citation

Abstract

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.

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References

  1. 1.

    Dye, C., Scheele, S., Dolin, P., Pathania, V. & Raviglione, M. C. Consensus statement. Global burden of tuberculosis: estimated incidence, prevalence, and mortality by country. WHO global surveillance and monitoring project. JAMA 282, 677–686 (1999).

  2. 2.

    Houben, R. M. & Dodd, P. J. The global burden of latent tuberculosis infection: a re-estimation using mathematical modelling. PLoS Med. 13, e1002152 (2016).

  3. 3.

    World Health Organization. Global Tuberculosis Report 2017. (WHO, 2017).

  4. 4.

    Thompson, E. G. et al. Host blood RNA signatures predict the outcome of tuberculosis treatment. Tuberculosis 107, 48–58 (2017).

  5. 5.

    Zak, D. E. et al. A blood RNA signature for tuberculosis disease risk: a prospective cohort study. Lancet 387, 2312–2322 (2016).

  6. 6.

    Esmail, H. et al. Characterization of progressive HIV-associated tuberculosis using 2-deoxy-2-[18F]fluoro-D-glucose positron emission and computed tomography. Nat. Med. 22, 1090–1093 (2016).

  7. 7.

    Barry, C. E. 3rd et al. The spectrum of latent tuberculosis: rethinking the biology and intervention strategies. Nat. Rev. Microbiol. 7, 845–855 (2009).

  8. 8.

    Pai, M. & Behr, M. Latent Mycobacterium tuberculosis infection and interferon-gamma release assays. Microbiol. Spectr. https://doi.org/10.1128/microbiolspec.TBTB2-0023-2016 (2016).

  9. 9.

    Mendel, F. Die von Pirquet’sche Hautreaktion und die intravenöse Tuberkulinbehandlung. Med. Klin. 4, 402–404 (1908).

  10. 10.

    Seibert, F. B. History of the development of purified protein derivative tuberculin. Am. Rev. Tuberc 44, 1–8 (1941).

  11. 11.

    Yang, H., Kruh-Garcia, N. A. & Dobos, K. M. Purified protein derivatives of tuberculin — past, present, and future. FEMS Immunol. Med. Microbiol. 66, 273–280 (2012).

  12. 12.

    Ma, N. et al. Clinical and epidemiological characteristics of individuals resistant to M. tuberculosis infection in a longitudinal TB household contact study in Kampala. BMC Infect. Dis. 14, 352 (2014).

  13. 13.

    Mandalakas, A. M. et al. Well-quantified tuberculosis exposure is a reliable surrogate measure of tuberculosis infection. Int. J. Tuberc Lung Dis. 16, 1033–1039 (2012).

  14. 14.

    Cowley, S. C. & Elkins, K. L. CD4+ T cells mediate IFN-gamma-independent control of Mycobacterium tuberculosis infection both in vitro and in vivo. J. Immunol. 171, 4689–4699 (2003).

  15. 15.

    Sakai, S. et al. CD4 T cell-derived IFN-gamma plays a minimal role in control of pulmonary Mycobacterium tuberculosis infection and must be actively repressed by PD-1 to prevent lethal disease. PLoS Pathog. 12, e1005667 (2016).

  16. 16.

    Smith, C. M. et al. Tuberculosis susceptibility and vaccine protection are independently controlled by host genotype. mBio 7, e01516 (2016).

  17. 17.

    Houk, V. N., Baker, J. H., Sorensen, K. & Kent, D. C. The epidemiology of tuberculosis infection in a closed environment. Arch. Environ. Health 16, 26–35 (1968).

  18. 18.

    Morrison, J., Pai, M. & Hopewell, P. C. Tuberculosis and latent tuberculosis infection in close contacts of people with pulmonary tuberculosis in low-income and middle-income countries: a systematic review and meta-analysis. Lancet Infect. Dis. 8, 359–368 (2008). This is a systematic review and meta-analysis of historical and contemporary case–contact studies that finds that 51.4% of individuals with a TB household contact have LTBI, although substantial study heterogeneity exists that likely reflects differing exposure intensities across studies and/or participants.

  19. 19.

    Amberson, J. B. & Riggins, H. Tuberculosis among student nurses: a five year study at Bellevue hospital. Ann. Intern. Med. 10, 156–165 (1936).

  20. 20.

    Daniels, M. Primary tuberculous infection in nurses: manifestations and prognosis. Lancet 244, 201–204 (1944).

  21. 21.

    Aziz, A., Ishaq, M. & Akhwand, R. Infection risk of sputum positive tuberculosis patients to their family contacts with and without chemotherapy. J. Pak. Med. Assoc. 35, 249–252 (1985).

  22. 22.

    Devadatta, S. et al. Attack rate of tuberculosis in a 5-year period among close family contacts of tuberculous patients under domiciliary treatment with isoniazid plus PAS or isoniazid alone. Bull. World Health Organ. 42, 337–351 (1970).

  23. 23.

    Lemos, A. C., Matos, E. D., Pedral-Sampaio, D. B. & Netto, E. M. Risk of tuberculosis among household contacts in Salvador, Bahia. Braz. J. Infect. Dis. 8, 424–430 (2004).

  24. 24.

    Hill, P. C. et al. Longitudinal assessment of an ELISPOT test for Mycobacterium tuberculosis infection. PLoS Med. 4, e192 (2007).

  25. 25.

    Aguilar, D. et al. Mycobacterium tuberculosis strains with the Beijing genotype demonstrate variability in virulence associated with transmission. Tuberculosis 90, 319–325 (2010).

  26. 26.

    Parwati, I., van Crevel, R. & van Soolingen, D. Possible underlying mechanisms for successful emergence of the Mycobacterium tuberculosis Beijing genotype strains. Lancet Infect. Dis. 10, 103–111 (2010).

  27. 27.

    Merker, M. et al. Evolutionary history and global spread of the Mycobacterium tuberculosis Beijing lineage. Nat. Genet. 47, 242–249 (2015).

  28. 28.

    Churchyard, G. J. et al. A trial of mass isoniazid preventive therapy for tuberculosis control. N. Engl. J. Med. 370, 301–310 (2014).

  29. 29.

    Cowie, R. L. Short course chemoprophylaxis with rifampicin, isoniazid and pyrazinamide for tuberculosis evaluated in gold miners with chronic silicosis: a double-blind placebo controlled trial. Tuber Lung Dis. 77, 239–243 (1996).

  30. 30.

    Vynnycky, E. et al. Tuberculosis control in South African gold mines: mathematical modeling of a trial of community-wide isoniazid preventive therapy. Am. J. Epidemiol. 181, 619–632 (2015).

  31. 31.

    Hanifa, Y. et al. Prevalence of latent tuberculosis infection among gold miners in South Africa. Int. J. Tuberc Lung Dis. 13, 39–46 (2009).

  32. 32.

    Wallis, R. S. Mathematical models of tuberculosis reactivation and relapse. Front. Microbiol. 7, 669 (2016). This study presents a Markov model that uses published estimates of annual risk of acquiring M. tuberculosis infection to estimate the probability that an induration of 0 mm in the PPD skin reactivity test indicates a true resister and finds that this value is 22% in South African non-miners and 93% in gold miners.

  33. 33.

    World Health Organization. Global tuberculosis report 2015, 20th ed. WHO http://apps.who.int/iris/handle/10665/191102 (2015).

  34. 34.

    Whalen, C. C. et al. Secondary attack rate of tuberculosis in urban households in Kampala, Uganda. PLoS ONE 6, e16137 (2011).

  35. 35.

    Stein, C. M., Hall, N. B., Malone, L. L. & Mupere, E. The household contact study design for genetic epidemiological studies of infectious diseases. Front. Genet. 4, 61 (2013).

  36. 36.

    Stein, C. M. et al. Resistance and susceptibility to Mycobacterium Tuberculosis infection and disease in tuberculosis households in Kampala, Uganda. Am. J. Epidemiol. https://doi.org/10.1093/aje/kwx380 (2018). This study of 872 households containing individuals with TB in Uganda monitors these individuals for ≥2 years and finds that ~10% of household contacts are resisters.

  37. 37.

    Andrews, J. R., Morrow, C. & Wood, R. Modeling the role of public transportation in sustaining tuberculosis transmission in South Africa. Am. J. Epidemiol. 177, 556–561 (2013).

  38. 38.

    Classen, C. N. et al. Impact of social interactions in the community on the transmission of tuberculosis in a high incidence area. Thorax 54, 136–140 (1999).

  39. 39.

    Verver, S. et al. Proportion of tuberculosis transmission that takes place in households in a high-incidence area. Lancet 363, 212–214 (2004).

  40. 40.

    Beckman, E. M. et al. Recognition of a lipid antigen by CD1-restricted alpha beta+ T cells. Nature 372, 691–694 (1994).

  41. 41.

    Gold, M. C. et al. Human mucosal associated invariant T cells detect bacterially infected cells. PLoS Biol. 8, e1000407 (2010).

  42. 42.

    Tanaka, Y. et al. Natural and synthetic non-peptide antigens recognized by human gamma delta T cells. Nature 375, 155–158 (1995).

  43. 43.

    Matos, D. S. et al. Differential interferon- gamma production characterizes the cytokine responses to Leishmania and Mycobacterium leprae antigens in concomitant mucocutaneous leishmaniasis and lepromatous leprosy. Clin. Infect. Dis. 40, e5–12 (2005).

  44. 44.

    Heimbeck, J. Incidence of tuberculosis in young adult women, with special reference to employment. Br. J. Tuberc. 32, 154–166 (1938).

  45. 45.

    Israel, H. L., Hetherington, H. W. & Ord, J. G. A study of tuberculosis among students of nursing. JAMA 117, 839–844 (1941).

  46. 46.

    Menzies, D. Interpretation of repeated tuberculin tests. Boosting, conversion, and reversion. Am. J. Respir. Crit. Care Med. 159, 15–21 (1999).

  47. 47.

    Chaussé, P. Nouvelles recherches sur la contagion de la tuberculose par l’air expiré pendant la toux. Ann. Inst. Pasteur 30, 613–641 (1916).

  48. 48.

    Lange, B. Die Epidemiologie der Tuberkulose. Zentralblatt für bakteriologie, parasitenkunde und infektionskrankheiten 127, 25–46 (1933).

  49. 49.

    Dean, M. et al. Genetic restriction of HIV-1 infection and progression to AIDS by a deletion allele of the CKR5 structural gene. hemophilia growth and development study, multicenter AIDS cohort study, multicenter hemophilia cohort study, San Francisco city cohort, ALIVE Study. Science 273, 1856–1862 (1996).

  50. 50.

    Lindesmith, L. et al. Human susceptibility and resistance to Norwalk virus infection. Nat. Med. 9, 548–553 (2003).

  51. 51.

    Lindesmith, L. C. et al. Mechanisms of GII.4 norovirus persistence in human populations. PLoS Med. 5, e31 (2008).

  52. 52.

    Miller, L. H., Mason, S. J., Clyde, D. F. & McGinniss, M. H. The resistance factor to Plasmodium vivax in blacks. The Duffy-blood-group genotype, FyFy. N. Engl. J. Med. 295, 302–304 (1976).

  53. 53.

    Comstock, G. W. Tuberculosis in twins: a re-analysis of the Prophit survey. Am. Rev. Respir. Dis. 117, 621–624 (1978).

  54. 54.

    Kallmann, F. & Reisner, D. Twin studies on the significance of genetic factors in tuberculosis. Am. Rev. Tuberc. 47, 549–574 (1943).

  55. 55.

    Casanova, J.-L. & Abel, L. Genetic dissection of immunity to mycobacteria: the human model. Annu. Rev. Immunol. 20, 581–620 (2002).

  56. 56.

    Hill, A. V. Aspects of genetic susceptibility to human infectious diseases. Annu. Rev. Genet. 40, 469–486 (2006).

  57. 57.

    Stein, C. M. et al. Genome scan of M. tuberculosis infection and disease in Ugandans. PLoS ONE 3, e4094 (2008). In this study, a genome scan identifies two loci (chromosome 2q21–22q24 and chromosome 5p13–15q22) that are linked to the resister phenotype; the latter locus overlaps with a region that was associated with the intensity of reactivity in the PPD skin test (that is, induration in millimetres) in an independent cohort study (reference 64).

  58. 58.

    Thye, T. et al. Genome-wide association analyses identifies a susceptibility locus for tuberculosis on chromosome 18q11.2. Nat. Genet. 42, 739–741 (2010). This analysis of a large population (11,425 patients) from two independent genome-wide association studies comparing patients with TB and healthy individuals identifies a SNP (on chromosome 18q11.2) that is associated with TB susceptibility, which demonstrates that non-MHC susceptibility loci can be identified, even in populations with high genetic diversity, when the sample size is increased by combining data from multiple studies.

  59. 59.

    Azad, A. K., Sadee, W. & Schlesinger, L. S. Innate immune gene polymorphisms in tuberculosis. Infect. Immun. 80, 3343–3359 (2012).

  60. 60.

    Tosh, K. et al. Variants in the SP110 gene are associated with genetic susceptibility to tuberculosis in West Africa. Proc. Natl Acad. Sci. USA 103, 10364–10368 (2006).

  61. 61.

    Sepulveda, R. L. et al. Evaluation of tuberculin reactivity in BCG-immunized siblings. Am. J. Respir. Crit. Care Med. 149, 620–624 (1994).

  62. 62.

    Horne, D. J. et al. Human ULK1 Variation and susceptibility to Mycobacterium tuberculosis infection. J. Infect. Dis. 214, 1260–1267 (2016).

  63. 63.

    Shah, J. A. et al. A functional TOLLIP variant is associated with BCG-specific immune responses and tuberculosis. Am. J. Respir. Crit. Care Med. 196, 502–511 (2017). This study identifies a SNP in the promoter region of TOLLIP that reduces the expression of TOLLIP (a negative regulator of signalling through TLR2, TLR4 and IL-1R) and finds that this polymorphism is associated with increased risk of LTBI in M. tuberculosis -exposed individuals.

  64. 64.

    Cobat, A. et al. Two loci control tuberculin skin test reactivity in an area hyperendemic for tuberculosis. J. Exp. Med. 206, 2583–2591 (2009). This study carries out a genome-wide linkage analysis in South Africans and identifies two loci that are associated with a negative result in the PPD skin reactivity test; one of these loci has been subsequently linked to a SNP that is associated with TNF production (see reference 65).

  65. 65.

    Cobat, A. et al. Identification of a major locus, TNF1, that controls BCG-triggered tumor necrosis factor production by leukocytes in an area hyperendemic for tuberculosis. Clin. Infect. Dis. 57, 963–970 (2013).

  66. 66.

    Sobota, R. S. et al. A chromosome 5q31.1 locus associates with tuberculin skin test reactivity in HIV-positive individuals from tuberculosis hyper-endemic regions in east Africa. PLoS Genet. 13, e1006710 (2017).

  67. 67.

    von Hertzen, L., Klaukka, T., Mattila, H. & Haahtela, T. Mycobacterium tuberculosis infection and the subsequent development of asthma and allergic conditions. J. Allergy Clin. Immunol. 104, 1211–1214 (1999).

  68. 68.

    von Mutius, E. et al. International patterns of tuberculosis and the prevalence of symptoms of asthma, rhinitis, and eczema. Thorax 55, 449–453 (2000).

  69. 69.

    Daya, M., van der Merwe, L., van Helden, P. D., Moller, M. & Hoal, E. G. Investigating the role of gene-gene interactions in TB susceptibility. PLoS ONE 10, e0123970 (2014).

  70. 70.

    Stein, C. M. et al. Genomics of human pulmonary tuberculosis: from genes to pathways. Curr. Genet. Med. Rep. 5, 149–166 (2017).

  71. 71.

    Zhang, F. et al. Identification of two new loci at IL23R and RAB32 that influence susceptibility to leprosy. Nat. Genet. 43, 1247–1251 (2011).

  72. 72.

    Hussell, T. & Bell, T. J. Alveolar macrophages: plasticity in a tissue-specific context. Nat. Rev. Immunol. 14, 81–93 (2014).

  73. 73.

    Kopf, M., Schneider, C. & Nobs, S. P. The development and function of lung-resident macrophages and dendritic cells. Nat. Immunol. 16, 36–44 (2015).

  74. 74.

    Torrelles, J. B. & Schlesinger, L. S. Integrating lung physiology, immunology, and tuberculosis. Trends Microbiol. 25, 688–697 (2017).

  75. 75.

    Liu, C. H., Liu, H. & Ge, B. Innate immunity in tuberculosis: host defense versus pathogen evasion. Cell. Mol. Immunol. 14, 963–975 (2017).

  76. 76.

    Warren, E., Teskey, G. & Venketaraman, V. Effector mechanisms of neutrophils within the innate immune system in response to Mycobacterium tuberculosis infection. J. Clin. Med. 6, 15 (2017).

  77. 77.

    Mortaz, E. et al. Interaction of pattern recognition receptors with mycobacterium tuberculosis. J. Clin. Immunol. 35, 1–10 (2015).

  78. 78.

    Stamm, C. E., Collins, A. C. & Shiloh, M. U. Sensing of Mycobacterium tuberculosis and consequences to both host and bacillus. Immunol. Rev. 264, 204–219 (2015).

  79. 79.

    Groschel, M. I., Sayes, F., Simeone, R., Majlessi, L. & Brosch, R. ESX secretion systems: mycobacterial evolution to counter host immunity. Nat. Rev. Microbiol. 14, 677–691 (2016).

  80. 80.

    Fabri, M. et al. Vitamin D is required for IFN-gamma-mediated antimicrobial activity of human macrophages. Sci. Transl. Med. 3, 104ra102 (2011).

  81. 81.

    Collins, A. C. et al. Cyclic GMP-AMP synthase is an innate immune DNA sensor for Mycobacterium tuberculosis. Cell Host Microbe 17, 820–828 (2015).

  82. 82.

    Watson, R. O. et al. The cytosolic sensor cGAS detects Mycobacterium tuberculosis DNA to induce type I interferons and activate autophagy. Cell Host Microbe 17, 811–819 (2015).

  83. 83.

    Behar, S. M., Divangahi, M. & Remold, H. G. Evasion of innate immunity by Mycobacterium tuberculosis: is death an exit strategy? Nat. Rev. Microbiol. 8, 668–674 (2010).

  84. 84.

    Verrall, A. J., Netea, M. G., Alisjahbana, B., Hill, P. C. & van Crevel, R. Early clearance of Mycobacterium tuberculosis: a new frontier in prevention. Immunology 141, 506–513 (2014).

  85. 85.

    Arbour, N. C. et al. TLR4 mutations are associated with endotoxin hyporesponsiveness in humans. Nat. Genet. 25, 187–191 (2000).

  86. 86.

    Hawn, T. R. et al. A common dominant TLR5 stop codon polymorphism abolishes flagellin signaling and is associated with susceptibility to legionnaires’ disease. J. Exp. Med. 198, 1563–1572 (2003).

  87. 87.

    Hawn, T. R. et al. A common human TLR1 polymorphism regulates the innate immune response to lipopeptides. Eur. J. Immunol. 37, 2280–2289 (2007).

  88. 88.

    Hoffman, H. M., Mueller, J. L., Broide, D. H., Wanderer, A. A. & Kolodner, R. D. Mutation of a new gene encoding a putative pyrin-like protein causes familial cold autoinflammatory syndrome and Muckle-Wells syndrome. Nat. Genet. 29, 301–305 (2001).

  89. 89.

    Ma, X. et al. Full-exon resequencing reveals toll-like receptor variants contribute to human susceptibility to tuberculosis disease. PLoS ONE 2, e1318 (2007).

  90. 90.

    Meyer, C. G. et al. TLR1 variant H305L associated with protection from pulmonary tuberculosis. PLoS ONE 11, e0156046 (2016).

  91. 91.

    Johnson, C. M. et al. Cutting edge: a common polymorphism impairs cell surface trafficking and functional responses of TLR1 but protects against leprosy. J. Immunol. 178, 7520–7524 (2007).

  92. 92.

    Velez, D. R. et al. Variants in toll-like receptors 2 and 9 influence susceptibility to pulmonary tuberculosis in Caucasians, African-Americans, and West Africans. Hum. Genet. 127, 65–73 (2010).

  93. 93.

    Davila, S. et al. Genetic association and expression studies indicate a role of toll-like receptor 8 in pulmonary tuberculosis. PLoS Genet. 4, e1000218 (2008).

  94. 94.

    Hawn, T. R. et al. A polymorphism in Toll-interleukin 1 receptor domain containing adaptor protein is associated with susceptibility to meningeal tuberculosis. J. Infect. Dis. 194, 1127–1134 (2006).

  95. 95.

    Khor, C. C. et al. A Mal functional variant is associated with protection against invasive pneumococcal disease, bacteremia, malaria and tuberculosis. Nat. Genet. 39, 523–528 (2007).

  96. 96.

    Thuong, N. T. et al. A polymorphism in human TLR2 is associated with increased susceptibility to tuberculous meningitis. Genes Immun. 8, 422–428 (2007).

  97. 97.

    Shah, J. A. et al. Human TOLLIP regulates TLR2 and TLR4 signaling and its polymorphisms are associated with susceptibility to tuberculosis. J. Immunol. 189, 1737–1746 (2012).

  98. 98.

    Shah, J. A. et al. Genetic variation in toll-interacting protein is associated with leprosy susceptibility and cutaneous expression of interleukin 1 receptor antagonist. J. Infect. Dis. 213, 1189–1197 (2016).

  99. 99.

    Barreiro, L. B. et al. Promoter variation in the DC-SIGN-encoding gene CD209 is associated with tuberculosis. PLoS Med. 3, e20 (2006).

  100. 100.

    Intemann, C. D. et al. Autophagy gene variant IRGM -261T contributes to protection from tuberculosis caused by Mycobacterium tuberculosis but not by M. africanum strains. PLoS Pathog. 5, e1000577 (2009).

  101. 101.

    Lu, Y. et al. Association of autophagy-related IRGM polymorphisms with latent versus active tuberculosis infection in a Chinese population. Tuberculosis 97, 47–51 (2016).

  102. 102.

    Tobin, D. M. et al. Host genotype-specific therapies can optimize the inflammatory response to mycobacterial infections. Cell 148, 434–446 (2012).

  103. 103.

    Picard, C. et al. Clinical features and outcome of patients with IRAK-4 and MyD88 deficiency. Medicine 89, 403–425 (2010).

  104. 104.

    Gutierrez, M. G. et al. Autophagy is a defense mechanism inhibiting BCG and Mycobacterium tuberculosis survival in infected macrophages. Cell 119, 753–766 (2004).

  105. 105.

    Singh, S. B., Davis, A. S., Taylor, G. A. & Deretic, V. Human IRGM induces autophagy to eliminate intracellular mycobacteria. Science 313, 1438–1441 (2006).

  106. 106.

    Kumar, D. et al. Genome-wide analysis of the host intracellular network that regulates survival of Mycobacterium tuberculosis. Cell 140, 731–743 (2010).

  107. 107.

    Watson, R. O., Manzanillo, P. S. & Cox, J. S. Extracellular M. tuberculosis DNA targets bacteria for autophagy by activating the host DNA-sensing pathway. Cell 150, 803–815 (2012).

  108. 108.

    Majlessi, L. & Brosch, R. Mycobacterium tuberculosis meets the cytosol: the role of cGAS in anti-mycobacterial immunity. Cell Host Microbe 17, 733–735 (2015).

  109. 109.

    Romagnoli, A. et al. ESX-1 dependent impairment of autophagic flux by Mycobacterium tuberculosis in human dendritic cells. Autophagy 8, 1357–1370 (2012).

  110. 110.

    Castillo, E. F. et al. Autophagy protects against active tuberculosis by suppressing bacterial burden and inflammation. Proc. Natl Acad. Sci. USA 109, E3168–E3176 (2012).

  111. 111.

    Kimmey, J. M. et al. Unique role for ATG5 in neutrophil-mediated immunopathology during M. tuberculosis infection. Nature 528, 565–569 (2015).

  112. 112.

    Seshadri, C. et al. Transcriptional networks are associated with resistance to Mycobacterium tuberculosis infection. PLoS ONE 12, e0175844 (2017). In this study, the transcriptional responses of monocytes from resisters and individuals with LTBI following ex vivo M. tuberculosis infection are shown to be distinct, and network analysis identifies HDACs as potential mediators of this difference.

  113. 113.

    Subramanian, A. et al. Gene set enrichment analysis: a knowledge-based approach for interpreting genome-wide expression profiles. Proc. Natl Acad. Sci. USA 102, 15545–15550 (2005).

  114. 114.

    Joseph, J. et al. Expression profiling of sodium butyrate (NaB)-treated cells: identification of regulation of genes related to cytokine signaling and cancer metastasis by NaB. Oncogene 23, 6304–6315 (2004).

  115. 115.

    Chandran, A. et al. Mycobacterium tuberculosis infection induces HDAC1-mediated suppression of IL-12B gene expression in macrophages. Front. Cell. Infect. Microbiol. 5, 90 (2015).

  116. 116.

    Wang, Y., Curry, H. M., Zwilling, B. S. & Lafuse, W. P. Mycobacteria inhibition of IFN-gamma induced HLA-DR gene expression by up-regulating histone deacetylation at the promoter region in human THP-1 monocytic cells. J. Immunol. 174, 5687–5694 (2005).

  117. 117.

    Coussens, A. K., Wilkinson, R. J. & Martineau, A. R. Phenylbutyrate is bacteriostatic against Mycobacterium tuberculosis and regulates the macrophage response to infection, synergistically with 25-hydroxy-vitamin D3. PLoS Pathog. 11, e1005007 (2015).

  118. 118.

    Mily, A. et al. Significant effects of oral phenylbutyrate and vitamin D3 adjunctive therapy in pulmonary tuberculosis: a randomized controlled trial. PLoS ONE 10, e0138340 (2015).

  119. 119.

    Behar, S. M., Dascher, C. C., Grusby, M. J., Wang, C. R. & Brenner, M. B. Susceptibility of mice deficient in CD1D or TAP1 to infection with Mycobacterium tuberculosis. J. Exp. Med. 189, 1973–1980 (1999).

  120. 120.

    Lin, P. L. et al. CD4 T cell depletion exacerbates acute Mycobacterium tuberculosis while reactivation of latent infection is dependent on severity of tissue depletion in cynomolgus macaques. AIDS Res. Hum. Retroviruses 28, 1693–1702 (2012).

  121. 121.

    Mogues, T., Goodrich, M. E., Ryan, L., LaCourse, R. & North, R. J. The relative importance of T cell subsets in immunity and immunopathology of airborne Mycobacterium tuberculosis infection in mice. J. Exp. Med. 193, 271–280 (2001).

  122. 122.

    Flynn, J. L. et al. An essential role for interferon gamma in resistance to Mycobacterium tuberculosis infection. J. Exp. Med. 178, 2249–2254 (1993).

  123. 123.

    Green, A. M., Difazio, R. & Flynn, J. L. IFN-gamma from CD4 T cells is essential for host survival and enhances CD8 T cell function during Mycobacterium tuberculosis infection. J. Immunol. 190, 270–277 (2013).

  124. 124.

    Kagina, B. M. N. et al. Specific T cell frequency and cytokine expression profile do not correlate with protection against tuberculosis after bacillus Calmette-Guérin vaccination of newborns. Am. J. Respir. Crit. Care Med. 182, 1073–1079 (2010).

  125. 125.

    Tameris, M. D. et al. Safety and efficacy of MVA85A, a new tuberculosis vaccine, in infants previously vaccinated with BCG: a randomised, placebo-controlled phase 2b trial. Lancet 381, 1021–1028 (2013).

  126. 126.

    Boussiotis, V. A. et al. IL-10-producing T cells suppress immune responses in anergic tuberculosis patients. J. Clin. Invest. 105, 1317–1325 (2000).

  127. 127.

    Delgado, J. C. et al. Antigen-specific and persistent tuberculin anergy in a cohort of pulmonary tuberculosis patients from rural Cambodia. Proc. Natl Acad. Sci. 99, 7576–7581 (2002). This investigation of a subset of patients with pulmonary TB indicates that persistent in vivo anergy in the PPD skin reactivity test following treatment completion is not a global anergy but instead is PPD antigen-specific and is correlated with elevated IL-10 production and reduced secretion of IL-2 and IFNγ by T cells following ex vivo stimulation with PPD antigens.

  128. 128.

    Redford, P. S., Murray, P. J. & O’Garra, A. The role of IL-10 in immune regulation during M. tuberculosis infection. Mucosal Immunol. 4, 261–270 (2011).

  129. 129.

    Thye, T. et al. IL10 haplotype associated with tuberculin skin test response but not with pulmonary TB. PLoS ONE 4, e5420 (2009).

  130. 130.

    Okamoto Yoshida, Y. et al. Essential role of IL-17A in the formation of a mycobacterial infection-induced granuloma in the lung. J. Immunol. 184, 4414–4422 (2010).

  131. 131.

    Wozniak, T. M., Saunders, B. M., Ryan, A. A. & Britton, W. J. Mycobacterium bovis BCG-specific Th17 cells confer partial protection against Mycobacterium tuberculosis infection in the absence of gamma interferon. Infect. Immun. 78, 4187–4194 (2010).

  132. 132.

    Gallegos, A. M. et al. A gamma interferon independent mechanism of CD4 T cell mediated control of M. tuberculosis infection in vivo. PLoS Pathog. 7, e1002052 (2011).

  133. 133.

    Han, M. & Hannick, L. I., DiBrino, M. & Robinson, M. A. Polymorphism of human CD1 genes. Tissue Antigens 54, 122–127 (1999).

  134. 134.

    Oteo, M. et al. Single strand conformational polymorphism analysis of human CD1 genes in different ethnic groups. Tissue Antigens 53, 545–550 (1999).

  135. 135.

    Seshadri, C. et al. T cell responses against mycobacterial lipids and proteins are poorly correlated in South African adolescents. J. Immunol. 195, 4595–4603 (2015). This study shows that the response of CD4 + T cells to mycobacterial lipid (CD1-restricted) antigens ex vivo correlates poorly with their response to peptide antigens. However, as the abundance of lipid-specific T cells does not differ between infected and uninfected individuals in this study, it is plausible that individuals negative for the IGRA are M. tuberculosis -exposed and that their T cells produce a similar repertoire of cytokines as those from IGRA-positive individuals, although they do not secrete IFNγ.

  136. 136.

    Van Rhijn, I., Ly, D. & Moody, D. B. CD1a, CD1b, and CD1c in immunity against mycobacteria. Adv. Exp. Med. Biol. 783, 181–197 (2013).

  137. 137.

    Kjer-Nielsen, L. et al. MR1 presents microbial vitamin B metabolites to MAIT cells. Nature 491, 717–723 (2012).

  138. 138.

    Martin, E. et al. Stepwise development of mait cells in mouse and human. PLoS Biol. 7, 0525–0536 (2009).

  139. 139.

    Porcelli, S., Yockey, C. E., Brenner, M. B. & Balk, S. P. Analysis of T cell antigen receptor (TCR) expression by human peripheral blood CD4-8- alpha/beta T cells demonstrates preferential use of several V beta genes and an invariant TCR alpha chain. J. Exp. Med. 178, 1–16 (1993).

  140. 140.

    Treiner, E. et al. Selection of evolutionarily conserved mucosal-associated invariant T cells by MR1. Nature 422, 164–169 (2003).

  141. 141.

    Chua, W. J. et al. Polyclonal mucosa-associated invariant T cells have unique innate functions in bacterial infection. Infect. Immun. 80, 3256–3267 (2012).

  142. 142.

    Seshadri, C. et al. A polymorphism in human MR1 is associated with mRNA expression and susceptibility to tuberculosis. Genes Immun. 18, 8–14 (2017).

  143. 143.

    Seshadri, C. et al. A polymorphism in human CD1A is associated with susceptibility to tuberculosis. Genes Immun. 15, 195–198 (2014).

  144. 144.

    Sandstrom, A. et al. The intracellular B30.2 domain of butyrophilin 3A1 binds phosphoantigens to mediate activation of human Vγ9Vδ2T Cells. Immunity 40, 490–500 (2014).

  145. 145.

    Vavassori, S. et al. Butyrophilin 3A1 binds phosphorylated antigens and stimulates human γδ T cells. Nat. Immunol. 14, 908–916 (2013).

  146. 146.

    Spencer, C. T., Abate, G., Blazevic, A. & Hoft, D. F. Only a subset of phosphoantigen-responsive 9 2T cells mediate protective tuberculosis immunity. J. Immunol. 181, 4471–4484 (2008).

  147. 147.

    Plotkin, S. A. Vaccines: correlates of vaccine-induced immunity. Clin. Infect. Dis. 47, 401–409 (2008).

  148. 148.

    Plotkin, S. A. Correlates of protection induced by vaccination. Clin. Vaccine Immunol. 17, 1055–1065 (2010).

  149. 149.

    Achkar, J. M., Chan, J. & Casadevall, A. B cells and antibodies in the defense against Mycobacterium tuberculosis infection. Immunol. Rev. 264, 167–181 (2015).

  150. 150.

    Kozakiewicz, L., Phuah, J., Flynn, J. & Chan, J. The role of B cells and humoral immunity in Mycobacterium tuberculosis infection. Adv. Exp. Med. Biol. 783, 225–250 (2013).

  151. 151.

    Balu, S. et al. A novel human IgA monoclonal antibody protects against tuberculosis. J. Immunol. 186, 3113–3119 (2011).

  152. 152.

    Hamasur, B. et al. A mycobacterial lipoarabinomannan specific monoclonal antibody and its F(ab’) fragment prolong survival of mice infected with Mycobacterium tuberculosis. Clin. Exp. Immunol. 138, 30–38 (2004).

  153. 153.

    Suter, E. Multiplication of tubercle bacilli within mononuclear phagocytes in tissue cultures derived from normal animals and animals vaccinated with BCG. J. Exp. Med. 97, 235–245 (1953).

  154. 154.

    Teitelbaum, R. et al. A mAb recognizing a surface antigen of Mycobacterium tuberculosis enhances host survival. Proc. Natl Acad. Sci. USA 95, 15688–15693 (1998).

  155. 155.

    Glatman-Freedman, A. & Casadevall, A. Serum therapy for tuberculosis revisited: reappraisal of the role of antibody-mediated immunity against Mycobacterium tuberculosis. Clin. Microbiol. Rev. 11, 514–532 (1998).

  156. 156.

    Fletcher, H. A. et al. T cell activation is an immune correlate of risk in BCG vaccinated infants. Nat. Commun. 7, 11290 (2016).

  157. 157.

    Phuah, J. et al. Effects of B cell depletion on early Mycobacterium tuberculosis infection in cynomolgus macaques. Infect. Immun. 84, 1301–1311 (2016).

  158. 158.

    Abreu, M. T. et al. Alterations in the peripheral blood B cell subpopulations of multidrug-resistant tuberculosis patients. Clin. Exp. Med. 14, 423–429 (2014).

  159. 159.

    Joosten, S. A. et al. Patients with tuberculosis have a dysfunctional circulating B-cell compartment, which normalizes following successful treatment. PLoS Pathog. 12, e1005687 (2016).

  160. 160.

    Phuah, J. Y., Mattila, J. T., Lin, P. L. & Flynn, J. L. Activated B cells in the granulomas of nonhuman primates infected with Mycobacterium tuberculosis. Am. J. Pathol. 181, 508–514 (2012).

  161. 161.

    Tsai, M. C. et al. Characterization of the tuberculous granuloma in murine and human lungs: cellular composition and relative tissue oxygen tension. Cell. Microbiol. 8, 218–232 (2006).

  162. 162.

    Casadevall, A. & Pirofski, L. A. A reappraisal of humoral immunity based on mechanisms of antibody-mediated protection against intracellular pathogens. Adv. Immunol. 91, 1–44 (2006).

  163. 163.

    Nimmerjahn, F. & Ravetch, J. V. Fcgamma receptors as regulators of immune responses. Nat. Rev. Immunol. 8, 34–47 (2008).

  164. 164.

    Lu, L. L. et al. A functional role for antibodies in tuberculosis. Cell 167, 433–443 e414 (2016). In this study, antibody profiling indicates that the pattern of glycosylation in the Fc domain of antibodies from individuals with LTBI is distinct from that of antibodies from patients with active TB and that addition of latent antibodies to macrophages previously infected with M. tuberculosis results in improved phagolysosomal maturation and killing of intracellular bacteria by these macrophages.

  165. 165.

    Riedel, S. Edward Jenner and the history of smallpox and vaccination. Proc 18, 21–25 (2005).

  166. 166.

    Liu, R. et al. Homozygous defect in HIV-1 coreceptor accounts for resistance of some multiply-exposed individuals to HIV-1 infection. Cell 86, 367–377 (1996).

  167. 167.

    Samson, M. et al. Resistance to HIV-1 infection in caucasian individuals bearing mutant alleles of the CCR-5 chemokine receptor gene. Nature 382, 722–725 (1996).

  168. 168.

    Gulick, R. M. et al. Maraviroc for previously treated patients with R5 HIV-1 infection. N. Engl. J. Med. 359, 1429–1441 (2008).

  169. 169.

    Jones-Lopez, E. C. et al. Cough Aerosols of Mycobacterium tuberculosis in the prediction of incident tuberculosis disease in household contacts. Clin. Infect. Dis. 63, 10–20 (2016).

  170. 170.

    Patterson, B. et al. Detection of Mycobacterium tuberculosis bacilli in bio-aerosols from untreated TB patients. Gates Open Res. 1, 11 (2017).

  171. 171.

    Zwerling, A. et al. Trajectories of tuberculosis-specific interferon-gamma release assay responses among medical and nursing students in rural India. J. Epidemiol. Glob. Health 3, 105–117 (2013).

  172. 172.

    Gagneux, S. et al. Variable host-pathogen compatibility in Mycobacterium tuberculosis. Proc. Natl Acad. Sci. USA 103, 2869–2873 (2006).

  173. 173.

    Hardy, M. A. & Schmidek, H. H. Epidemiology of tuberculosis aboard a ship. JAMA 203, 175–179 (1968).

  174. 174.

    Badger, T. L. & Spink, W. W. First-infection type of tuberculosis in adults — a five-year study of student nurses at the Boston City Hospital. New Engl. J. Med. 217, 424–431 (1937).

  175. 175.

    Myers, J. A., Boynton, R. E. & Diehl, R. E. Prevention of tuberculosis among students of nursing. Am. J. Nurs. 47, 661–666 (1947).

  176. 176.

    Dickie, H. A. Tuberculosis in student nurses and medical students at the University of Wisconsin. Ann. Intern. Med. 33, 941–959 (1950).

  177. 177.

    Stein, C. M. et al. Resistance and susceptibility to Mycobacterium tuberculosis infection and disease in tuberculosis households in Kampala, Uganda. Am. J. Epidemiol. https://doi.org/10.1093/aje/kwx380 (2018).

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Acknowledgements

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.

Author information

Affiliations

  1. Department of Medicine, University of Washington, Seattle, WA, USA

    • Jason D. Simmons
    • , Chetan Seshadri
    • , Monica Campo
    •  & Thomas R. Hawn
  2. Department of Population & Quantitative Health Sciences, Case Western Reserve University, Cleveland, OH, USA

    • Catherine M. Stein
  3. Department of Medicine, Case Western Reserve University, Cleveland, OH, USA

    • Catherine M. Stein
    • , Robert S. Wallis
    •  & W. Henry Boom
  4. Ragon Institute of MGH, MIT and Harvard, Cambridge, MA, USA

    • Galit Alter
  5. Department of Immunology and Infectious Diseases, Harvard School of Public Health, Boston, MA, USA

    • Sarah Fortune
  6. Program in Infectious Diseases and Immunity in Global Health, Research Institute of the McGill University Health Centre, Montreal, Québec, Canada

    • Erwin Schurr
  7. The Aurum Institute, Parktown, South Africa

    • Robert S. Wallis
    •  & Gavin Churchyard
  8. Department of Medicine, School of Medicine, Makerere University, Kampala, Uganda

    • Harriet Mayanja-Kizza

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Contributions

J.D.S., C.S. and T.R.H. contributed to the drafting and editing of all sections. Focused contributions were made to the Epidemiology and Genetics sections (C.M.S., E.S. and G.C.), the B cell-mediated resistance section (G.A.) and the Macrophage-mediated resistance section (M.C.). Initial figure drafts were provided by J.D.S., M.C. and G.A. Detailed review and editing were additionally provided by S.F., R.S.W., W.H.B. and H.M.-K.

Competing interests

The authors declare no competing interests.

Corresponding author

Correspondence to Jason D. Simmons.

Glossary

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.

Resister

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.

Silicosis

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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