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Striking the right immunological balance prevents progression of tuberculosis

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Abstract

Introduction

Tuberculosis (TB) caused by infection with Mycobacterium tuberculosis (Mtb) is a major burden for human health worldwide. Current standard treatments for TB require prolonged administration of antimycobacterial drugs leading to exaggerated inflammation and tissue damage. This can result in the reactivation of latent TB culminating in TB progression. Thus, there is an unmet need to develop therapies that would shorten the duration of anti-TB treatment and to induce optimal protective immune responses to control the spread of mycobacterial infection with minimal lung pathology.

Findings

Granulomata is the hallmark structure formed by the organized accumulation of immune cells including macrophages, natural killer cells, dendritic cells, neutrophils, T cells, and B cells to the site of Mtb infection. It safeguards the host by containing Mtb in latent form. However, granulomata can undergo caseation and contribute to the reactivation of latent TB, if the immune responses developed to fight mycobacterial infection are not properly controlled. Thus, an optimal balance between innate and adaptive immune cells might play a vital role in containing mycobacteria in latent form for prolonged periods and prevent the spread of Mtb infection from one individual to another.

Conclusion

Optimal and well-regulated immune responses against Mycobacterium tuberculosis may help to prevent the reactivation of latent TB. Moreover, therapies targeting balanced immune responses could help to improve treatment outcomes among latently infected TB patients and thereby limit the dissemination of mycobacterial infection.

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References

  1. Kiran D, Podell BK, Chambers M, Basaraba RJ. Host-directed therapy targeting the Mycobacterium tuberculosis granulomata: a review. Semin Immunopathol. 2016;38:167–83.

    Article  CAS  PubMed  Google Scholar 

  2. Nathan C. What can immunology contribute to the control of the world’s leading cause of death from bacterial infection? Immunol Rev. 2015;264:2–5.

    Article  PubMed  PubMed Central  Google Scholar 

  3. Ndlovu H, Marakalala MJ. Granulomatas and inflammation: host-directed therapies for tuberculosis. Front Immunol. 2016;7:434.

    Article  PubMed  PubMed Central  Google Scholar 

  4. Flynn JL, Chan J, Lin PL. Macrophages and control of granulomatatous inflammation in tuberculosis. Mucosal Immunol. 2011;4:271–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. da Silva MV, Tiburcio MG, Machado JR, Silva DA, Rodrigues DB, Rodrigues V, et al. Complexity and controversies over the cytokine profiles of T helper cell subpopulations in tuberculosis. J Immunol Res. 2015;2015:639107.

    PubMed  PubMed Central  Google Scholar 

  6. Raja A. Immunology of tuberculosis. Indian J Med Res. 2004;120:213–32.

    CAS  PubMed  Google Scholar 

  7. Schluger NW, Rom WN. The host immune response to tuberculosis. Am J Respir Crit Care Med. 1998;157:679–91.

    Article  CAS  PubMed  Google Scholar 

  8. van Crevel R, Ottenhoff TH, van der Meer JW. Innate immunity to Mycobacterium tuberculosis. Clin Microbiol Rev. 2002;15:294–309.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  9. Lin PL, Flynn JL. Understanding latent tuberculosis: a moving target. J Immunol. 2010;185:15–22.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. O’Garra A, Redford PS, McNab FW, Bloom CI, Wilkinson RJ, Berry MP. The immune response in tuberculosis. Annu Rev Immunol. 2013;31:475–527.

    Article  PubMed  CAS  Google Scholar 

  11. Zumla A, Rao M, Dodoo E, Maeurer M. Potential of immunomodulatory agents as adjunct host-directed therapies for multidrug-resistant tuberculosis. BMC medicine. 2016;14:89.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  12. Forget EJ, Menzies D. Adverse reactions to first-line antituberculosis drugs. Expert opinion on drug safety. 2006;5:231–49.

    Article  CAS  PubMed  Google Scholar 

  13. Ramakrishnan L. Revisiting the role of the granulomata in tuberculosis. Nat Rev Immunol. 2012;12:352–66.

    CAS  PubMed  Google Scholar 

  14. Cole ST, Brosch R, Parkhill J, Garnier T, Churcher C, Harris D, et al. Deciphering the biology of Mycobacterium tuberculosis from the complete genome sequence. Nature. 1998;393:537–44.

    Article  CAS  PubMed  Google Scholar 

  15. Ernst JD. The immunological life cycle of tuberculosis. Nat Rev Immunol. 2012;12:581–91.

    Article  CAS  PubMed  Google Scholar 

  16. Sasindran SJ, Torrelles JB. Mycobacterium Tuberculosis infection and inflammation: what is beneficial for the host and for the bacterium? Front Microbiol. 2011;2:2.

    Article  PubMed  PubMed Central  Google Scholar 

  17. Weiss G, Schaible UE. Macrophage defense mechanisms against intracellular bacteria. Immunol Rev. 2015;264:182–203.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Koul A, Herget T, Klebl B, Ullrich A. Interplay between mycobacteria and host signaling pathways. Nat Rev Microbiol. 2004;2:189–202.

    Article  CAS  PubMed  Google Scholar 

  19. Diacovich L, Gorvel JP. Bacterial manipulation of innate immunity to promote infection. Nat Rev Microbiol. 2010;8:117–28.

    Article  CAS  PubMed  Google Scholar 

  20. Behar SM, Martin CJ, Booty MG, Nishimura T, Zhao X, Gan HX, et al. Apoptosis is an innate defense function of macrophages against Mycobacterium tuberculosis. Mucosal Immunol. 2011;4:279–87.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Hinchey J, Lee S, Jeon BY, Basaraba RJ, Venkataswamy MM, Chen B, et al. Enhanced priming of adaptive immunity by a proapoptotic mutant of Mycobacterium tuberculosis. J Clin Investig. 2007;117:2279–88.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Rovetta AI, Pena D, Hernandez Del Pino RE, Recalde GM, Pellegrini J, Bigi F, et al. IFNG-mediated immune responses enhance autophagy against Mycobacterium tuberculosis antigens in patients with active tuberculosis. Autophagy. 2014;10:2109–21.

    Article  CAS  PubMed  Google Scholar 

  23. Gutierrez MG, Master SS, Singh SB, Taylor GA, Colombo MI, Deretic V. Autophagy is a defense mechanism inhibiting BCG and Mycobacterium tuberculosis survival in infected macrophages. Cell. 2004;119:753–66.

    Article  CAS  PubMed  Google Scholar 

  24. Watson RO, Manzanillo PS, Cox JS. Extracellular M. tuberculosis DNA targets bacteria for autophagy by activating the host DNA-sensing pathway. Cell. 2012;150:803–15.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Landes MB, Rajaram MV, Nguyen H, Schlesinger LS. Role for NOD2 in Mycobacterium tuberculosis-induced iNOS expression and NO production in human macrophages. J Leukoc Biol. 2015;97:1111–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Sugawara I, Udagawa T, Yamada H. Rat neutrophils prevent the development of tuberculosis. Infect Immun. 2004;72:1804–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Eruslanov EB, Lyadova IV, Kondratieva TK, Majorov KB, Scheglov IV, Orlova MO, et al. Neutrophil responses to Mycobacterium tuberculosis infection in genetically susceptible and resistant mice. Infect Immun. 2005;73:1744–53.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Nandi B, Behar SM. Regulation of neutrophils by interferon-gamma limits lung inflammation during tuberculosis infection. J Exp Med. 2011;208:2251–62.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Hall LJ, Murphy CT, Hurley G, Quinlan A, Shanahan F, Nally K, et al. Natural killer cells protect against mucosal and systemic infection with the enteric pathogen Citrobacter rodentium. Infect Immun. 2013;81:460–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Brill KJ, Li Q, Larkin R, Canaday DH, Kaplan DR, Boom WH, et al. Human natural killer cells mediate killing of intracellular Mycobacterium tuberculosis H37Rv via granule-independent mechanisms. Infect Immun. 2001;69:1755–65.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Wolf AJ, Desvignes L, Linas B, Banaiee N, Tamura T, Takatsu K, et al. Initiation of the adaptive immune response to Mycobacterium tuberculosis depends on antigen production in the local lymph node, not the lungs. J Exp Med. 2008;205:105–15.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Torrado E, Robinson RT, Cooper AM. Cellular response to mycobacteria: balancing protection and pathology. Trends Immunol. 2011;32:66–72.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Torrado E, Cooper AM. Cytokines in the balance of protection and pathology during mycobacterial infections. Adv Exp Med Biol. 2013;783:121–40.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Mogues T, Goodrich ME, Ryan L, LaCourse R, North RJ. The relative importance of T cell subsets in immunity and immunopathology of airborne Mycobacterium tuberculosis infection in mice. J Exp Med. 2001;193:271–80.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Lin PL, Rutledge T, Green AM, Bigbee M, Fuhrman C, Klein E, 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 Retrovir. 2012;28:1693–702.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Saunders BM, Frank AA, Orme IM, Cooper AM. CD4 is required for the development of a protective granulomatatous response to pulmonary tuberculosis. Cell Immunol. 2002;216:65–72.

    Article  CAS  PubMed  Google Scholar 

  37. Jones BE, Young SM, Antoniskis D, Davidson PT, Kramer F, Barnes PF. Relationship of the manifestations of tuberculosis to CD4 cell counts in patients with human immunodeficiency virus infection. Am Rev Respir Dis. 1993;148:1292–7.

    Article  CAS  PubMed  Google Scholar 

  38. Mihret A. The role of dendritic cells in Mycobacterium tuberculosis infection. Virulence. 2012;3:654–9.

    Article  PubMed  PubMed Central  Google Scholar 

  39. Tian T, Woodworth J, Skold M, Behar SM. In vivo depletion of CD11c+ cells delays the CD4+ T cell response to Mycobacterium tuberculosis and exacerbates the outcome of infection. J Immunol. 2005;175:3268–72.

    Article  CAS  PubMed  Google Scholar 

  40. Wolf AJ, Linas B, Trevejo-Nunez GJ, Kincaid E, Tamura T, Takatsu K, et al. Mycobacterium tuberculosis infects dendritic cells with high frequency and impairs their function in vivo. J Immunol. 2007;179:2509–19.

    Article  CAS  PubMed  Google Scholar 

  41. Kang DD, Lin Y, Moreno JR, Randall TD, Khader SA. Profiling early lung immune responses in the mouse model of tuberculosis. PLoS One. 2011;6:e16161.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Dorhoi A, Kaufmann SH. Versatile myeloid cell subsets contribute to tuberculosis-associated inflammation. Eur J Immunol. 2015;45:2191–202.

    Article  CAS  PubMed  Google Scholar 

  43. Mayer-Barber KD, Andrade BB, Barber DL, Hieny S, Feng CG, Caspar P, et al. Innate and adaptive interferons suppress IL-1alpha and IL-1beta production by distinct pulmonary myeloid subsets during Mycobacterium tuberculosis infection. Immunity. 2011;35:1023–34.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Koh VH, Ng SL, Ang ML, Lin W, Ruedl C, Alonso S. Role and contribution of pulmonary CD103+ dendritic cells in the adaptive immune response to Mycobacterium tuberculosis. Tuberculosis. 2017;102:34–46.

    Article  CAS  PubMed  Google Scholar 

  45. Lozza L, Farinacci M, Bechtle M, Staber M, Zedler U, Baiocchini A, et al. Communication between human dendritic cell subsets in tuberculosis: requirements for Naive CD4(+) T Cell Stimulation. Front Immunol. 2014;5:324.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  46. Roberts LL, Robinson CM. Mycobacterium tuberculosis infection of human dendritic cells decreases integrin expression, adhesion and migration to chemokines. Immunology. 2014;141:39–51.

    Article  CAS  PubMed  Google Scholar 

  47. Srivastava S, Ernst JD. Cell-to-cell transfer of M. tuberculosis antigens optimizes CD4 T cell priming. Cell Host Microbe. 2014;15:741–52.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Srivastava S, Grace PS, Ernst JD. Antigen export reduces antigen presentation and limits T cell control of M. tuberculosis. Cell Host Microbe. 2016;19:44–54.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Divangahi M, Desjardins D, Nunes-Alves C, Remold HG, Behar SM. Eicosanoid pathways regulate adaptive immunity to Mycobacterium tuberculosis. Nat Immunol. 2010;11:751–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Griffiths KL, Ahmed M, Das S, Gopal R, Horne W, Connell TD, et al. Targeting dendritic cells to accelerate T-cell activation overcomes a bottleneck in tuberculosis vaccine efficacy. Nat Commun. 2016;7:13894.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Reiley WW, Calayag MD, Wittmer ST, Huntington JL, Pearl JE, Fountain JJ, et al. ESAT-6-specific CD4 T cell responses to aerosol Mycobacterium tuberculosis infection are initiated in the mediastinal lymph nodes. Proc Natl Acad Sci USA. 2008;105:10961–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Kaufmann SH, Cole ST, Mizrahi V, Rubin E, Nathan C. Mycobacterium tuberculosis and the host response. J Exp Med. 2005;201:1693–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Bhatt K, Verma S, Ellner JJ, Salgame P. Quest for correlates of protection against tuberculosis. Clin Vaccine Immunol. 2015;22:258–66.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Serbina NV, Lazarevic V, Flynn JL. CD4(+) T cells are required for the development of cytotoxic CD8(+) T cells during Mycobacterium tuberculosis infection. J Immunol. 2001;167:6991–7000.

    Article  CAS  PubMed  Google Scholar 

  55. Yao S, Huang D, Chen CY, Halliday L, Wang RC, Chen ZW. CD4+ T cells contain early extrapulmonary tuberculosis (TB) dissemination and rapid TB progression and sustain multieffector functions of CD8+ T and CD3- lymphocytes: mechanisms of CD4+ T cell immunity. J Immunol. 2014;192:2120–32.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Zhu J, Jankovic D, Oler AJ, Wei G, Sharma S, Hu G, et al. The transcription factor T-bet is induced by multiple pathways and prevents an endogenous Th2 cell program during Th1 cell responses. Immunity. 2012;37:660–73.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Cooper AM, Solache A, Khader SA. Interleukin-12 and tuberculosis: an old story revisited. Curr Opin Immunol. 2007;19:441–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Cooper AM, Roberts AD, Rhoades ER, Callahan JE, Getzy DM, Orme IM. The role of interleukin-12 in acquired immunity to Mycobacterium tuberculosis infection. Immunology. 1995;84:423–32.

    CAS  PubMed  PubMed Central  Google Scholar 

  59. Cooper AM, Kipnis A, Turner J, Magram J, Ferrante J, Orme IM. Mice lacking bioactive IL-12 can generate protective, antigen-specific cellular responses to mycobacterial infection only if the IL-12 p40 subunit is present. J Immunol. 2002;168:1322–7.

    Article  CAS  PubMed  Google Scholar 

  60. Fenton MJ, Vermeulen MW, Kim S, Burdick M, Strieter RM, Kornfeld H. Induction of gamma interferon production in human alveolar macrophages by Mycobacterium tuberculosis. Infect Immun. 1997;65:5149–56.

    CAS  PubMed  PubMed Central  Google Scholar 

  61. Caruso AM, Serbina N, Klein E, Triebold K, Bloom BR, Flynn JL. Mice deficient in CD4 T cells have only transiently diminished levels of IFN-gamma, yet succumb to tuberculosis. J Immunol. 1999;162:5407–16.

    CAS  PubMed  Google Scholar 

  62. Cleary AM, Tu W, Enright A, Giffon T, Dewaal-Malefyt R, Gutierrez K, et al. Impaired accumulation and function of memory CD4 T cells in human IL-12 receptor beta 1 deficiency. J Immunol. 2003;170:597–603.

    Article  CAS  PubMed  Google Scholar 

  63. Pearl JE, Khader SA, Solache A, Gilmartin L, Ghilardi N, deSauvage F, et al. IL-27 signaling compromises control of bacterial growth in mycobacteria-infected mice. J Immunol. 2004;173:7490–6.

    Article  CAS  PubMed  Google Scholar 

  64. Allen M, Bailey C, Cahatol I, Dodge L, Yim J, Kassissa C, et al. Mechanisms of control of Mycobacterium tuberculosis by NK cells: role of Glutathione. Front Immunol. 2015;6:508.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  65. Kawakami K, Kinjo Y, Uezu K, Miyagi K, Kinjo T, Yara S, et al. Interferon-gamma production and host protective response against Mycobacterium tuberculosis in mice lacking both IL-12p40 and IL-18. Microbes Infect. 2004;6:339–49.

    Article  CAS  PubMed  Google Scholar 

  66. Flynn JL, Chan J, Triebold KJ, Dalton DK, Stewart TA, Bloom BR. An essential role for interferon gamma in resistance to Mycobacterium tuberculosis infection. J Exp Med. 1993;178:2249–54.

    Article  CAS  PubMed  Google Scholar 

  67. Ottenhoff TH, Kumararatne D, Casanova JL. Novel human immunodeficiencies reveal the essential role of type-I cytokines in immunity to intracellular bacteria. Immunol Today. 1998;19:491–4.

    Article  CAS  PubMed  Google Scholar 

  68. Slight SR, Khader SA. Chemokines shape the immune responses to tuberculosis. Cytokine Growth Factor Rev. 2013;24:105–13.

    Article  CAS  PubMed  Google Scholar 

  69. Nunes-Alves C, Booty MG, Carpenter SM, Jayaraman P, Rothchild AC, Behar SM. In search of a new paradigm for protective immunity to TB. Nat Rev Microbiol. 2014;12:289–99.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Herbst S, Schaible UE, Schneider BE. Interferon gamma activated macrophages kill mycobacteria by nitric oxide induced apoptosis. PLoS One. 2011;6:e19105.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. Cowley SC, Elkins KL. CD4+ T cells mediate IFN-gamma-independent control of Mycobacterium tuberculosis infection both in vitro and in vivo. J Immunol. 2003;171:4689–99.

    Article  CAS  PubMed  Google Scholar 

  72. Canaday DH, Wilkinson RJ, Li Q, Harding CV, Silver RF, Boom WH. CD4(+) and CD8(+) T cells kill intracellular Mycobacterium tuberculosis by a perforin and Fas/Fas ligand-independent mechanism. J Immunol. 2001;167:2734–42.

    Article  CAS  PubMed  Google Scholar 

  73. Cavalcanti YV, Brelaz MC, Neves JK, Ferraz JC, Pereira VR. Role of TNF-Alpha, IFN-Gamma, and IL-10 in the development of Pulmonary Tuberculosis. Pulm Med. 2012;2012:745483.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  74. Kaneko H, Yamada H, Mizuno S, Udagawa T, Kazumi Y, Sekikawa K, et al. Role of tumor necrosis factor-alpha in Mycobacterium-induced granulomata formation in tumor necrosis factor-alpha-deficient mice. Laboratory investigation. J Tech Methods Pathol. 1999;79:379–86.

    CAS  Google Scholar 

  75. Harris J, Keane J. How tumour necrosis factor blockers interfere with tuberculosis immunity. Clin Exp Immunol. 2010;161:1–9.

    CAS  PubMed  PubMed Central  Google Scholar 

  76. Nunez Martinez O, Ripoll Noiseux C, Carneros Martin JA, Gonzalez Lara V, Gregorio Maranon HG. Reactivation tuberculosis in a patient with anti-TNF-alpha treatment. Am J Gastroenterol. 2001;96:1665–6.

    CAS  PubMed  Google Scholar 

  77. Gil DP, Leon LG, Correa LI, Maya JR, Paris SC, Garcia LF, et al. Differential induction of apoptosis and necrosis in monocytes from patients with tuberculosis and healthy control subjects. J Infect Dis. 2004;189:2120–8.

    Article  PubMed  Google Scholar 

  78. Saukkonen JJ, Bazydlo B, Thomas M, Strieter RM, Keane J, Kornfeld H. Beta-chemokines are induced by Mycobacterium tuberculosis and inhibit its growth. Infect Immun. 2002;70:1684–93.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  79. Roach DR, Bean AG, Demangel C, France MP, Briscoe H, Britton WJ. TNF regulates chemokine induction essential for cell recruitment, granulomata formation, and clearance of mycobacterial infection. J Immunol. 2002;168:4620–7.

    Article  CAS  PubMed  Google Scholar 

  80. Dwivedi VP, Bhattacharya D, Chatterjee S, Prasad DV, Chattopadhyay D, Van Kaer L, et al. Mycobacterium tuberculosis directs T helper 2 cell differentiation by inducing interleukin-1beta production in dendritic cells. J Biol Chem. 2012;287:33656–63.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  81. Gordon S, Martinez FO. Alternative activation of macrophages: mechanism and functions. Immunity. 2010;32:593–604.

    Article  CAS  PubMed  Google Scholar 

  82. Harris J, De Haro SA, Master SS, Keane J, Roberts EA, Delgado M, et al. T helper 2 cytokines inhibit autophagic control of intracellular Mycobacterium tuberculosis. Immunity. 2007;27:505–17.

    Article  CAS  PubMed  Google Scholar 

  83. Ashenafi S, Aderaye G, Bekele A, Zewdie M, Aseffa G, Hoang AT, et al. Progression of clinical tuberculosis is associated with a Th2 immune response signature in combination with elevated levels of SOCS3. Clin Immunol. 2014;151:84–99.

    Article  CAS  PubMed  Google Scholar 

  84. Heitmann L, Abad Dar M, Schreiber T, Erdmann H, Behrends J, McKenzie AN, et al. The IL-13/IL-4Ralpha axis is involved in tuberculosis-associated pathology. J Pathol. 2014;234:338–50.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  85. Lyadova IV, Panteleev AV. Th1 and Th17 cells in tuberculosis: protection, pathology, and biomarkers. Mediators Inflamm. 2015;2015:854507.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  86. Lockhart E, Green AM, Flynn JL. IL-17 production is dominated by gammadelta T cells rather than CD4 T cells during Mycobacterium tuberculosis infection. J Immunol. 2006;177:4662–9.

    Article  CAS  PubMed  Google Scholar 

  87. Umemura M, Yahagi A, Hamada S, Begum MD, Watanabe H, Kawakami K, et al. IL-17-mediated regulation of innate and acquired immune response against pulmonary Mycobacterium bovis bacille Calmette-Guerin infection. J Immunol. 2007;178:3786–96.

    Article  CAS  PubMed  Google Scholar 

  88. Wozniak TM, Ryan AA, Britton WJ. Interleukin-23 restores immunity to Mycobacterium tuberculosis infection in IL-12p40-deficient mice and is not required for the development of IL-17-secreting T cell responses. J Immunol. 2006;177:8684–92.

    Article  CAS  PubMed  Google Scholar 

  89. Hoeve MA, Savage ND, de Boer T, Langenberg DM, de Waal Malefyt R, Ottenhoff TH, et al. Divergent effects of IL-12 and IL-23 on the production of IL-17 by human T cells. Eur J Immunol. 2006;36:661–70.

    Article  CAS  PubMed  Google Scholar 

  90. Okamoto Yoshida Y, Umemura M, Yahagi A, O’Brien RL, Ikuta K, Kishihara K, et al. Essential role of IL-17A in the formation of a mycobacterial infection-induced granulomata in the lung. J Immunol. 2010;184:4414–22.

    Article  CAS  PubMed  Google Scholar 

  91. Gopal R, Monin L, Slight S, Uche U, Blanchard E, Junecko BAF, et al. Unexpected role for IL-17 in protective immunity against hypervirulent Mycobacterium tuberculosis HN878 infection. PLoS Pathog. 2014;10:e1004099.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  92. Goswami R, Kaplan MH. A brief history of IL-9. J Immunol. 2011;186:3283–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  93. Hauber HP, Bergeron C, Hamid Q. IL-9 in allergic inflammation. Int Arch Allergy Immunol. 2004;134:79–87.

    Article  CAS  PubMed  Google Scholar 

  94. Ye ZJ, Yuan ML, Zhou Q, Du RH, Yang WB, Xiong XZ, et al. Differentiation and recruitment of Th9 cells stimulated by pleural mesothelial cells in human Mycobacterium tuberculosis infection. PLoS One. 2012;7:e31710.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  95. Wu B, Huang C, Kato-Maeda M, Hopewell PC, Daley CL, Krensky AM, et al. IL-9 is associated with an impaired Th1 immune response in patients with tuberculosis. Clin Immunol. 2008;126:202–10.

    Article  CAS  PubMed  Google Scholar 

  96. Larson RP, Shafiani S, Urdahl KB. Foxp3(+) regulatory T cells in tuberculosis. Adv Exp Med Biol. 2013;783:165–80.

    Article  CAS  PubMed  Google Scholar 

  97. Shafiani S, Tucker-Heard G, Kariyone A, Takatsu K, Urdahl KB. Pathogen-specific regulatory T cells delay the arrival of effector T cells in the lung during early tuberculosis. J Exp Med. 2010;207:1409–20.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  98. Redford PS, Boonstra A, Read S, Pitt J, Graham C, Stavropoulos E, et al. Enhanced protection to Mycobacterium tuberculosis infection in IL-10-deficient mice is accompanied by early and enhanced Th1 responses in the lung. Eur J Immunol. 2010;40:2200–10.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  99. Redford PS, Murray PJ, O’Garra A. The role of IL-10 in immune regulation during M. tuberculosis infection. Mucosal Immunol. 2011;4:261–70.

    Article  CAS  PubMed  Google Scholar 

  100. Turner J, Gonzalez-Juarrero M, Ellis DL, Basaraba RJ, Kipnis A, Orme IM, et al. In vivo IL-10 production reactivates chronic pulmonary tuberculosis in C57BL/6 mice. J Immunol. 2002;169:6343–51.

    Article  CAS  PubMed  Google Scholar 

  101. Gong JH, Zhang M, Modlin RL, Linsley PS, Iyer D, Lin Y, et al. Interleukin-10 down-regulates Mycobacterium tuberculosis-induced Th1 responses and CTLA-4 expression. Infect Immun. 1996;64:913–8.

    CAS  PubMed  PubMed Central  Google Scholar 

  102. Schreiber T, Ehlers S, Heitmann L, Rausch A, Mages J, Murray PJ, et al. Autocrine IL-10 induces hallmarks of alternative activation in macrophages and suppresses antituberculosis effector mechanisms without compromising T cell immunity. J Immunol. 2009;183:1301–12.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  103. Rodrigues MF, Barsante MM, Alves CC, Souza MA, Ferreira AP, Amarante-Mendes GP, et al. Apoptosis of macrophages during pulmonary Mycobacterium bovis infection: correlation with intracellular bacillary load and cytokine levels. Immunology. 2009;128:e691–9.

    Article  PubMed  PubMed Central  Google Scholar 

  104. Patel NR, Swan K, Li X, Tachado SD, Koziel H. Impaired M. tuberculosis-mediated apoptosis in alveolar macrophages from HIV+ persons: potential role of IL-10 and BCL-3. J Leukoc Biol. 2009;86:53–60.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  105. Neurath MF. IL-12 family members in experimental colitis. Mucosal Immunol. 2008;1(Suppl 1):S28–30.

    Article  CAS  PubMed  Google Scholar 

  106. Tadokera R, Wilkinson KA, Meintjes GA, Skolimowska KH, Matthews K, Seldon R, et al. Role of the interleukin 10 family of cytokines in patients with immune reconstitution inflammatory syndrome associated with HIV infection and tuberculosis. J Infect Dis. 2013;207:1148–56.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  107. Lewinsohn DM, Briden AL, Reed SG, Grabstein KH, Alderson MR. Mycobacterium tuberculosis-reactive CD8+ T lymphocytes: the relative contribution of classical versus nonclassical HLA restriction. J Immunol. 2000;165:925–30.

    Article  CAS  PubMed  Google Scholar 

  108. Behar SM, Dascher CC, Grusby MJ, Wang CR, Brenner MB. Susceptibility of mice deficient in CD1D or TAP1 to infection with Mycobacterium tuberculosis. J Exp Med. 1999;189:1973–80.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  109. Sousa AO, Mazzaccaro RJ, Russell RG, Lee FK, Turner OC, Hong S, et al. Relative contributions of distinct MHC class I-dependent cell populations in protection to tuberculosis infection in mice. Proc Natl Acad Sci USA. 2000;97:4204–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  110. Chen CY, Huang D, Wang RC, Shen L, Zeng G, Yao S, et al. A critical role for CD8 T cells in a nonhuman primate model of tuberculosis. PLoS Pathog. 2009;5:e1000392.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  111. Turner J, Dockrell HM. Stimulation of human peripheral blood mononuclear cells with live Mycobacterium bovis BCG activates cytolytic CD8+ T cells in vitro. Immunology. 1996;87:339–42.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  112. Woodworth JS, Wu Y, Behar SM. Mycobacterium tuberculosis-specific CD8+ T cells require perforin to kill target cells and provide protection in vivo. J Immunol. 2008;181:8595–603.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  113. Stenger S, Hanson DA, Teitelbaum R, Dewan P, Niazi KR, Froelich CJ, et al. An anti-microbial activity of cytolytic T cells mediated by granulysin. Science. 1998;282:121–5.

    Article  CAS  PubMed  Google Scholar 

  114. Vani J, Shaila MS, Rao MK, Krishnaswamy UM, Kaveri SV, Bayry J. B lymphocytes from patients with tuberculosis exhibit hampered antigen-specific responses with concomitant overexpression of interleukin-8. J Infect Dis. 2009;200:481–2 (author reply 482–4).

    Article  CAS  PubMed  Google Scholar 

  115. Kozakiewicz L, Phuah J, Flynn J, Chan J. The role of B cells and humoral immunity in Mycobacterium tuberculosis infection. Adv Exp Med Biol. 2013;783:225–50.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  116. Kozakiewicz L, Chen Y, Xu J, Wang Y, Dunussi-Joannopoulos K, Ou Q, et al. B cells regulate neutrophilia during Mycobacterium tuberculosis infection and BCG vaccination by modulating the interleukin-17 response. PLoS Pathog. 2013;9:e1003472.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  117. Maglione PJ, Xu J, Chan J. B cells moderate inflammatory progression and enhance bacterial containment upon pulmonary challenge with Mycobacterium tuberculosis. J Immunol. 2007;178:7222–34.

    Article  CAS  PubMed  Google Scholar 

  118. Roach SK, Schorey JS. Differential regulation of the mitogen-activated protein kinases by pathogenic and nonpathogenic mycobacteria. Infect Immun. 2002;70:3040–52.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  119. Moriuchi H, Moriuchi M, Fauci AS. Nuclear factor-kappa B potently up-regulates the promoter activity of RANTES, a chemokine that blocks HIV infection. J Immunol. 1997;158:3483–91.

    CAS  PubMed  Google Scholar 

  120. Saunders BM, Cooper AM. Restraining mycobacteria: role of granulomatas in mycobacterial infections. Immunol Cell Biol. 2000;78:334–41.

    Article  CAS  PubMed  Google Scholar 

  121. Lesley R, Ramakrishnan L. Insights into early mycobacterial pathogenesis from the zebrafish. Curr Opin Microbiol. 2008;11:277–83.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  122. Helming L, Gordon S. The molecular basis of macrophage fusion. Immunobiology. 2007;212:785–93.

    Article  CAS  PubMed  Google Scholar 

  123. Russell DG, Cardona PJ, Kim MJ, Allain S, Altare F. Foamy macrophages and the progression of the human tuberculosis granulomata. Nat Immunol. 2009;10:943–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  124. Monin L, Khader SA. Chemokines in tuberculosis: the good, the bad and the ugly. Semin Immunol. 2014;26:552–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  125. Algood HM, Flynn JL. CCR5-deficient mice control Mycobacterium tuberculosis infection despite increased pulmonary lymphocytic infiltration. J Immunol. 2004;173:3287–96.

    Article  PubMed  Google Scholar 

  126. Seiler P, Aichele P, Bandermann S, Hauser AE, Lu B, Gerard NP, et al. Early granulomata formation after aerosol Mycobacterium tuberculosis infection is regulated by neutrophils via CXCR3-signaling chemokines. Eur J Immunol. 2003;33:2676–86.

    Article  CAS  PubMed  Google Scholar 

  127. Groom JR, Luster AD. CXCR3 ligands: redundant, collaborative and antagonistic functions. Immunol Cell Biol. 2011;89:207–15.

    Article  CAS  PubMed  Google Scholar 

  128. Elkington PT, D’Armiento JM, Friedland JS. Tuberculosis immunopathology: the neglected role of extracellular matrix destruction. Sci Transl Med. 2011;3:71ps6.

    Article  PubMed  PubMed Central  Google Scholar 

  129. Gideon HP, Flynn JL. Latent tuberculosis: what the host “sees”? Immunol Res. 2011;50:202–12.

    Article  PubMed  PubMed Central  Google Scholar 

  130. O’Garra A, Vieira PL, Vieira P, Goldfeld AE. IL-10-producing and naturally occurring CD4+ Tregs: limiting collateral damage. J Clin Investig. 2004;114:1372–8.

    Article  PubMed  PubMed Central  Google Scholar 

  131. Bekker LG, Moreira AL, Bergtold A, Freeman S, Ryffel B, Kaplan G. Immunopathologic effects of tumor necrosis factor alpha in murine mycobacterial infection are dose dependent. Infect Immun. 2000;68:6954–61.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  132. Serhan CN. Pro-resolving lipid mediators are leads for resolution physiology. Nature. 2014;510:92–101.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  133. Mayer-Barber KD, Sher A. Cytokine and lipid mediator networks in tuberculosis. Immunol Rev. 2015;264:264–75.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  134. Tobin DM, Roca FJ, Oh SF, McFarland R, Vickery TW, Ray JP, et al. Host genotype-specific therapies can optimize the inflammatory response to mycobacterial infections. Cell. 2012;148:434–46.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  135. Tobin DM, Vary JC Jr, Ray JP, Walsh GS, Dunstan SJ, Bang ND, et al. The lta4 h locus modulates susceptibility to mycobacterial infection in zebrafish and humans. Cell. 2010;140:717–30.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  136. Roca FJ, Ramakrishnan L. TNF dually mediates resistance and susceptibility to mycobacteria via mitochondrial reactive oxygen species. Cell. 2013;153:521–34.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  137. Prieto P, Cuenca J, Traves PG, Fernandez-Velasco M, Martin-Sanz P, Bosca L. Lipoxin A4 impairment of apoptotic signaling in macrophages: implication of the PI3 K/Akt and the ERK/Nrf-2 defense pathways. Cell Death Differ. 2010;17:1179–88.

    Article  CAS  PubMed  Google Scholar 

  138. Divangahi M, Behar SM, Remold H. Dying to live: how the death modality of the infected macrophage affects immunity to tuberculosis. Adv Exp Med Biol. 2013;783:103–20.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  139. Bourigault ML, Segueni N, Rose S, Court N, Vacher R, Vasseur V, et al. Relative contribution of IL-1alpha, IL-1beta and TNF to the host response to Mycobacterium tuberculosis and attenuated M. bovis BCG. Immun Inflamm Dis. 2013;1:47–62.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  140. Carlsson F, Kim J, Dumitru C, Barck KH, Carano RA, Sun M, et al. Host-detrimental role of Esx-1-mediated inflammasome activation in mycobacterial infection. PLoS Pathog. 2010;6:e1000895.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  141. Dorhoi A, Yeremeev V, Nouailles G, Weiner J 3rd, Jorg S, Heinemann E, et al. Type I IFN signaling triggers immunopathology in tuberculosis-susceptible mice by modulating lung phagocyte dynamics. Eur J Immunol. 2014;44:2380–93.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  142. Berry MP, Graham CM, McNab FW, Xu Z, Bloch SA, Oni T, et al. An interferon-inducible neutrophil-driven blood transcriptional signature in human tuberculosis. Nature. 2010;466:973–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  143. Bloom CI, Graham CM, Berry MP, Wilkinson KA, Oni T, Rozakeas F, et al. Detectable changes in the blood transcriptome are present after two weeks of antituberculosis therapy. PLoS One. 2012;7:e46191.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  144. Amaral EP, Lasunskaia EB, D’Imperio-Lima MR. Innate immunity in tuberculosis: how the sensing of mycobacteria and tissue damage modulates macrophage death. Microbes Infect. 2016;18:11–20.

    Article  CAS  PubMed  Google Scholar 

  145. Krishnan N, Robertson BD, Thwaites G. Pathways of IL-1beta secretion by macrophages infected with clinical Mycobacterium tuberculosis strains. Tuberculosis. 2013;93:538–47.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  146. Jayaraman P, Sada-Ovalle I, Nishimura T, Anderson AC, Kuchroo VK, Remold HG, et al. IL-1beta promotes anti-microbial immunity in macrophages by regulating TNFR signaling and caspase-3 activation. J Immunol. 2013;190:4196–204.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  147. Desvignes L, Ernst JD. Interferon-gamma-responsive nonhematopoietic cells regulate the immune response to Mycobacterium tuberculosis. Immunity. 2009;31:974–85.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  148. Juffermans NP, Florquin S, Camoglio L, Verbon A, Kolk AH, Speelman P, et al. Interleukin-1 signaling is essential for host defense during murine pulmonary tuberculosis. J Infect Dis. 2000;182:902–8.

    Article  CAS  PubMed  Google Scholar 

  149. Cruz A, Khader SA, Torrado E, Fraga A, Pearl JE, Pedrosa J, et al. Cutting edge: IFN-gamma regulates the induction and expansion of IL-17-producing CD4 T cells during mycobacterial infection. J Immunol. 2006;177:1416–20.

    Article  CAS  PubMed  Google Scholar 

  150. Cruz A, Fraga AG, Fountain JJ, Rangel-Moreno J, Torrado E, Saraiva M, et al. Pathological role of interleukin 17 in mice subjected to repeated BCG vaccination after infection with Mycobacterium tuberculosis. J Exp Med. 2010;207:1609–16.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  151. MacMicking JD, North RJ, LaCourse R, Mudgett JS, Shah SK, Nathan CF. Identification of nitric oxide synthase as a protective locus against tuberculosis. Proc Natl Acad Sci USA. 1997;94:5243–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  152. Barber DL, Mayer-Barber KD, Feng CG, Sharpe AH, Sher A. CD4 T cells promote rather than control tuberculosis in the absence of PD-1-mediated inhibition. J Immunol. 2011;186:1598–607.

    Article  CAS  PubMed  Google Scholar 

  153. Roy E, Brennan J, Jolles S, Lowrie DB. Beneficial effect of anti-interleukin-4 antibody when administered in a murine model of tuberculosis infection. Tuberculosis. 2008;88:197–202.

    Article  CAS  PubMed  Google Scholar 

  154. Ehlers S, Benini J, Held HD, Roeck C, Alber G, Uhlig S. Alphabeta T cell receptor-positive cells and interferon-gamma, but not inducible nitric oxide synthase, are critical for granulomata necrosis in a mouse model of mycobacteria-induced pulmonary immunopathology. J Exp Med. 2001;194:1847–59.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  155. Marzo E, Vilaplana C, Tapia G, Diaz J, Garcia V, Cardona PJ. Damaging role of neutrophilic infiltration in a mouse model of progressive tuberculosis. Tuberculosis. 2014;94:55–64.

    Article  CAS  PubMed  Google Scholar 

  156. Green AM, Mattila JT, Bigbee CL, Bongers KS, Lin PL, Flynn JL. CD4(+) regulatory T cells in a cynomolgus macaque model of Mycobacterium tuberculosis infection. J Infect Dis. 2010;202:533–41.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  157. Leepiyasakulchai C, Ignatowicz L, Pawlowski A, Kallenius G, Skold M. Failure to recruit anti-inflammatory CD103+ dendritic cells and a diminished CD4+ Foxp3+ regulatory T cell pool in mice that display excessive lung inflammation and increased susceptibility to Mycobacterium tuberculosis. Infect Immun. 2012;80:1128–39.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  158. Cilfone NA, Perry CR, Kirschner DE, Linderman JJ. Multi-scale modeling predicts a balance of tumor necrosis factor-alpha and interleukin-10 controls the granulomata environment during Mycobacterium tuberculosis infection. PLoS One. 2013;8:e68680.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  159. Cardona PJ. The progress of therapeutic vaccination with regard to tuberculosis. Front Microbiol. 2016;7:1536.

    PubMed  PubMed Central  Google Scholar 

  160. Lazar-Molnar E, Chen B, Sweeney KA, Wang EJ, Liu W, Lin J, et al. Programmed death-1 (PD-1)-deficient mice are extraordinarily sensitive to tuberculosis. Proc Natl Acad Sci USA. 2010;107:13402–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  161. Yuk JM, Jo EK. Host immune responses to mycobacterial antigens and their implications for the development of a vaccine to control tuberculosis. Clin Exp Vaccine Res. 2014;3:155–67.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  162. Bradfute SB, Castillo EF, Arko-Mensah J, Chauhan S, Jiang S, Mandell M, et al. Autophagy as an immune effector against tuberculosis. Curr Opin Microbiol. 2013;16:355–65.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  163. Castillo EF, Dekonenko A, Arko-Mensah J, Mandell MA, Dupont N, Jiang S, et al. Autophagy protects against active tuberculosis by suppressing bacterial burden and inflammation. Proc Natl Acad Sci USA. 2012;109:E3168–76.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  164. Russell DG, Barry CE 3rd, Flynn JL. Tuberculosis: what we don’t know can, and does, hurt us. Science. 2010;328:852–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  165. Chan ED, Iseman MD. Multidrug-resistant and extensively drug-resistant tuberculosis: a review. Curr Opin Infect Dis. 2008;21:587–95.

    Article  CAS  PubMed  Google Scholar 

  166. Denholm JT, McBryde ES. The use of anti-tuberculosis therapy for latent TB infection. Infect Drug Resist. 2010;3:63–72.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  167. Pai M, Behr MA, Dowdy D, Dheda K, Divangahi M, Boehme CC, et al. Tuberculosis. Nat Rev Dis Prim. 2016;2:16076.

    Article  PubMed  Google Scholar 

  168. Zumla AI, Gillespie SH, Hoelscher M, Philips PP, Cole ST, Abubakar I, et al. New antituberculosis drugs, regimens, and adjunct therapies: needs, advances, and future prospects. Lancet Infect Dis. 2014;14:327–40.

    Article  CAS  PubMed  Google Scholar 

  169. Kaufmann SH, Lange C, Rao M, Balaji KN, Lotze M, Schito M, et al. Progress in tuberculosis vaccine development and host-directed therapies–a state of the art review. Lancet Respir Med. 2014;2:301–20.

    Article  CAS  PubMed  Google Scholar 

  170. Schiebler M, Brown K, Hegyi K, Newton SM, Renna M, Hepburn L, et al. Functional drug screening reveals anticonvulsants as enhancers of mTOR-independent autophagic killing of Mycobacterium tuberculosis through inositol depletion. EMBO Mol Med. 2015;7:127–39.

    Article  CAS  PubMed  Google Scholar 

  171. Yu X, Li C, Hong W, Pan W, Xie J. Autophagy during Mycobacterium tuberculosis infection and implications for future tuberculosis medications. Cell Signal. 2013;25:1272–8.

    Article  CAS  PubMed  Google Scholar 

  172. Ivanyi J, Zumla A. Nonsteroidal antiinflammatory drugs for adjunctive tuberculosis treatment. J Infect Dis. 2013;208:185–8.

    Article  PubMed  Google Scholar 

  173. Mayer-Barber KD, Andrade BB, Oland SD, Amaral EP, Barber DL, Gonzales J, et al. Host-directed therapy of tuberculosis based on interleukin-1 and type I interferon crosstalk. Nature. 2014;511:99–103.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  174. Skerry C, Harper J, Klunk M, Bishai WR, Jain SK. Adjunctive TNF inhibition with standard treatment enhances bacterial clearance in a murine model of necrotic TB granulomatas. PLoS One. 2012;7:e39680.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  175. Kagina BM, Abel B, Scriba TJ, Hughes EJ, Keyser A, Soares A, et al. Specific T cell frequency and cytokine expression profile do not correlate with protection against tuberculosis after bacillus Calmette-Guerin vaccination of newborns. Am J Respir Crit Care Med. 2010;182:1073–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  176. Diel R, Loddenkemper R, Meywald-Walter K, Niemann S, Nienhaus A. Predictive value of a whole blood IFN-gamma assay for the development of active tuberculosis disease after recent infection with Mycobacterium tuberculosis. Am J Respir Crit Care Med. 2008;177:1164–70.

    Article  PubMed  Google Scholar 

  177. Higuchi K, Harada N, Fukazawa K, Mori T. Relationship between whole-blood interferon-gamma responses and the risk of active tuberculosis. Tuberculosis. 2008;88:244–8.

    Article  CAS  PubMed  Google Scholar 

  178. Cardona PJ. RUTI: a new chance to shorten the treatment of latent tuberculosis infection. Tuberculosis. 2006;86:273–89.

    Article  PubMed  Google Scholar 

  179. Stanford JL. Improving on BCG. APMIS. 1991;99:103–13.

    Article  CAS  PubMed  Google Scholar 

  180. Ottenhoff TH, Kaufmann SH. Vaccines against tuberculosis: where are we and where do we need to go? PLoS Pathog. 2012;8:e1002607.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  181. Gil O, Guirado E, Gordillo S, Diaz J, Tapia G, Vilaplana C, et al. Intragranulomatatous necrosis in lungs of mice infected by aerosol with Mycobacterium tuberculosis is related to bacterial load rather than to any one cytokine or T cell type. Microbes Infect. 2006;8:628–36.

    Article  CAS  PubMed  Google Scholar 

  182. Curtis J, Luo Y, Zenner HL, Cuchet-Lourenco D, Wu C, Lo K, et al. Susceptibility to tuberculosis is associated with variants in the ASAP1 gene encoding a regulator of dendritic cell migration. Nat Genet. 2015;47:523–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  183. Minion J, Leung E, Talbot E, Dheda K, Pai M, Menzies D. Diagnosing tuberculosis with urine lipoarabinomannan: systematic review and meta-analysis. Eur Respir J. 2011;38:1398–405.

    Article  CAS  PubMed  Google Scholar 

  184. Singh PK, Singh AV, Chauhan DS. Current understanding on micro RNAs and its regulation in response to Mycobacterial infections. J Biomed Sci. 2013;20:14.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  185. Wang J, Chen J, Sen S. MicroRNA as biomarkers and diagnostics. J Cell Physiol. 2016;231:25–30.

    Article  CAS  PubMed  Google Scholar 

  186. Gupta S, Shenoy VP, Bairy I, Srinivasa H, Mukhopadhyay C. Diabetes mellitus and HIV as co-morbidities in tuberculosis patients of rural south India. J Infect Public Health. 2011;4:140–4.

    Article  PubMed  Google Scholar 

  187. Griffiths G, Nystrom B, Sable SB, Khuller GK. Nanobead-based interventions for the treatment and prevention of tuberculosis. Nat Rev Microbiol. 2010;8:827–34.

    Article  CAS  PubMed  Google Scholar 

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    Shachi Pranjal Vyas & Ritobrata Goswami

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Vyas, S.P., Goswami, R. Striking the right immunological balance prevents progression of tuberculosis. Inflamm. Res. 66, 1031–1056 (2017). https://doi.org/10.1007/s00011-017-1081-z

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