Routing Innate and Adaptive Immune response against M. tuberculosis and boosting Mycobacterium bovis Bacillus Calmette Güerin (BCG) vaccine immunity through prime boost protocols

Gloria G. Guerrero, Rogelio Hernández-Pando

Article ID: 2451
Vol 7, Issue 2, 2023

VIEWS - 278 (Abstract) 105 (PDF)


Tuberculosis (Tb) is still a global health problem, especially in developing countries. Several factors contribute to this, among them the increasing multidrug resistance strains, the dangerous liaisons with other intracellular pathogens, such as HIV, and more recently, SARS-CoV2 pandemics. There are many aspects that remain to understand the bacterial molecular mechanism of pathogenicity and the immune response induced by the interaction of M. tuberculosis (MTb) with the host. The official and current vaccine based on the attenuated Mycobacterium bovis Bacillus Calmette Guerin (BCG) is protective against several forms of Tb meningitis and Miliary TB or disseminated disease in young children. However, it fails to protect young and adult individuals. There are several new promising candidates for vaccines to replace or boost BCG-induced immunity. Several evidences exist from humans and mice on the role of the trained innate memory of monocytes and NK cells, on the second encounter with the same mycobacterial pathogen or other respiratory pathogens. This type of immune response is nonspecific and independent of the T and B cells. Thus, BCG vaccination is a double immunogen that activate specific immune responses and is also able to stimulate nonspecific immune responses. Here, it is outlined the host immunity against MTb, the potential of BCG vaccination and prime boost protocols for routing innate and adaptive immune responses in TB.


M. tuberculosis; prime boost protocols; BCG based vaccine

Full Text:



1. World Health Organization (WHO). The top 10 causes of death. Available online: (accessed on 19 October 2023).

2. World Health Organization (WHO). Global Tuberculosis Control; Surveillance, Planning Financing. WHO; 2022.

3. Maher D, Raviglione M. Global epidemiology of tuberculosis. Clinics in Chest Medicine 2005; 26: 167–182. doi: 10.1016/j.ccm.2005.02.009

4. Young DB, Perkins MD, Duncan K, Barry CE III. Confronting the scientific obstacles to global control of tuberculosis. The Journal of clinical investigation 2008; 118: 1255–1265. doi: 10.1172/jci34614

5. Zumla A, Maeurer M. Host-directed therapies for tackling multi-drug resistant tuberculosis: Learning from the pasteur-bechamp debates. Clinical Infectious Diseases: An Official Publication of the Infectious Diseases Society of America 2015; 61(9): 1432–1438. doi: 10.1093/cid/civ631

6. Rodrigues LC, Diwan VK, Wheeler JG. Protective effect of BCG against tuberculous meningitis and miliary tuberculosis: A meta-analysis. International Journal of Epidemiology 1993; 22(6): 1154–1158. doi: 10.1093/ije/22.6.1154

7. Fine PEM. Variation in protection by BCG: Implications of and for heterologous immunity. Lancet 1995; 346(8986): 1339–1345. doi: 10.1016/s0140-6736(95)92348-9

8. Trunz BB, Fine P, Dye C. Effect of BCG vaccination on childhood tuberculous meningitis and miliary tuberculosis worldwide: A meta-analysis and assessment of cost-effectiveness. Lancet 2006; 367(9517): 1173–1180. doi: 10.1016/S0140-6736(06)68507-3

9. Swaminathan S, Rekha B. Pediatric tuberculosis: Global overview and challenges. Clinical Infectious Diseases: An Official Publication of the Infectious Diseases Society of America 2010; 50: S184–S194. doi: 10.1086/651490

10. Andersen P, Doherty TM. The success and failure of BCG—Implications for a novel tuberculosis vaccine. Nature Reviews. Microbiology 2005; 3: 656–662. doi: 10.1038/nrmicro1211

11. Mangtani P, Abubakar I, Ariti C, et al. Protection by BCG vaccine against tuberculosis: A systematic review of randomized controlled trials. Clinical Infectious Diseases: An Official Publication of the Infectious Diseases Society of America 2013; 58(4): 470–480. doi: 10.1093/cid/cit790

12. da Costa AC, Nogueira SV, Kipnis A, Junqueira-Kipnis AP. Recombinant BCG: Innovations on an old vaccine. Scope of BCG strains and strategies to improve long-lasting memory. Frontiers in Immunology 2014; 5: 152. doi: 10.3389/fimmu.2014.00152

13. Van Der Meeren O, Hatherill M, Nduba V, et al. Phase 2b controlled trial of M72/AS01E vaccine to prevent tuberculosis. The New England Journal of Medicine 2018; 379(17): 1621–1634. doi: 10.1056/nejmoa1803484

14. Hansen SG, Zak DE, Xu G, et al. Prevention of tuberculosis in rhesus macaques by a cytomegalovirus-based vaccine. Nature Medicine 2018; 24(2): 130–143. doi: 10.1038/nm.4473

15. Andersen P, Scriba TJ. Moving tuberculosis vaccines from theory to practice. Nature Reviews Immunology 2019; 19: 550–562. doi: 10.1038/s41577-019-0174-z

16. Gonzalo-Asensio J, Marinova D, Martin C, Aguilo N. MTBVAC: Attenuating the human pathogen of tuberculosis (TB) toward a promising vaccine against the TB epidemic. Frontiers in Immunology 2017; 8: 1803. doi: 10.3389/fimmu.2017.01803

17. Abebe F. Is interferon-gamma the right marker for bacille Calmette–Guérin-induced immune protection? The missing link in our understanding of tuberculosis immunology. Clinical and Experimental Immunology 2012; 169(3): 213–219. doi: 10.1111/j.1365-2249.2012.04614.x

18. O’Garra A, Redford PS, McNab FW, et al. The immune response in tuberculosis. Annual Review of Immunology 2013; 31: 475–527. doi: 10.1146/annurev-immunol-032712-095939

19. Rodo MJ, Rozot V, Nemes E, et al. A comparison of antigen-specific T cell responses induced by six novel tuberculosis vaccine candidates. PLoS Pathogens 2019; 15(3): e1007643. doi: 10.1371/journal.ppat.1007643

20. Koul A, Herget T, Klebl B, Ullrich A. Interplay between mycobacteria and host signalling pathways. Nature Reviews. Microbiology 2004; 2(3): 189–202. doi: 10.1038/nrmicro840

21. Flynn JL, Chan J. Immunology of tuberculosis. Annual Review of Immunology 2001; 19: 93–129. doi: 10.1146/annurev.immunol.19.1.93

22. Cooper AM. Cell-mediated immune responses in tuberculosis. Annual Review of Immunology 2009; 27: 393–422. doi: 10.1146/annurev.immunol.021908.132703

23. Jo EK. Mycobacterial interaction with innate receptors: TLRs, C-type lectins, and NLRs. Current Opinion in Infectious Diseases 2008; 21(3): 279–286. doi: 10.1097/qco.0b013e3282f88b5d

24. Chen CY, Huang D, Wang RC, et al. A critical role for CD8 T cells in a nonhuman primate model of tuberculosis. PLoS Pathogens 2009; 5(4): e1000392. doi: 10.1371/journal.ppat.1000392

25. Nathan C, Shiloh MU. Reactive oxygen and nitrogen intermediates in the relationship between mammalian hosts and microbial pathogens. Proceedings of the National Academy of Sciences of the United States of America 2000; 97(16): 8841–8848. doi: 10.1073/pnas.97.16.8841

26. Zhu XW, Friedland JS. Multinucleate giant cells and the control of chemokine secretion in response to Mycobacterium tuberculosis. Clinical Immunology 2006; 120(1): 10–20. doi: 10.1016/j.clim.2006.01.009

27. Shu CC, Wu MF, Hsu CL, et al. Apoptosis-associated biomarkers in tuberculosis: Promising for diagnosis and prognosis prediction. BMC Infectious Diseases 2013; 13: 45. doi: 10.1186/1471-2334-13-45

28. Stamm CE, Collins AC, Shiloh MU. Sensing of Mycobacterium tuberculosis and consequences to both host and bacillus. Immunological Reviews 2015; 264(1): 204–219. doi: 10.1111/imr.12263

29. Blomgran R, Desvignes L, Briken V, Ernst JD. Mycobacterium tuberculosis inhibits neutrophil apoptosis, leading to delayed activation of naive CD4 T cells. Cell Host & Microbe 2012; 11(1): 81–90. doi: 10.1016/j.chom.2011.11.012

30. Blomgran R, Ernst JD. Lung neutrophils facilitate activation of naive antigen-specific CD4+ T cells during mycobacterium tuberculosis infection. The Journal of Immunology 2011; 186(12): 7110–7119. doi: 10.4049/jimmunol.1100001

31. Köster S, Upadhyay S, Chandra P, et al. Mycobacterium tuberculosis is protected from NADPH oxidase and LC3-associated phagocytosis by the LCP protein CpsA. Proceedings of the National Academy of Sciences of the United States of America 2017; 114(41): E8711–E8720. doi: 10.1073/pnas.1707792114

32. Mishra BB, Moura-Alves P, Sonawane A, et al. Mycobacterium tuberculosis protein ESAT-6 is a potent activator of the NLRP3/ASC inflammasome. Cellular Microbiology 2010; 12(8): 1046–1063. doi: 10.1111/j.1462-5822.2010.01450.x

33. Ouimet M, Koster S, Sakowski E, et al. Mycobacterium tuberculosis induces the miR-33 locus to reprogram autophagy and host lipid metabolism. Nature Immunology 2016; 17: 677–686. doi: 10.1038/ni.3434

34. Martin CJ, Booty MG, Rosebrock TR, et al. Efferocytosis is an innate antibacterial mechanism. Cell Host & Microbe 2012; 12(3): 289–300. doi: 10.1016/j.chom.2012.06.010

35. Kimmey JM, Stallings CL. Bacterial pathogens versus autophagy: Implications for therapeutic interventions. Trends in Molecular Medicine 2016; 22(12): 1060–1076. doi: 10.1016/j.molmed.2016.10.008

36. Zeng G, Chen CY, Huang D, et al. Membrane-bound IL-22 after de novo production in tuberculosis and anti-mycobacterium tuberculosis effector function of IL-22+ CD4+ T cells. The Journal of Immunology 2011; 187(1): 190–199. doi: 10.4049/jimmunol.1004129

37. Mohr I, Sonenberg N. Host translation at the nexus of infection and immunity. Cell Host & Microbe 2012; 12(4): 470–483. doi: 10.1016/j.chom.2012.09.006

38. Pulendran B, Ahmed R. Translating innate immunity into immunological memory: Implications for vaccine development. Cell 2006; 124(4): 849–863. doi: 10.1016/j.cell.2006.02.019

39. Ahmad S. Pathogenesis, immunology, and diagnosis of latent mycobacterium tuberculosis infection. Clinical and Developmental Immunology 2011; 2011: 814943. doi: 10.1155/2011/814943

40. Tsolaki AG, Varghese MP, Kishore U. Innate immune pattern recognition receptors of Mycobacterium tuberculosis: Nature and consequences for pathogenesis of tuberculosis. In: Kishore U (editor). Microbial Pathogenesis: Infection and Immunity. Springer, Cham; 2021. Volume 1313. pp. 179–215. doi: 10.1007/978-3-030-67452-6-9

41. Moreira-Teixeira L, Redford PS, Stavropoulos E, et al. T cell-derived IL-10 impairs host resistance to Mycobacterium tuberculosis infection. The Journal of Immunology 2017; 199(2): 613–623. doi: 10.4049/jimmunol.1601340

42. Jeyanathan M, Mu J, Kugathasan K, et al. Airway delivery of soluble mycobacterial antigens restores protective mucosal immunity by single intramuscular plasmid DNA tuberculosis vaccinations: Role of proinflammatory signals in the lung. Journal of Immunology 2008; 181(8): 5618–5626. doi: 10.4049/jimmunol.181.8.5618

43. Dhiman R, Indramohan M, Barnes PF, et al. IL-22 produced by human NK cells inhibits growth of mycobacterium tuberculosis by enhancing phagolysosomal fusion. The Journal of Immunology 2009; 183(10): 6639–6645. doi: 10.4049/jimmunol.0902587

44. El Fenniri L, Toossi Z, Aung H, et al. Polyfunctional Mycobacterium tuberculosis-specific effector memory CD4+ T cells at sites of pleural TB. Tuberculosis 2011; 91(3): 224–230. doi: 10.1016/

45. Ewer K, Millington KA, Deeks JJ, et al. Dynamic antigen-specific T-cell responses after point-source exposure to Mycobacterium tuberculosis. American Journal of Respiratory and Critical Care Medicine 2006; 174(7): 831–839. doi: 10.1164/rccm.200511-1783oc

46. Hernández-Pando R, Jeyanathan M, Mengistu G, et al. Persistence of DNA from Mycobacterium tuberculosis in superficially normal lung tissue during latent infection. Lancet 2000; 356(9248): 2133–2138. doi: 10.1016/s0140-6736(00)03493-0

47. Harris J, Master SS, De Haro SA, et al. Th1–Th2 polarisation and autophagy in the control of intracellular mycobacteria by macrophages. Veterinary Immunology and Immunopathology 2009; 128(1–3): 37–43. doi: 10.1016/j.vetimm.2008.10.293

48. Barry CE 3rd, Boshoff HI, Dartois V, et al. The spectrum of latent tuberculosis: Rethinking the biology and intervention strategies. Nature Reviews. Microbiology 2009; 7(12): 845–855. doi: 10.1038/nrmicro2236

49. Daniel J, Maamar H, Deb C, et al. Mycobacterium tuberculosis uses host triacylglycerol to accumulate lipid droplets and acquires a dormancy-like phenotype in lipid-loaded macrophages. PLoS Pathogens 2011; 7(6): e1002093. doi: 10.1371/journal.ppat.1002093

50. Chen M, Divangahi M, Gan H, et al. Lipid mediators in innate immunity against tuberculosis: Opposing roles of PGE2 and LXA4 in the induction of macrophage death. The Journal of Experimental Medicine 2008; 205(12): 2791–2801. doi: 10.1084/jem.20080767

51. Sutherland JS, de Jong BC, Jeffries DJ, et al. Production of TNF-α, IL-12(p40) and IL-17 can discriminate between active TB disease and latent infection in a West African cohort. PLoS One 2010; 5(8): e12365. doi: 10.1371/journal.pone.0012365

52. McAleer JP, Kolls JK. Mechanisms controlling Th17 cytokine expression and host defense. Journal of Leukocyte Biology 2011; 90(2): 263–270. doi: 10.1189/jlb.0211099

53. Verhagen LM, Zomer A, Maes M, et al. A predictive signature gene set for discriminating active from latent tuberculosis in Warao Amerindian children. BMC Genomics 2013; 14: 74. doi: 10.1186/1471-2164-14-74

54. Wallis RS, Kim P, Cole S, et al. Tuberculosis biomarkers discovery: Developments, needs, and challenges. The Lancet. Infectious Diseases 2013; 13(4): 362–372. doi: 10.1016/S1473-3099(13)70034-3

55. Mistry R, Cliff JM, Clayton CL, et al. Gene-expression patterns in whole blood identify subjects at risk for recurrent tuberculosis. The Journal of Infectious Diseases 2007; 195(3): 357–365. doi: 10.1086/510397

56. Locht C, Hougardy JM, Rouanet C, et al. Heparin-binding hemagglutinin, from an extrapulmonary dissemination factor to a powerful diagnostic and protective antigen against tuberculosis. Tuberculosis 2006; 86(3–4): 303–309. doi: 10.1016/

57. Walzl G, Ronacher K, Hanekom W, et al. Immunological biomarkers of tuberculosis. Nature Reviews. Immunology 2011; 11(5): 343–354. doi: 10.1038/nri2960

58. Berry MPR, Graham CM, McNab FW, et al. An interferon-inducible neutrophil-driven blood transcriptional signature in human tuberculosis. Nature 2010; 466(7309): 973–977. doi: 10.1038/nature09247

59. Kolloli A, Subbian S. Host-directed therapeutic strategies for tuberculosis. Frontiers in Medicine 2017; 4: 171. doi: 10.3389/fmed.2017.00171

60. Kaufmann SHE, Dorhoi A, Hotchkiss RS, Bartenschlager R. Host-directed therapies for bacterial and viral infections. Nature Reviews. Drug Discovery 2017; 17(1): 35–56. doi: 10.1038/nrd.2017.162

61. Ernst JD. Mechanisms of M. tuberculosis immune evasion as challenges to TB vaccine design. Cell Host & Microbe 2018; 24(1): 34–42. doi: 10.1016/j.chom.2018.06.004

62. Liu CH, Liu H, Ge B. Innate immunity in tuberculosis: Host defense vs pathogen evasion. Cellular & Molecular Immunology 2017; 14(12): 963–975. doi: 10.1038/cmi.2017.88

63. Marrakchi H, Lanéelle MA, Daffé M. Mycolic acids: Structures, biosynthesis, and beyond. Chemistry & Biology 2014; 21(1): 67–85. doi: 10.1016/j.chembiol.2013.11.011

64. Kalscheuer R, Palacios A, Anso I, et al. The Mycobacterium tuberculosis capsule: A cell structure with key implications in pathogenesis. The Biochemical Journal 2019; 476(14): 1995–2016. doi: 10.1042/bcj20190324

65. Abrahams KA, Besra GS. Mycobacterial cell wall biosynthesis: A multifaceted antibiotic target. Parasitology 2016; 145(2): 116–133. doi: 10.1017/s0031182016002377

66. Kanji A, Hasan R, Hasan Z. Efflux pump as alternate mechanism for drug resistance in Mycobacterium tuberculosis. Indian Journal of Tuberculosis 2019; 66(1): 20–25. doi: 10.1016/j.ijtb.2018.07.008

67. Kleinnijenhuis J, Oosting M, Joosten LAB, et al. Innate immune recognition of Mycobacterium tuberculosis. Clinical and Developmental Immunology 2011; 2011: 405310. doi: 10.1155/2011/405310

68. Arcos J, Sasindran SJ, Fujiwara N, et al. Human lung hydrolases delineate Mycobacterium tuberculosis–macrophage interactions and the capacity to control infection. The Journal of Immunology 2011; 187(1): 372–381. doi: 10.4049/jimmunol.1100823

69. Wei S, Wang D, Li H, et al. Fatty acylCoA synthetase FadD13 regulates proinflammatory cytokine secretion dependent on the NF-κB signalling pathway by binding to eEF1A1. Cellular Microbiology 2019; 21(12): e13090. doi: 10.1111/cmi.13090

70. Wang J, Ge P, Qiang L, et al. The mycobacterial phosphatase PtpA regulates the expression of host genes and promotes cell proliferation. Nature Communications 2017; 8(1): 244. doi: 10.1038/s41467-017-00279-z

71. Wong KW. The role of ESX-1 in Mycobacterium tuberculosis pathogenesis. Microbiology Spectrum 2017; 5(3). doi: 10.1128/microbiolspec.TBTB2-0001-2015

72. Canezin PH, Caleffi-Ferracioli KR, Scodro RBdL, et al. Intramacrophage Mycobacterium tuberculosis efflux pump gene regulation after rifampicin and verapamil exposure. Journal of Antimicrobial Chemotherapy 2018; 73(7): 1770–1776. doi: 10.1093/jac/dky091

73. Richa M, Sakshi K, Nitish M, et al. Targeting redox heterogeneity to counteract drug tolerance in replicating Mycobacterium tuberculosis. Science Translational Medicine 2019; 11: eaaw6635. doi: 10.1126/scitranslmed.aaw6635

74. Delgado MA, Deretic V. Toll-like receptors in control of immunological autophagy. Cell Death and Differentiation 2009; 16(7): 976–983. doi: 10.1038/cdd.2009.40

75. Sanjuan MA, Dillon CP, Tait SWG, et al. Toll-like receptor signalling in macrophages links the autophagy pathway to phagocytosis. Nature 2007; 450(7173): 1253–1257. doi: 10.1038/nature06421

76. Korbel DS, Schneider BE, Schaible UE. Innate immunity in tuberculosis: Myths and truth. Microbes and Infection 2008; 10(9): 995–1004. doi: 10.1016/j.micinf.2008.07.039

77. Songane M, Kleinnijenhuis J, Netea MG, van Crevel R. The role of autophagy in host defence against Mycobacterium tuberculosis infection. Tuberculosis 2012; 92(5): 388–396. doi: 10.1016/

78. Umemura M, Matsuzaki G. Innate and acquired immune responses to mycobacterial infections: Involvement of IL-17A/IL-23 axis in protective immunity. Nihon Hansenbyō Gakkai Zasshi Japanese Journal of Leprosy: Official Organ of the Japanese Leprosy Association 2013; 82(3): 123–132. doi: 10.5025/hansen.82.123

79. Zuñiga J, Torres-García D, Santos-Mendoza T, et al. Cellular and humoral mechanisms involved in the control of tuberculosis. Clinical and Developmental Immunology 2012; 2012: 193923. doi: 10.1155/2012/193923

80. Kumar A, Farhana A, Guidry L, et al. Redox homeostasis in mycobacteria: The key to tuberculosis control? Expert Reviews in Molecular Medicine 2011; 13: e39. doi: 10.1017/s1462399411002079

81. Ji-Hae P, Dahee S, Keu Eun SK., et al. Understanding metabolic regulation between host and pathogens: New opportunities for the development of improved therapeutic strategies against mycobacterium infection. Front. Cell Infect. Microbiol. 2021; 11, 635335. doi: 10.3389/fcimb.2021.635335

82. Krakauer T. Inflammasomes, autophagy, and cell death: The trinity of innate host defense against intracellular bacteria. Mediators of Inflammation 2019; 2019: 2471215. doi: 10.1155/2019/2471215

83. Van Crevel R, Ottenhoff TH, van der Meer JW. Innate immunity to Mycobacterium tuberculosis. Clinical Microbiology Reviews 2002; 15(2): 294–309. doi: 10.1128/CMR.15.2.294-309.2002

84. Kawai T, Akira S. The role of pattern-recognition receptors in innate immunity: Update on Toll-like receptors. Nature Immunology 2010; 11(5): 373–384. doi: 10.1038/ni.1863

85. Meylan E, Tschopp J, Karin M. Intracellular pattern recognition receptors in the host response. Nature 2006; 442(7098): 39–44. doi: 10.1038/nature04946

86. Mortaz E, Adcock IM, Tabarsi P, et al. Interaction of pattern recognition receptors with mycobacterium tuberculosis. Journal of Clinical Immunology 2014; 35(1): 1–10. doi: 10.1007/s10875-014-0103-7

87. Giacomini E, Iona E, Ferroni L, et al. Infection of human macrophages and dendritic cells with Mycobacterium tuberculosisInduces a differential cytokine gene expression that modulates T cell response. The Journal of Immunology 2001; 166(12): 7033–7041. doi: 10.4049/jimmunol.166.12.7033

88. Houben EN, Nguyen L, Pieters J. Interaction of pathogenic mycobacteria with the host immune system. Current Opinion in Microbiology 2006; 9(1): 76–85. doi: 10.1016/j.mib.2005.12.014

89. Fun-Kyeong J. Mycobacterial interaction with innate receptors: TLRs, C-type lectins, and NLRs. Current Opinion in Infectious Diseases 2008; 21(3): 279–286. doi: 10.1097/qco.0b013e3282f88b5d

90. Wang Y, Shi Q, Chen Q, et al. Emerging advances in identifying signal transmission molecules involved in the interaction between Mycobacterium tuberculosis and the host. Frontiers in Cellular and Infection Microbiology 2022; 12: 956311. doi: 10.3389/fcimb.2022.956311

91. Ting JPY, Lovering RC, Alnemri ES, et al. The NLR gene family: A standard nomenclature. Immunity 2008; 28(3): 285–287. doi: 10.1016/j.immuni.2008.02.005

92. Juárez E, Carranza C, Hernández-Sánchez F, et al. NOD2 enhances the innate response of alveolar macrophages to Mycobacterium tuberculosis in humans. European Journal of Immunology 2012; 42(4): 880–889. doi: 10.1002/eji.201142105

93. Chen GY, Nuñez G. Sterile inflammation: Sensing and reacting to damage. Nature Reviews. Immunology 2010; 10(12): 826–837. doi: 10.1038/nri2873

94. Akira S. Toll-like receptor signaling. Journal of Biological Chemistry 2003; 278(40): 38105–38108. doi: 10.1074/jbc.r300028200

95. Akira S, Uematsu S, Takeuchi O. Pathogen recognition and innate immunity. Cell 2006; 124(4): 783–801. doi: 10.1016/j.cell.2006.02.015

96. Takeuchi O, Akira S. Pattern recognition receptors and inflammation. Cell 2010; 140(6): 805–820. doi: 10.1016/j.cell.2010.01.022

97. Aderem A, Ulevitch RJ. Toll-like receptors in the induction of the innate immune response. Nature 2000; 406(6797): 782–787. doi: 10.1038/35021228

98. Medzhitov R, Preston-Hurlburt P, Janeway CA Jr. A human homologue of the Drosophila Toll protein signals activation of adaptive immunity. Nature 1997; 388(6640): 394–397. doi: 10.1038/41131

99. Doyle SL, O’Neill LAJ. Toll-like receptors: From the discovery of NFκB to new insights into transcriptional regulations in innate immunity. Biochemical Pharmacology 2006; 72(9): 1102–1113. doi: 10.1016/j.bcp.2006.07.010

100. Gan L, Li L. Regulations and roles of the interleukin-1 receptor associated kinases (IRAKs) in innate and adaptive immunity. Immunologic Research 2006; 35(3): 295–302. doi: 10.1385/IR:35:3:295

101. Zenaro E, Donini M, Dusi S. Induction of Th1/Th17 immune response by Mycobacterium tuberculosis: Role of dectin-1, Mannose Receptor, and DC-SIGN. Journal of Leukocyte Biology 2009; 86(6): 1393–1401. doi: 10.1189/jlb.0409242

102. Sanjuan MA, Milasta S, Green DR. Toll-like receptor signaling in the lysosomal pathways. Immunological Reviews 2008; 227(1): 203–220. doi: 10.1111/j.1600-065x.2008.00732.x

103. Dinarello CA. Immunological and inflammatory functions of the interleukin-1 family. Annual Review of Immunology 2009; 27: 519–550. doi: 10.1146/annurev.immunol.021908.132612

104. Mayer-Barber KD, Barber DL, Shenderov K, et al. Cutting edge: Caspase-1 independent IL-1β production is critical for host resistance to Mycobacterium tuberculosis and does not require TLR signaling in vivo. The Journal of Immunology 2010; 184(7): 3326–3330. doi: 10.4049/jimmunol.0904189

105. Shi S, Blumenthal A, Hickey CM, et al. Expression of many immunologically important genes in Mycobacterium tuberculosis-infected macrophages is independent of both TLR2 and TLR4 but dependent on IFN-αβ receptor and STAT1. The Journal of Immunology 2005; 175(5): 3318–3328. doi: 10.4049/jimmunol.175.5.3318

106. Hossain M, Norazmi MN. Pattern recognition receptors and cytokines in Mycobacterium tuberculosis infection—The double-edged sword? BioMed Research International 2013; 2013: 179174. doi: 10.1155/2013/179174

107. Khan N, Vidyarthi A, Pahari S, Agrewala JN. Distinct strategies employed by dendritic cells and macrophages in restricting Mycobacterium tuberculosis infection: Different philosophies but same desire. International Reviews of Immunology 2015; 35(5): 386–398. doi: 10.3109/08830185.2015.1015718

108. Li CW, Lee YL, Chen BS. Genetic-and-epigenetic interspecies networks for cross-talk mechanisms in human macrophages and dendritic cells during MTB infection. Frontiers in Cellular and Infection Microbiology 2016; 6: 124. doi: 10.3389/fcimb.2016.00124

109. Rovetta AI, Peña D, Hernández Del Pino RE, et al. IFNG-mediated immune responses enhance autophagy against Mycobacterium tuberculosis antigens in patients with active tuberculosis. Autophagy 2014; 10(12): 2109–2121. doi: 10.4161/15548627.2014.981791

110. Deretic V. Autophagy in inflammation, infection, and immunometabolism. Immunity 2021; 54(3): 437–453. doi: 10.1016/j.immuni.2021.01.018

111. Bah A, Vergne I. Macrophage autophagy and bacterial infections. Frontiers in Immunology 2017; 8: 1483. doi: 10.3389/fimmu.2017.01483

112. Castillo EF, Dekonenko A, Arko-Mensah J, et al. Autophagy protects against active tuberculosis by suppressing bacterial burden and inflammation. Proceedings of the National Academy of Sciences of the United States of America 2012; 109(46): E3168–E3176. doi: 10.1073/pnas.1210500109

113. Paik S, Kim JK, Chung C, Jo EK. Autophagy: A new strategy for host-directed therapy of tuberculosis. Virulence 2018; 10(1): 448–459. doi: 10.1080/21505594.2018.1536598

114. Intemann CD, Thye T, Niemann S, et al. Autophagy gene variant IRGM−261T contributes to protection from tuberculosis caused by Mycobacterium tuberculosis but Not by M. africanum Strains. PLoS Pathogens 2009; 5(9): e1000577. doi: 10.1371/journal.ppat.1000577

115. Lerena MC, Colombo MI. Mycobacterium marinum induces a marked LC3 recruitment to its containing phagosome that depends on a functional ESX-1 secretion system. Cellular Microbiology 2011; 13(6): 814–835. doi: 10.1111/j.1462-5822.2011.01581.x

116. Siregar TAP, Prombutara P, Kanjanasirirat P, et al. The autophagy-resistant Mycobacterium tuberculosis Beijing strain upregulates KatG to evade starvation-induced autophagic restriction. Pathogens and Disease 2022; 80(1): ftac004. doi: 10.1093/femspd/ftac004

117. Laopanupong T, Prombutara P, Kanjanasirirat P, et al. Lysosome repositioning as an autophagy escape mechanism by Mycobacterium tuberculosis Beijing strain. Scientific Reports 2021; 11(1): 4342. doi: 10.1038/s41598-021-83835-4

118. Gupta A, Misra A, Deretic V. Targeted pulmonary delivery of inducers of host macrophage autophagy as a potential host-directed chemotherapy of tuberculosis. Advanced Drug Delivery Reviews 2016; 102: 10–20. doi: 10.1016/j.addr.2016.01.016

119. Van Rhijn I, Kasmar A, de Jong A, et al. A conserved human T cell population targets mycobacterial antigens presented by CD1b. Nature Immunology 2013; 14(7): 706–713. doi: 10.1038/ni.2630

120. Shahine A. The intricacies of self-lipid antigen presentation by CD1b. Molecular Immunology 2018; 104: 27–36. doi: 10.1016/j.molimm.2018.09.022

121. Laochumroonvorapong P, Wang J, Liu CC, et al. Perforin, a cytotoxic molecule which mediates cell necrosis, is not required for the early control of mycobacterial infection in mice. Infection and Immunity 1997; 65(1): 127–132. doi: 10.1128/iai.65.1.127-132.1997

122. Goletti D, Petruccioli E, Romagnoli A, et al. Autophagy in Mycobacterium tuberculosis infection: A passepartout to flush the intruder out? Cytokine & Growth Factor Reviews 2013; 24(4): 335–343. doi: 10.1016/j.cytogfr.2013.01.002

123. Romagnoli A, Etna MP, Giacomini E, et al. ESX-1 dependent impairment of autophagic flux by Mycobacterium tuberculosis in human dendritic cells. Autophagy 2012; 8(9): 1357–1370. doi: 10.4161/auto.20881

124. Pellegrini JM, Tateosian NL, Morelli MP, García VE. Shedding light on autophagy during human tuberculosis. A long way to go. Frontiers in Cellular and Infection Microbiology 2022; 11: 820095. doi: 10.3389/fcimb.2021.820095

125. Pellegrini JM, Sabbione F, Morelli MP, et al. Neutrophil autophagy during human active tuberculosis is modulated by SLAMF1. Autophagy 2020; 17(9): 2629–2638. doi: 10.1080/15548627.2020.1825273

126. Besnard AG, Sabat R, Dumoutier L, et al. Dual role of IL-22 in allergic airway inflammation and its cross-talk with IL-17A. American Journal of Respiratory and Critical Care Medicine 2011; 183(9): 1153–1163. doi: 10.1164/rccm.201008-1383oc

127. Lee SJ, Koh JY. Roles of zinc and metallothionein-3 in oxidative stress-induced lysosomal dysfunction, cell death, and autophagy in neurons and astrocytes. Molecular Brain 2010; 3(1): 30. doi: 10.1186/1756-6606-3-30

128. Ulrichs T, Moody DB, Grant E, et al. T-cell responses to CD1-presented lipid antigens in humans with Mycobacterium tuberculosis infection. Infection and Immunity 2003; 71(6): 3076–3087. doi: 10.1128/iai.71.6.3076-3087.2003

129. Thomssen H, Ivanyi J, Espitia C, et al. Human CD4-CD8- alpha beta + T-cell receptor T cells recognize different mycobacteria strains in the context of CD1b. Immunology 1995; 85(1): 33–40.

130. Van Rhijn I, Ly D, Moody DB. CD1a, CD1b, and CD1c in immunity against mycobacteria..Adv Exp Med Biol. 2013;783:181-97. doi: 10.1007/978-1-4614-6111-1_10.

131. Lockhart E, Green AM, Flynn JL. IL-17 production is dominated by gammadelta T cells rather than CD4 T cells during Mycobacterium tuberculosis infection. Journal of Immunology 2006; 177(7): 4662–4669. doi: 10.4049/jimmunol.177.7.4662

132. Sutton CE, Lalor SJ, Sweeney CM, et al. Interleukin-1 and IL-23 induce innate IL-17 production from γδ T cells, amplifying Th17 responses and autoimmunity. Immunity 2009; 31(2): 331–341. doi: 10.1016/j.immuni.2009.08.001

133. Coulter F, Parrish A, Manning D, et al. IL-17 production from T helper 17, mucosal-associated invariant T, and γδ cells in tuberculosis infection and disease. Frontiers in Immunology 2017; 8: 1252. doi: 10.3389/fimmu.2017.01252

134. Freches D, Korf H, Denis O, et al. Mice genetically inactivated in interleukin-17A receptor are defective in long-term control of Mycobacterium tuberculosis infection. Immunology 2013; 140(2): 220–231. doi: 10.1111/imm.12130

135. Khader SA, Cooper AM. IL-23 and IL-17 in tuberculosis. Cytokine 2008; 41(2): 79–83. doi: 10.1016/j.cyto.2007.11.022

136. Khader SA, Gopal R. IL-17 in protective immunity to intracellular pathogens. Virulence 2010; 1(5): 423–427. doi: 10.4161/viru.1.5.12862

137. Bandaru A, Devalraju KP, Paidipally P, et al. Phosphorylated STAT3 and PD-1 regulate IL-17 production and IL-23 receptor expression in Mycobacterium tuberculosis infection. European Journal of Immunology 2014; 44(7): 2013–2024. doi: 10.1002/eji.201343680

138. Khader SA, Pearl JE, Sakamoto K, et al. IL-23 compensates for the absence of IL-12p70 and is essential for the IL-17 response during tuberculosis but is dispensable for protection and antigen-specific IFN-γ responses if IL-12p70 is available. The Journal of Immunology 2005; 175(2): 788–795. doi: 10.4049/jimmunol.175.2.788

139. Teixeira-Coelho M, Cruz A, Carmona J, et al. TLR2 deficiency by compromising p19 (IL-23) expression limits Th 17 cell responses to Mycobacterium tuberculosis. International Immunology 2010; 23(2): 89–96. doi: 10.1093/intimm/dxq459

140. Zielinski CE, Mele F, Aschenbrenner D, et al. Pathogen-induced human TH17 cells produce IFN-γ or IL-10 and are regulated by IL-1β. Nature 2012; 484(7395): 514–518. doi: 10.1038/nature10957

141. Zhang M, Wang Z, Graner MW, et al. B cell infiltration is associated with the increased IL-17 and IL-22 expression in the lungs of patients with tuberculosis. Cellular Immunology 2011; 270(2): 217–223. doi: 10.1016/j.cellimm.2011.05.009

142. Romagnani S, Maggi E, Liotta F, et al. Properties and origin of human Th17 cells. Molecular Immunology 2009; 47(1): 3–7. doi: 10.1016/j.molimm.2008.12.019

143. Khader SA, Guglani L, Rangel-Moreno J, et al. IL-23 is required for long-term control of Mycobacterium tuberculosis and B cell follicle formation in the infected lung. The Journal of Immunology 2011; 187(10): 5402–5407. doi: 10.4049/jimmunol.1101377

144. Khader SA, Bell GK, Pearl JE, et al. IL-23 and IL-17 in the establishment of protective pulmonary CD4+ T cell responses after vaccination and during Mycobacterium tuberculosis challenge. Nature Immunology 2007; 8(4): 369–377. doi: 10.1038/ni1449

145. Jurado JO, Pasquinelli V, Alvarez IB, et al. IL-17 and IFN-γ expression in lymphocytes from patients with active tuberculosis correlates with the severity of the disease. Journal of Leukocyte Biology 2012; 91(6): 991–1002. doi: 10.1189/jlb.1211619

146. Basile JI, Kviatcovsky D, Romero MM, et al. Mycobacterium tuberculosis multi-drug-resistant strain M induces IL-17+IFNγ– CD4+ T cell expansion through an IL-23 and TGF-β-dependent mechanism in patients with MDR-TB tuberculosis. Clinical and Experimental Immunology 2016; 187(1): 160–173. doi: 10.1111/cei.12873

147. Cruz A, Fraga AG, Fountain JJ, et al. Pathological role of interleukin 17 in mice subjected to repeated BCG vaccination after infection with Mycobacterium tuberculosis. Journal of Experimental Medicine 2010; 207(8): 1609–1616. doi: 10.1084/jem.20100265

148. Segueni N, Jacobs M, Ryffel B. Innate type 1 immune response, but not IL-17 cells control tuberculosis infection. Biomedical Journal 2021; 44(2): 165–171. doi: 10.1016/

149. Singh S, Maniakis-Grivas G, Singh UK, et al. Interleukin-17 regulates matrix metalloproteinase activity in human pulmonary tuberculosis. The Journal of Pathology 2018; 244(3): 311–322. doi: 10.1002/path.5013

150. Devalraju KP, Neela VSK, Ramaseri SS, et al. IL-17 and IL-22 production in HIV+ individuals with latent and active tuberculosis. BMC Infectious Diseases 2018; 18(1): 321. doi: 10.1186/s12879-018-3236-0

151. Li Q, Li J, Tian J, et al. IL-17 and IFN-γ production in peripheral blood following BCG vaccination and Mycobacterium tuberculosis infection in human. European Review for Medical and Pharmacological Sciences 2012; 16(14): 2029–2036.

152. Gutierrez MG, Master SS, Singh SB, et al. Autophagy is a defense mechanism inhibiting BCG and Mycobacterium tuberculosis survival in infected macrophages. Cell 2004; 119(6): 753–766. doi: 10.1016/j.cell.2004.11.038

153. Khan A, Bakhru P, Saikolappan S, et al. An autophagy-inducing and TLR-2 activating BCG vaccine induces a robust protection against tuberculosis in mice. NPJ Vaccines 2019; 4(1): 34. doi: 10.1038/s41541-019-0122-8

154. Foster WS, Lee JL, Thakur N, et al. Tfh cells and the germinal center are required for memory B cell formation & humoral immunity after ChAdOx1 nCoV-19 vaccination. Cell Reports. Medicine 2022; 3(12): 100845. doi: 10.1016/j.xcrm.2022.100845

155. Soto JA, Galvez NMS, Andrade CA, et al. BCG vaccination induces cross-protective immunity against pathogenic microorganisms. Trends in Immunology 2022; 43(4): 322–335. doi: 10.1016/

156. Ferluga J, Yasmin H, Al-Ahdal MN, et al. Natural and trained innate immunity against Mycobacterium tuberculosis. Immunobiology 2020; 225(3): 151951. doi: 10.1016/j.imbio.2020.151951

157. Yao Y, Jeyanathan M, Haddadi S, et al. Induction of autonomous memory alveolar macrophages requires T cell help and is critical to trained immunity. Cell 2018; 175(6): 1634–1650. doi: 10.1016/j.cell.2018.09.042

158. Xing Z, Afkhman S, Bayananthasivam J, et al. Innate immune memory of tissue-resident macrophages and trained innate immunity: Re-vamping vaccine concept and strategies. Journal of Leukocyte Biology 2020; 108(3): 825–834. doi: 10.1002/JLB.4MR0220-446R

159. Jeyanathan M, Vaseghi-Shanjani M, Afkhami S, et al. Parenteral BCG vaccine induces lung-resident memory macrophages and trained immunity via the gut-lung axis. Nature Immunology 2022; 23(12): 1687–1702. doi: 10.1038/s41590-022-01354-4

160. Guerra-Maupome M, Vang DX, McGill JL. Aerosol vaccination with Bacille Calmette-Guerin induces a trained innate immune phenotype in calves. PLoS One 2019; 14(2): e0212751. doi: 10.1371/journal.pone.0212751

161. Umemura M, Yahagi A, Hamada S, et al. IL-17-mediated regulation of innate and acquired immune response against pulmonary Mycobacterium bovis bacille Calmette-Guérin infection. The Journal of Immunology 2007; 178(6): 3786–3796. doi: 10.4049/jimmunol.178.6.3786

162. Khader SA, Divangahi M, Hanekom W, et al. Targeting innate immunity for tuberculosis vaccination. Journal of Clinical Investigation 2020; 129(9): 3482–3491. doi: 10.1172/jci128877

163. Du J, Su Y, Wang R, et al. Research progress on specific and non-specific immune effects of BCG and the possibility of BCG protection against COVID-19. Frontiers in Immunology 2023; 14: 1118378. doi: 10.3389/fimmu.2023.1118378

164. Buffen K, Oosting M, Quintin J, et al. Autophagy controls BCG-induced trained immunity and the response to intravesical BCG therapy for bladder cancer. PLoS Pathogens 2014; 10(10): e1004485. doi: 10.1371/journal.ppat.1004485

165. Arts RJW, Carvalho A, La Rocca C, et al. Immunometabolic pathways in BCG-induced trained immunity. Cell Reports 2016; 17(10): 2562–2571. doi: 10.1016/j.celrep.2016.11.011

166. Lai R, Afkami S, Haddadi S, et al. Mucosal immunity and novel tuberculosis vaccine strategies: Route of immunisation-determined T-cell homing to restricted lung mucosal. European Respiratory Review: An Official Journal of the European Respiratory Society 2015; 24(136): 356–360. doi: 10.1183/16000617.00002515

167. Covián C, Fernández-Fierro A, Retamal-Díaz A, et al. BCG-induced cross-protection and development of trained immunity: Implication for vaccine design. Frontiers in Immunology 2019; 10: 2806. doi: 10.3389/fimmu.2019.02806

168. Hu Z, Wong KW, Zhao HM, et al. Sendai virus mucosal vaccination establishes lung-resident memory CD8 T cell immunity and boosts BCG-primed protection against TB in mice. Molecular Therapy 2017; 25(5): 1222–1233. doi: 10.1016/j.ymthe.2017.02.018

169. Kaveh DA, Bachy VS, Hewinson RG, Hogarth PJ. Systemic BCG immunization induces persistent lung mucosal multifunctional CD4 TEM cells which expand following virulent mycobacterial challenge. PLoS One 2011; 6(6): e21566. doi: 10.1371/journal.pone.0021566

170. 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. The Journal of Immunology 2006; 177(12): 8684–8692. doi: 10.4049/jimmunol.177.12.8684

171. Wang J, Thorson L, Stokes RW, et al. Single mucosal, but not parenteral, immunization with recombinant adenoviral-based vaccine provides potent protection from pulmonary tuberculosis. The Journal of Immunology 2004; 173(10): 6357–6365. doi: 10.4049/jimmunol.173.10.6357

172. Santosuosso M, Zhang X, McCormick S, et al. Mechanisms of mucosal and parenteral tuberculosis vaccinations: Adenoviral-based mucosal immunization preferentially elicits sustained accumulation of immune protective CD4 and CD8 T cells within the airway lumen. The Journal of Immunology 2005; 174(12): 7986–7994. doi: 10.4049/jimmunol.174.12.7986

173. Santosuosso M, McCormick S, Zhang X, et al. Intranasal boosting with an adenovirus-vectored vaccine markedly enhances protection by parenteral Mycobacterium bovis BCG immunization against pulmonary tuberculosis. Infection and Immunity 2006; 74(8): 4634–4643. doi: 10.1128/IAI.00517-06

174. McShane H, Pathan AA, Sander CR, et al. Boosting BCG with MVA85A: The first candidate subunit vaccine for tuberculosis in clinical trials. Tuberculosis 2005; 85(1–2): 47–52. doi: 10.1016/

175. McShane H, Hill A. Prime-boost immunisation strategies for tuberculosis. Microbes and Infection 2005; 7(5–6): 962–967. doi: 10.1016/j.micinf.2005.03.009

176. Xing Z, Charters TJ. Heterologous boost vaccines for bacillus Calmette–Guérin prime immunization against tuberculosis. Expert Review of Vaccines 2007; 6(4): 539–546. doi: 10.1586/14760584.6.4.539

177. Palgen JL, Feraoun Y, Dzangué-Tchoupou G, et al. Optimize prime/boost vaccine strategies: Trained immunity as a new player in the game. Frontiers in Immunology 2021; 12: 612747. doi: 10.3389/fimmu.2021.612747

178. Sheehan S, Harris SA, Satti I, et al. A phase I, open-label trial, evaluating the safety and immunogenicity of candidate tuberculosis vaccines AERAS-402 and MVA85A, administered by prime-boost regime in BCG-vaccinated healthy adults. PLoS One 2015; 10(11): e0141687. doi: 10.1371/journal.pone.0141687

179. Guerrero GG, Debrie AS, Locht C. Boosting with mycobacterial heparin-binding haemagglutinin enhances protection of Mycobacterium bovis BCG-vaccinated newborn mice against M. tuberculosis. Vaccine 2010; 28(27): 4340–4347. doi: 10.1016/j.vaccine.2010.04.062

180. Guerrero GG, Locht C. Recombinant HBHA boosting effect on BCG-induced immunity against Mycobacterium tuberculosis infection. Clinical and Developmental Immunology 2011; 2011: 1–8. doi: 10.1155/2011/730702

181. Guerrero GG, Rangel-Moreno J, Islas-Trujillo S, Rojas-Espinosa Ó. Successive intramuscular boosting with IFN-Alpha protects Mycobacterium bovis BCG-vaccinated mice against M. lepraemurium infection. BioMed Research International 2015; 2015: 1–9. doi: 10.1155/2015/414027

182. Guerrero GG, Rangel-Moreno J, Islas-Trujillo SO, Rojas-Espinosa O. Intramuscular boosting with hIFN-Alpha 2b enhances BCGphipps-induced protection in a murine model of leprosy. Microbiology Research 2021; 12(3): 711–726. doi: 10.3390/microbiolres12030051

183. Rivas-Santiago CE, Guerrero GG. IFN-α boosting of Mycobacterium bovis Bacillus Calmette Güerin-Vaccine promoted Th1 type cellular response and protection against M. tuberculosis infection. BioMed Research International 2017; 2017: 1–8. doi: 10.1155/2017/8796760

184. Jeyanathan M, Heriazon A, Xing Z. Airway luminal T cells: A newcomer on the stage of TB vaccination strategies. Trends in Immunology 2010; 31(7): 247–252. doi: 10.1016/

185. Perdomo C, Zedler U, Kühl AA, et al. Mucosal BCG vaccination induces protective lung-resident memory T cell populations against tuberculosis. mBio 2016; 7(6): e01686-16. doi: 10.1128/mbio.01686-16

186. Wilkie M, Tanner R, Wright D, et al. Functional in-vitro evaluation of the non-specific effects of BCG vaccination in a randomised controlled clinical study. Scientific Reports 2022; 12(1): 7808. doi: 10.1038/s41598-022-11748-x



  • There are currently no refbacks.

Copyright (c) 2023 Gloria G. Guerrero, Rogelio Hernández-Pando

License URL:

This site is licensed under a Creative Commons Attribution 4.0 International License.