Skip to main content

Advertisement

Log in

Revisiting the Natural History of Tuberculosis

The Inclusion of Constant Reinfection, Host Tolerance, and Damage-Response Frameworks Leads to a Better Understanding of Latent Infection and its Evolution towards Active Disease

  • Review
  • Published:
Archivum Immunologiae et Therapiae Experimentalis Aims and scope

Abstract

Once Mycobacterium tuberculosis infects a person it can persist for a long time in a process called latent tuberculosis infection (LTBI). LTBI has traditionally been considered to involve the bacilli remaining in a non-replicating state (dormant) in old lesions but still retaining their ability to induce reactivation and cause active tuberculosis (TB) once a disruption of the immune response takes place. The present review aims to challenge these concepts by including recent experimental data supporting LTBI as a constant endogenous reinfection process as well as the recently introduced concepts of damage-response and tolerance frameworks to explain TB induction. These frameworks highlight the key role of an exaggerated and intolerant host response against M. tuberculosis bacilli which induces the classical TB cavity in immunocompetent adults once the constant endogenous reinfection process has resulted in the presence of bacilli in the upper lobes, where they can grow faster and the immune response is delayed. This essay intends to provide new clues to understanding the induction of TB in non-immunosuppressed patients.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7

Similar content being viewed by others

References

  • Andersen P (1997) Host responses and antigens involved in protective immunity to Mycobacterium tuberculosis. Scand J Immunol 45:115–131

    Article  CAS  PubMed  Google Scholar 

  • Ayres JS, Schneider DS (2008) A signaling protease required for melanization in Drosophila affects resistance and tolerance of infections. PLoS Biol 6:2764–2773

    Article  CAS  PubMed  Google Scholar 

  • Bermudez LE, Danelishvili L, Early J (2006) Mycobacteria and macrophage apoptosis: complex struggle for survival. Microbe 1:372–375

    Google Scholar 

  • Bolin CA, Whipple DL, Khanna KV et al (1997) Infection of swine with Mycobacterium bovis as a model of human tuberculosis. J Infect Dis 176:1559–1566

    Article  CAS  PubMed  Google Scholar 

  • Buchanan RE (1918) Life phases in a bacterial culture. J Infect Dis 23:109–125

    Google Scholar 

  • Buddle BM, Skinner MA, Wedlock DN et al (2005) Cattle as a model for development of vaccines against human tuberculosis. Tuberculosis 85:19–24

    Article  CAS  PubMed  Google Scholar 

  • Bui TD, Dabdub D, George SC (1998) Modeling bronchial circulation with application to soluble gas exchange: description and sensitivity analysis. J Appl Physiol 84:2070–2088

    CAS  PubMed  Google Scholar 

  • Caceres N, Tapia G, Ojanguren I et al (2009) Evolution of foamy macrophages in the pulmonary granulomas of experimental tuberculosis models. Tuberculosis 89:175–182

    Article  CAS  PubMed  Google Scholar 

  • Cardona PJ (2006) RUTI: a new chance to shorten the treatment of latent tuberculosis infection. Tuberculosis 86:273–289

    Article  PubMed  Google Scholar 

  • Cardona PJ (2007) New insights on the nature of latent tuberculosis infection and its treatment. Inflamm Allergy Drug Targets 6:27–39

    Article  CAS  PubMed  Google Scholar 

  • Cardona PJ (2009) A dynamic reinfection hypothesis of latent tuberculosis infection. Infection 37:80–86

    Article  PubMed  Google Scholar 

  • Cardona PJ, Llatjós R, Gordillo S et al (2000) Evolution of granulomas in mice infected aerogenically with Mycobacterium tuberculosis. Scan J Immunol 52:156–163

    Article  CAS  Google Scholar 

  • Cardona PJ, Gordillo S, Díaz J et al (2003) Widespread bronchogenic dissemination makes DBA/2 mice more susceptible than C57BL/6 mice to experimental aerosol infection with Mycobacterium tuberculosis. Infect Immun 71:5845–5854

    Article  CAS  PubMed  Google Scholar 

  • Casadevall A, Pirofski LA (2003) The damage response framework of microbial pathogenesis. Nat Rev Microbiol 1:17–24

    Article  CAS  PubMed  Google Scholar 

  • D’Avila H, Melo RC, Parreira GG et al (2006) Mycobacterium bovis bacillus Calmette-Guerin induces TLR2-mediated formation of lipid bodies: intracellular domains for eicosanoid synthesis in vivo. J Immunol 176:3087–3097

    PubMed  Google Scholar 

  • Dannenberg AM Jr (2006) Pathogenesis of human pulmonary tuberculosis: insights from the rabbit model. ASM Press, Washington

    Google Scholar 

  • Doenhoff MJ (1998) Granulomatous inflammation and the transmission of infection: schistosomiasis and TB too? Immunol Today 19:462–467

    Article  CAS  PubMed  Google Scholar 

  • Dvorak AM, Dvorak HF, Peters SP et al (1983) Lipid bodies: cytoplasmic organelles important to arachidonate metabolism in macrophages and mast cells. J Immunol 131:2965–2976

    CAS  PubMed  Google Scholar 

  • Fukumura D, Jain RK (2008) Imaging angiogenesis and the microenvironment. APMIS 116:695–715

    Article  CAS  PubMed  Google Scholar 

  • Garton NJ, Christensen H, Minnikin DE et al (2002) Intracellular lipophilic inclusions of mycobacteria in vitro and in sputum. Microbiology 148(Pt 10):2951–2958

    CAS  PubMed  Google Scholar 

  • Garton NJ, Waddell SJ, Sherratt AL et al (2008) Cytological and transcript analyses reveal fat and lazy persister-like bacilli in tuberculous sputum. PLoS Med 5:e75

    Article  PubMed  Google Scholar 

  • Gil O, Diaz I, Vilaplana C, et al. (2009) Combined therapy with isoniazid and RUTI is safe and effective in a new latent tuberculosis infection model in mini-pigs. Keystone Symposium, Keystone, Colorado, USA, January 2009

  • Gill WP, Harik NS, Whiddon MR et al (2009) A replication clock for Mycobacterium tuberculosis. Nat Med 15:211–214

    Article  CAS  PubMed  Google Scholar 

  • Gordon S, Mwandumba H (2008) Respiratory tuberculosis. In: Barnes PF, Gordon SB, Davies PDO (eds) Clinical Tuberculosis. Hodder and Stoughton, London

    Google Scholar 

  • Grosset J (1980) Bacteriologic basis of short-course chemotherapy for tuberculosis. Clin Chest Med 1:231–241

    CAS  PubMed  Google Scholar 

  • Grosset J (2003) Mycobacterium tuberculosis in the extracellular compartment: an underestimated adversary. Antimicrob Agents Chemother 47:833–836

    Article  CAS  PubMed  Google Scholar 

  • Kaufmann SH, Cole ST, Mizrahi V et al (2005) Mycobacterium tuberculosis and the host response. J Exp Med 201:1693–1697

    Article  CAS  PubMed  Google Scholar 

  • Lipman M, Breen R (2006) Immune reconstitution inflammatory syndrome in HIV. Curr Opin Infect Dis 19:20–25

    Article  PubMed  Google Scholar 

  • Lurie MB (1964) Resistance to tuberculosis: experimental studies in native and acquired defensive mechanisms. Harvard University Press, Cambridge

    Google Scholar 

  • Martinez D, Vermeulen M, von Euw E et al (2007) Extracellular acidosis triggers the maturation of human dendritic cells and the production of IL-12. J Immunol 179:1950–1959

    CAS  PubMed  Google Scholar 

  • Milic-Emili J (2005) Ventilation distribution. In: Hamid Q, Shannon J, Martin J (eds) Physiologic basis of respiratory disease. BC Decker Inc., Hamilton

    Google Scholar 

  • Mitchison DA (1979) Basic mechanisms of chemotherapy. Chest 76(6 suppl):771–781

    Article  CAS  PubMed  Google Scholar 

  • Muñoz-Elias EJ, Timm J, Botha T et al (2005) Replication dynamics of Mycobacterium tuberculosis in chronically infected mice. Infect Immun 73:546–551

    Article  PubMed  Google Scholar 

  • Murphy DJ (2001) The biogenesis and functions of lipid bodies in animals, plants and microorganisms. Prog Lipid Res 40:325–438

    Article  CAS  PubMed  Google Scholar 

  • Orme I, Gonzalez-Juarrero M (2007) Animal models of M. tuberculosis infection. Curr Protoc Microbiol Chapter 10:Unit 10A.5

  • Parish T, Stoker NG (2001) Mycobacterium tuberculosis protocols. Humana Press Inc., Totowa

    Google Scholar 

  • Park MK, Myers RA, Marzella L (1992) Oxygen tensions and infections: modulation of microbial growth, activity of antimicrobial agents, and immunologic responses. Clin Infect Dis 14:720–740

    CAS  PubMed  Google Scholar 

  • Peyron P, Vaubourgeix J, Poquet Y et al (2008) Foamy macrophages from tuberculous patients’ granulomas constitute a nutrient-rich reservoir for M. tuberculosis persistence. PLoS Pathog 4:e1000204

    Article  PubMed  Google Scholar 

  • Rook GA (2007) Th2 cytokines in susceptibility to tuberculosis. Curr Mol Med 7:327–337

    Article  CAS  PubMed  Google Scholar 

  • Ross R (1999) Atherosclerosis: an inflammatory disease. N Engl J Med 340:115–126

    Article  CAS  PubMed  Google Scholar 

  • Schneider DS, Ayres JS (2008) Two ways to survive infection: what resistance and tolerance can teach us about treating infectious diseases. Nat Rev Immunol 8:889–895

    Article  CAS  PubMed  Google Scholar 

  • Ulrichs T, Kaufmann SH (2006) New insights into the function of granulomas in human tuberculosis. J Pathol 208:261–269

    Article  CAS  PubMed  Google Scholar 

  • Wallace JG (1961) The heat resistance of tubercle bacilli in the lungs of infected mice. Am Rev Respir Dis 83:866–871

    CAS  PubMed  Google Scholar 

  • Wayne LG, Sohaskey CD (2001) Nonreplicating persistence of Mycobacterium tuberculosis. Annu Rev Microbiol 55:139–163

    Article  CAS  PubMed  Google Scholar 

  • Wolf AJ, Desvignes L, Linas B et al (2008) Initiation of the adaptive immune response to Mycobacterium tuberculosis depends on antigen production in the local lymph node, not the lungs. J Exp Med 205:105–115

    Article  CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Pere-Joan Cardona.

About this article

Cite this article

Cardona, PJ. Revisiting the Natural History of Tuberculosis. Arch. Immunol. Ther. Exp. 58, 7–14 (2010). https://doi.org/10.1007/s00005-009-0062-5

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00005-009-0062-5

Keywords

Navigation