Elsevier

Tuberculosis

Volume 86, Issue 5, September 2006, Pages 337-348
Tuberculosis

REVIEW
Animal models of cavitation in pulmonary tuberculosis

https://doi.org/10.1016/j.tube.2005.09.001Get rights and content

Summary

Transmission of tuberculosis occurs with the highest frequency from patients with extensive, cavitary, pulmonary disease and positive sputum smear microscopy. In animal models of tuberculosis, the development of caseous necrosis is an important prerequisite for the formation of cavities although the immunological triggers for liquefaction are unknown. We review the relative merits and the information gleaned from the available animal models of pulmonary cavitation. Understanding the host–pathogen interaction important to the formation of cavities may lead to new strategies to prevent cavitation and thereby, block transmission.

Section snippets

Cavitary tuberculosis in humans

Patients co-infected with human immunodeficiency virus (HIV) are more likely to have impaired DTH responses due to a deficiency of CD4 T cells, and less likely to have cavitary disease.18 These data indirectly point to an important role for the CD4+ T cell in the pathogenesis of cavitation. A study comparing the bronchoalveolar lavage (BAL) fluid of 7 patients with active cavitary disease to 7 others without cavities showed more CD4+ T cells in the BAL of non-cavitary patients.19 However, this

Tuberculosis in mice

Mice have little measurable delayed-type hypersensitivity (DTH) response and do not form true caseous necrosis in response to aerosol or parenteral infection with M. tuberculosis (Table 1, Table 2). Mice develop an acquired cell-mediated response that is primarily mediated by T cells. After low-dose aerosol, they develop cellular aggregates in the lung with bacillary proliferation that reaches a plateau around 106 organisms in the lung.30, 31 After 4 weeks, an equilibrium is maintained that

Tuberculosis in guinea pigs

Guinea pigs develop good DTH responses to mycobacterial antigens, and have tuberculin sensitivity similar to that of humans. After parenteral and aerosol infection with M. tuberculosis, guinea pigs form impressive caseous necrosis in their lungs (Table 1, Table 2, Fig. 1B). They are also very susceptible hosts and develop chronic progressive disease after very low-dose aerosol infection.39, 40 Virulent M. tuberculosis multiplies logarithmically and is followed by a stationary phase where

Cavitation in tuberculous primates

Non-human primates have been used as an animal model of tuberculosis primarily for vaccine52, 53, 54, 55, 56 and therapeutic drug testing.57, 58, 59, 60 Some information on the susceptibility of non-human primates has also been gleaned from outbreaks within colonies and from health reports of monkeys during shipment.61, 62, 63 Due to their size, increasingly difficult availability and cost, they lost favor and only recently have become reinvigorated as an animal model mimicking various types of

Cavitation in tuberculous rabbits

Rabbits mount a moderate DTH response and form caseous necrosis after either aerosol or intravenous infection with M. bovis3, 68 and with more virulent strains of M. tuberculosis69, 70 (Fig. 1D). Sporadic reports of cavitation in rabbits were published as early as the 1900s.51 With virulent M. tuberculosis, rabbits are relatively resistant to infection and require 500–3000 bacilli inhaled to form one grossly visible tubercle at 5 weeks after infection.69 By 6 months, most animals will heal

Other animal species

Swine are natural hosts for mycobacterial infections83, 84 and have been used as an experimental model for tuberculosis.85 After intratracheal infection with M. bovis, swine can form pulmonary tubercles with caseous necrosis, followed by liquefaction and cavity formation. Swine readily develop good tuberculin responses.86, 87 Lack of immunologic reagents has precluded further investigation of the immunopathogenesis.

Using a low-dose M. bovis respiratory challenge model, cattle form large caseous

Pathogenesis of caseation and cavitation: a comparison of the animal models

Guinea pigs, monkeys, and rabbits all form granuloma with caseous necrosis with strikingly similar architecture to that of humans (Fig. 1). Caseous necrosis is a pathologic prerequisite for cavity formation. Monkeys and guinea pigs can form cavities, but do not do so invariably.64, 91 Rabbits infected by aerosol with low-dose M. bovis, uniformly develop cavities. Fig. 2 shows low-power views of small cavitary lesions in humans (1A), guinea pigs (1B), cynomolgus monkeys (1C), and rabbits (1D).

Implications for human disease

The pathogenesis of smear-positive cavitary tuberculosis remains an important area of study because of the high likelihood for these patients to transmit disease to close contacts.7, 8 Animal models have identified host immune components that may be important in human cavity formation. In rabbits, host recognition of both cell wall and protein components of the bacilli were needed for cavity formation.80 Corroborative evidence for pre-sensitization exist in humans: alcoholic homeless patients

Acknowledgments

The authors would like to thank Dr. Arthur M. Dannenberg, Jr. for his invaluable advice and editorial assistance. The authors would also like to thank Dr. David N. McMurray and Dr. JoAnne L. Flynn for graciously providing pulmonary tissue sections of guinea pig and cynomolgus macaques respectively and for invaluable scientific input. This work was supported by funding from the National Institutes of Health, 1R01 HL71554 (YCM) and RR07002 (KLH).

References (99)

  • A.R. Rich

    The pathogenesis of tuberculosis

    (1991)
  • A.M. Dannenberg et al.

    Liquefaction of caseous foci in tuberculosis

    Am Rev Respir Dis

    (1976)
  • P.J. Converse

    Pulmonary bovine-type tuberculosis in rabbits: bacillary virulence, inhaled dose effects, tuberculin sensitivity, and Mycobacterium vaccae immunotherapy

    Clin Diagn Lab Immunol

    (1998)
  • G. Canetti

    The tubercle bacillus

    (1955)
  • J.S. Blanchard

    Molecular mechanisms of drug resistance in Mycobacterium tuberculosis

    Annu Rev Biochem

    (1996)
  • J. Grosset

    Mycobacterium tuberculosis in the extracellular compartment: an underestimated adversary

    Antimicrob Agents Chemother

    (2003)
  • C.E. Rose et al.

    Establishing priority during investigation of tuberculosis contacts

    Am Rev Respir Dis

    (1979)
  • D.A. Mitchison

    Assessment of new sterilizing drugs for treating pulmonary tuberculosis by culture at 2 months

    Am Rev Respir Dis

    (1993)
  • J. Hiyama et al.

    Factors influencing response to treatment of pulmonary tuberculosis

    Acta Med Okayama

    (2000)
  • C. Lienhardt

    Factors determining the outcome of treatment of adult smear-positive tuberculosis cases in The Gambia

    Int J Tuberc Lung Dis

    (1998)
  • A. Dominguez-Castellano

    Factors associated with time to sputum smear conversion in active pulmonary tuberculosis

    Int J Tuberc Lung Dis

    (2003)
  • R. Singla

    Factors predicting persistent sputum smear positivity among pulmonary tuberculosis patients 2 months after treatment

    Int J Tuberc Lung Dis

    (2003)
  • D. Benator

    Rifapentine and isoniazid once a week versus rifampicin and isoniazid twice a week for treatment of drug-susceptible pulmonary tuberculosis in HIV-negative patients: a randomised clinical trial

    Lancet

    (2002)
  • F.M. Salaniponi et al.

    Sputum smear status at two months and subsequent treatment outcome in new patients with smear-positive pulmonary tuberculosis

    Int J Tuberc Lung Dis

    (1999)
  • R.J. Brindle

    Quantitative bacillary response to treatment in HIV-associated pulmonary tuberculosis

    Am Rev Respir Dis

    (1993)
  • G. Mazzarella

    T lymphocyte phenotypic profile in lung segments affected by cavitary and non-cavitary tuberculosis

    Clin Exp Immunol

    (2003)
  • R. Condos et al.

    Local immune responses correlate with presentation and outcome in tuberculosis

    Am J Respir Crit Care Med

    (1998)
  • R. van Crevel

    Increased production of interleukin 4 by CD4+ and CD8+ T cells from patients with tuberculosis is related to the presence of pulmonary cavities

    J Infect Dis

    (2000)
  • A. Somoskovi

    Different cytokine patterns correlate with the extension of disease in pulmonary tuberculosis

    Eur Cytokine Network

    (1999)
  • D.R. Roach

    TNF regulates chemokine induction essential for cell recruitment, granuloma formation, and clearance of mycobacterial infection

    J Immunol

    (2002)
  • V.P. Mohan

    Effects of tumor necrosis factor alpha on host immune response in chronic persistent tuberculosis: possible role for limiting pathology

    Infect Immun

    (2001)
  • A.G. Bean

    Structural deficiencies in granuloma formation in TNF gene-targeted mice underlie the heightened susceptibility to aerosol Mycobacterium tuberculosis infection, which is not compensated for by lymphotoxin

    J Immunol

    (1999)
  • A. Zganiacz

    TNF-alpha is a critical negative regulator of type 1 immune activation during intracellular bacterial infection

    J Clin Invest

    (2004)
  • I. Orme et al.
  • J.L. Flynn et al.
  • P.L. Dunn et al.

    Virulence ranking of some Mycobacterium tuberculosis and Mycobacterium bovis strains according to their ability to multiply in the lungs, induce lung pathology, and cause mortality in mice

    Infect Immun

    (1995)
  • J.L. Flynn et al.

    Immunology of tuberculosis

    Annu Rev Immunol

    (2001)
  • S. Ehlers et al.

    Lethal granuloma disintegration in mycobacteria-infected TNFRp55−/− mice is dependent on T cells and IL-12

    J Immunol

    (2000)
  • S. Ehlers

    Alphabeta T cell receptor-positive cells and interferon-gamma, but not inducible nitric oxide synthase, are critical for granuloma necrosis in a mouse model of mycobacteria-induced pulmonary immunopathology

    J Exp Med

    (2001)
  • J. Benini et al.

    Different types of pulmonary granuloma necrosis in immunocompetent vs. TNFRp55-gene-deficient mice aerogenically infected with highly virulent Mycobacterium avium

    J Pathol

    (1999)
  • M. Florido et al.

    Immunological basis of the development of necrotic lesions following Mycobacterium avium infection

    Immunology

    (2002)
  • A. Wangoo

    Contribution of Th1 and Th2 cells to protection and pathology in experimental models of granulomatous lung disease

    J Immunol

    (2001)
  • D.W. Smith et al.

    Host-parasite relationships in experimental airborne tuberculosis. IV. Early events in the course of infection in vaccinated and nonvaccinated guinea pigs

    Am Rev Respir Dis

    (1970)
  • E.H. Wiegeshaus et al.

    Host-parasite relationships in experimental airborne tuberculosis. 3. Relevance of microbial enumeration to acquired resistance in guinea pigs

    Am Rev Respir Dis

    (1970)
  • A.I. Alsaadi et al.

    The fate of virulent and attenuated Mycobacteria in guinea pigs infected by the respiratory route

    Am Rev Respir Dis

    (1973)
  • V. Balasubramanian et al.

    Growth characteristics of recent sputum isolates of Mycobacterium tuberculosis in guinea pigs infected by the respiratory route

    Infect Immun

    (1992)
  • J. Francis

    Tuberculosis in animals and man. A study in comparative pathology

    (1958)
  • J.S. Fok et al.

    Host-parasite relationships in experimental airborne tuberculosis. V. Lack of hematogenous dissemination of Mycobacterium tuberculosis to the lungs in animals vaccinated with Bacille Calmette–Guerin

    J Infect Dis

    (1976)
  • R.S. Ho et al.

    Host-parasite relationships in experimental airborne tuberculosis. VII. Fate of Mycobacterium tuberculosis in primary lung lesions and in primary lesion-free lung tissue infected as a result of bacillemia

    J Infect Dis

    (1978)
  • Cited by (67)

    • Tuberculosis in free-ranging and captive wild animals: Pathological and molecular diagnosis with histomorphological differentiation of granulomatous lesions

      2022, Microbial Pathogenesis
      Citation Excerpt :

      A cavity was formed due to the communication of liquefied caseum with the airways, which provides more oxygenated air to bacilli. Hence, an increased rate of multiplication of bacilli was observed [44]. Lung lesions with mild intensity were observed in some sloth bears, indicating the initial stages of granulomas [35].

    • Quantitative and qualitative iNKT repertoire associations with disease susceptibility and outcome in macaque tuberculosis infection

      2017, Tuberculosis
      Citation Excerpt :

      Furthermore, peripheral blood iNKT numbers are reduced in human TB patients with iNKTs exhibiting an activated phenotype [37,38], indicating a role for these innate T cells in the host immune defence against TB. Non-human primate models allow in depth exploration of immunity to Mtb while detailing disease progression and outcome [9,11,39]. However, studies investigating iNKTs in these well-characterised NHP models are lacking.

    • The formation of the granuloma in tuberculosis infection

      2014, Seminars in Immunology
      Citation Excerpt :

      In his review Hunter also points to various further characteristics of these events, including high power micrographs showing highly clumped bacilli (which could be biofilms, as we have suggested) which seem to form “pellicles” on the cavity surface (again, consistent with our new model [8]). A further important point he makes is that another element of contemporary literature that he feels may be misleading is the emphasis on rabbit models in which highly liquefied cavities are rapidly caused by exposure to virulent Mycobacterium bovis [55]. As he argues, M. tuberculosis does not do this in these animals, suggesting a different basic mechanism of pathogenesis.

    View all citing articles on Scopus
    View full text