REVIEWAnimal models of cavitation in pulmonary tuberculosis
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).
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Tuberculosis in free-ranging and captive wild animals: Pathological and molecular diagnosis with histomorphological differentiation of granulomatous lesions
2022, Microbial PathogenesisCitation 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].
Diverse Cavity Types and Evidence that Mechanical Action on the Necrotic Granuloma Drives Tuberculous Cavitation
2018, American Journal of PathologyQuantitative and qualitative iNKT repertoire associations with disease susceptibility and outcome in macaque tuberculosis infection
2017, TuberculosisCitation 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 ImmunologyCitation 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.