Cavitary tuberculosis produced in rabbits by aerosolized virulent tubercle bacilli

Abstract

Liquefaction of solid caseous tuberculous lesions and the subsequent cavity formation are probably the most dangerous processes in the pathogenesis of human pulmonary tuberculosis. In liquefied caseum, the tubercle bacilli grow extracellularly for the first time since the onset of the disease and can reach such large numbers that mutants with antimicrobial resistance may develop. From a cavity, the bacilli enter the bronchial tree and spread to other parts of the lung and also to other people. Of the commonly used laboratory animals, the rabbit is the only one in which cavitary tuberculosis can be readily produced. This report is the first to describe and analyze the complete course of cavitary tuberculosis, produced by aerosolized virulent bovine-type tubercle bacilli in commercially available New Zealand white rabbits. After the inhalation of 220 to 880 bacillary units, all of the rabbits were overtly well until they were sacrificed at 33 weeks. After the inhalation of 3,900 to 5,800 bacillary units, half of the rabbits died of progressive tuberculosis between 5 and 9 weeks and the other half lived until they were sacrificed at 18 weeks. Pulmonary cavities developed in both low-and high-dose groups, some beginning as early as 6 weeks. Bacilli from primary cavities sometimes caused nearby secondary cavities, but more frequently, they ascended the bronchial escalator, were swallowed, and caused secondary tubercles in the lymphoid tissue of the appendix and ileocecal junction. Histologically, and by culture, the number of bacilli found in the liquefied caseum varied from many to comparatively few. Strong tuberculin reactions at 4 weeks after infection were associated with fewer primary lesions, while strong tuberculin reactions at 33 weeks were associated with more cavitary lesions. In the tuberculous granulation tissue surrounding caseous and liquefied pulmonary foci and cavities, we found many mature epithelioid macrophages that contained high levels of the proteinase cathepsin D. Therefore, cathepsin D probably plays a major role in the liquefaction of solid caseous material and in the subsequent cavity formation. MATERIALS AND METHODS Rabbits and the number of bacillary units they inhaled. We exposed Pasteurella-free New Zealand White rabbits to high and low doses of M. bovis

Mycobacterium tuberculosis dysregulates MMP/TIMP balance to drive rapid cavitation and unrestrained bacterial proliferation

“…In low-prevalence settings, where the population prevalence of TST positivity is low, TST positivity is present in 90% of individuals with active TB [32]. Experimental data from rabbits indicate that DTH, as measured by any induration of TST, either from pre-sensitization or through prolonged infection, predicts cavity formation [24,25,29,34]. By recapitulating post-primary DTH, our model rapidly generates cavities that are highly representative of human pathology: there is a fibrotic layer surrounded by monocytes, within which lies a layer of epithelioid macrophages that are progressively more necrotic towards the centre of the cavity, which contains high numbers of culturable, acid-fast bacilli [5,12,13].…”

“…Both cavitation (p < 0.01; Figure 5E) and consolidation (p < 0.05; Figure 5F) signatures within the TB lesions increased progressively during the early stages after infection (days [21][22][23][24][25][26][27][28][29][30][31][32][33][34][35]. Interestingly, neither the mass not the volume of the regions of consolidation decreased during the appearance of cavitation, suggesting that while cavitation originates in these areas, cavities do not lead to a substantial reduction in consolidated tissue.…”

αβ T Cell Receptor-positive Cells and Interferon-γ, but not Inducible Nitric Oxide Synthase, Are Critical for Granuloma Necrosis in a Mouse Model of Mycobacteria-induced Pulmonary Immunopathology

“…This is due to the fact that the most commonly used animal model, the laboratory mouse, does not show granuloma necrosis in response to aerosol infection with M. tuberculosis , but characteristically develops a chronic fibrosis of the infected lung (11,12). On the other hand, guinea pigs and rabbits do develop caseating necrosis as a consequence of M. tuberculosis infection (13)(14)(15), but most immunological reagents, including gene-deficient strains, are not available for these species.…”

Immune responses in tuberculosis: antibodies and CD4‐CD8 lymphocytes with vascular adhesion molecules and cytokines (chemokines) cause a rapid antigen‐specific cell infiltration at sites of bacillus Calmette–Guérin reinfection

“…27,28 Yet antibodies circulate 2,13±15 and plasma cells are common in the lesions. 29 The studies presented here suggest a role for antibodies that has not been previously considered. We asked the question: what immune mechanism caused large numbers of cells to in®ltrate at 3 hr into reinfection BCG lesions, but not into primary BCG lesions?…”