Widespread Bronchogenic Dissemination Makes DBA/2 Mice More Susceptible than C57BL/6 Mice to Experimental Aerosol Infection withMycobacterium tuberculosis

Abstract

We have used the murine model of aerosol-induced experimental tuberculosis to assess the effects of four clinical isolates and a reference strain of Mycobacterium tuberculosis on resistant C57BL/6 mice and susceptible DBA/2 mice. Histological studies and detection of 25 cytokines potentially involved in the infection were carried out. DBA/2 mice showed higher concentrations of bacilli in bronchoalveolar lavage fluid and lung tissue. Furthermore, these mice evidenced a larger granulomatous infiltration in the parenchyma due to an increased rate of emigration of infected foamy macrophages from the granulomas to the neighboring pulmonary alveolar spaces. The better control of bacillary concentrations and pulmonary infiltration observed in C57BL/6 mice from week 3 postinfection could result from their higher RANTES, ICAM-1, and gamma interferon (IFN-␥) mRNA levels. On the other hand, the higher MIP-2 and MCP-3 mRNA levels seen in DBA/2 mice would result in stronger lung recruitment of macrophages and neutrophils. Additionally, DBA/2 mice showed increased inducible nitric oxide synthase expression, induced by the larger number of foamy macrophages, at weeks 18 and 22. This increment was a consequence of phagocytosed bacillary debris, was independent of IFN-␥ expression, and could exert only a bacteriostatic effect. The results of the study suggest that DBA/2 mice are more susceptible than C57BL/6 mice to M. tuberculosis infection due to a higher bronchial dissemination of bacilli inside poorly activated foamy macrophages.

On the nature ofMycobacterium tuberculosis-latent bacilli

“…in the alveolar spaces), or even the constant expression of local interferon-c [55], support the theory of a constant bacillary growth and destruction. Even the progressive occupation of the lung parenchyma during chronic infection [48,52,53] supports this idea. The findings in the murine model of TB must be considered with caution, since the human response against M. tuberculosis is not that tolerant, but the murine model might give us an idea about what happens at the beginning of infection when there is no well-established fibrosis in granulomas and the chances for trafficking material from these to the alveolar spaces is feasible.…”

“…This is a consequence of the migration of macrophages, filled with tissue debris and bacilli, to the alveolar spaces [47]. Interestingly, most macrophages are activated either directly by specific lymphocytes or by ingesting cell wall components from M. tuberculosis, as evidenced by the expression of nitric oxide synthase (NOS) [48]. It is difficult to explain why some of these cells have one or two bacilli inside.…”

“…These authors hypothesised that a continuous bacterial turnover would lead to an accumulation of bacterial [46,48]). Immediately after the infection of alveolar macrophages (a) and the building of the first pre-granulomas, there is dissemination throughout the parenchyma generating the secondary granulomas (b).…”

“…Therefore, these foamy cells may be a kind of a "sanctuary" for the stressed bacilli. Finally, some of them start to grow inside the foamy macrophages, until they are destroyed [45,46,48]. This growth inside the alveolar space and outside the granulomas is especially harmful, as dissemination takes place very easily from this area.…”

Inflammation and Immunopathogenesis of Tuberculosis Progression

“…To elucidate whether the extent of inflammation affects TB progression in a "normal" population, several groups have compared immune responses in mice genetically resistant and susceptible to TB. In different models, susceptible mice produced more proinflammatory cytokines and developed stronger neutrophilic inflammation than resistant mice (Cardona et al, 2003;Eruslanov et al, 2004;Eruslanov et al, 2005;Keller et al, 2006). To directly address an association between inflammatory reactions and TB progression, we have recently analyzed TB severity and immune reactivity in a panel of genetically heterogeneous (A/SnxI/St)F2 hybrid mice (Lyadova et al, 2010).…”