Evolution of Granulomas in Lungs of Mice Infected Aerogenically with Mycobacterium tuberculosis

Abstract

Aerogenous infection of C57Bl/6 mice with a virulent strain of Mycobacterium tuberculosis (CL 511) leads to the formation of primary granulomas in the lung where neutrophils, macrophages and subsequently, lymphocytes accumulate progressively around an initial cluster of infected macrophages. The spread of infection through the lung parenchyma gives rise to secondary granulomas featuring numerous lymphocytes that surround a small number of infected macrophages. Afterwards, foamy macrophages add an outer layer to the granulomas, which characteristically respect the pulmonary interstitium and remain confined within the alveolar spaces. This feature, in conjunction with the constant presence of M. tuberculosis in the products of broncho-alveolar lavage, suggests that the upward bronchial migration of infected macrophages may contribute significantly to pulmonary dissemination of mycobacterial infection. The latter would be in agreement with the persistence of chronic pulmonary infection in spite of a concomitant strong T helper 1 cell response.

Cell Wall Deficiency in Mycobacteria: Latency and Persistence

“…Considering this hypothesis, constant "escape" of bacilli from granulomas before fibrosis is the primary source of bacteria, reactivation would never occur after a specific time period, unless the host suffered an immunosuppressive episode (Cardona & Ruiz-Manzano, 2004). Of special interest is the finding that foamy macrophages are able to maintain a stressful environment that keeps the bacilli in non-replicating state, but on the other hand, allow them to escape from granulomas, making them more resistant to future stressful conditions (Cardona et al, 2000;2003;Cardona, 2009). …”

New insights into the function of granulomas in human tuberculosis

“…Development of the tuberculous granuloma is controlled by chemokines and cytokines produced by local tissue cells and infiltrating leukocytes. Various animal models have documented the spatio-temporal sequence of infiltrating leukocytes during the course of granuloma formation [8][9][10]. In addition, coordinated activation of cells is crucial for a productive granuloma to develop, and thus for longterm containment of mycobacteria at distinct sites of infection.…”

On the nature of Mycobacterium tuberculosis-latent bacilli

“…In fact, granulomas in mice are generated by an initial accumulation of macrophages in the infectious focus, which is surrounded by lymphocytes triggered by specific immunity. Subsequently, another cellular ring of foamy macrophages starts to surround these granulomas [46]. This is a consequence of the migration of macrophages, filled with tissue debris and bacilli, to the alveolar spaces [47].…”

“…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.…”

“…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).…”