Increased pathology in lungs of mice after infection with an α-crystallin mutant of Mycobacterium tuberculosis: changes in cathepsin proteases and certain cytokines

Abstract

Latency and reactivation are a significant problem that contributes to the incidence, transmission and pathogenesis of tuberculosis. The mechanisms involved in these processes, at the level of both the bacillus and the host, are poorly understood. InMycobacterium tuberculosistheα-crystallin (acr) gene has been linked to latency, because it is highly expressed during hypoxic growth conditions. Deletion of theacrgene inM. tuberculosisH37Rv (Δacrstrain) was previously shown to reduce the intracellular growth of bacilli in macrophages; however, its impact on pathogenesisin vivowas unknown. This study demonstrated that infection of C57BL6 mice with Δacrresults in lung bacillary loads 1-2 log units higher in comparison to parental H37Rv. Haematoxylin/eosin staining of lungs revealed exacerbated pathology characterized by extensive obliteration of alveolar air spaces by granulomatous inflammation. RT-PCR analysis and immunostaining of lungs showed that infection with either H37Rv or Δacrresults in the differential expression of lysosomal cathepsin proteases. A slight increase in the expression of the matrix-degrading acidic-type cathepsins B, D and H was noted in Δacr-infected mice and was associated with clusters of macrophages within lung granulomas. Δacr-infected mice also showed high serum levels of TNF-α, IFN-γand G-CSF, suggesting that Acr may play a role in modulating the host response to infection.