Characterization of a Mycobacterium tuberculosis Rv3351c mutant
Pavlicek, Rebecca Lou
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The primary mode of transmission for Mycobacterium tuberculosis, the causative agent of tuberculosis (TB) is through inhalation of aerosolized bacilli. It is well established that alveolar macrophages are important in the ultimate success or failure of an M. tuberculosis infection, however, for other lung pathogens, type II alveolar epithelial pneumocytes also pay a significant role in disease outcome. Our research demonstrated that within hours of an M. tuberculosis aerosol infection of mice and rabbits, intracellular mycobacteria were readily detected in type I and type II pneumocytes and alveolar macrophages. Concomitantly, two M. tuberculosis genes were examined whose products appear to interact exclusively with pneumocytes: hbhA, which encodes a heparin-binding hemagglutinin adhesin, and Rv3351c, which when deleted from an M. tuberculosis strain, produces significantly less pneumocyte killing compared with controls. A recently identified hypervirulent clinical strain of M. tuberculosis, RDRIO, was found to possess a 10-gene deletion including Rv3351c. However, deleting the entire region in M. tuberculosis strain Erdman did not produce a hypervirulent phenotype in type II pneumocytes, but instead showed reduced virulence similar to infections with ∆Rv3351. In the lungs of aerosol-infected mice, ∆Rv3351c replicated more slowly and disseminated less efficiently compared with the parent strain, the opposite of what has been reported with strain RDRIO in humans. In examining transcription levels from in vitro-grown strain Erdman, genes comprising the RDRIO deletion region did not demonstrate transcriptional overlap. These data indicate that Rv3351c may not be transcribed as part of an operon, at least in vitro. However, the four genes that constituted a putative Rv3351c operon were constitutively expressed. This suggests that the encoded gene products are available throughout the bacterial growth cycle and thus, may be available for the attachment process or early endocytosis by epithelial cells. Mechanisms responsible for observed virulence differences among strain ∆Rv3351c and the RDRIO clinical strain have not yet been defined. An understanding of these processes in vivo could ultimately help define a potential new aspect of M. tuberculosis virulence and a more robust understanding of the role of epithelial cells in pulmonary tuberculosis.
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