Characterization of a Novel Heat Shock Protein (Hsp22.5) Involved in the Pathogenesis of Mycobacterium tuberculosis

Abstract

Tuberculosis is a worldwide health problem, given that one-third of the world's population is currently infected with Mycobacterium tuberculosis. Understanding the regulation of virulence on the molecular level will provide a better understanding of how M. tuberculosis can establish chronic infection. Using in vivo microarray analysis (IVMA), we previously identified a group of genes that are activated in BALB/c mouse lungs compared to in vitro cultures, including the rv0990c gene. Our analysis indicated that this gene is a member of the heat shock regulon and was activated under other stress conditions, including survival in macrophages or during the late phase of chronic tuberculosis in the murine lungs. Deletion of rv0990c from the genome of M. tuberculosis strain H37Rv affected the transcriptional profiles of many genes (n = 382) and operons involved in mycobacterial survival, including the dormancy regulon, ATP synthesis, respiration, protein synthesis, and lipid metabolism. Comparison of the proteomes of the mutant to those of the wild-type strain further confirmed the differential expression of 15 proteins, especially those involved in the heat shock response (e.g., DnaK and GrpE). Finally, the rv0990c mutant strain showed survival equivalent to that of the isogenic wild-type strain during active tuberculosis in guinea pigs, despite showing significant attenuation in BALB/c mice during the chronic phase of the disease. Overall, we suggest that rv0990c encodes a heat shock protein that plays an important role in mycobacterial virulence. Hence, we renamed rv0990c heat shock protein 22.5 (hsp22.5), reflecting its molecular mass.