The sensor kinase MtrB of Mycobacterium tuberculosis regulates hypoxic survival and establishment of infection [Microbiology]

Paired two-component systems (TCSs), having a sensor kinase (SK) and a cognate response regulator (RR), enable the human pathogen Mycobacterium tuberculosis to respond to the external environment and to persist within its host. Here, we inactivated the SK gene of the TCS MtrAB, mtrB, generating the strain ΔmtrB. We show that mtrB loss reduces the bacterium's ability to survive in macrophages and increases its association with autophagosomes and autolysosomes. Notably, the ΔmtrB strain was markedly defective in establishing lung infection in mice, with no detectable lung pathology following aerosol challenge. ΔmtrB was less able to withstand hypoxic and acid stresses and to form biofilms and had decreased viability under hypoxia. Transcriptional profiling of ΔmtrB by gene microarray analysis, validated by quantitative RT-PCR, indicated down-regulation of the hypoxia-associated dosR regulon, as well as genes associated with other pathways linked to adaptation of M. tuberculosis to the host environment. Using in vitro biochemical assays, we demonstrate that MtrB interacts with DosR (a noncognate RR) in a phosphorylation-independent manner. Electrophoretic mobility shift assays revealed that MtrB enhances the binding of DosR to the hspX promoter, suggesting an unexpected role of MtrB in DosR-regulated gene expression in M. tuberculosis. Taken together, these findings indicate that MtrB functions as a regulator of DosR-dependent gene expression and in the adaptation of M. tube...
Source: Journal of Biological Chemistry - Category: Chemistry Authors: Tags: Microbiology Source Type: research