Abstract
Reactive oxygen species (ROS) are an unavoidable host environmental cue for intracellular pathogens such as Mycobacterium tuberculosis and Mycobacterium bovis; however, the signaling pathway in mycobacteria for sensing and responding to environmental stress remains largely unclear. Here, we characterize a novel CmtR-Zur-ESX3-Zn2+ regulatory pathway in M. bovis that aids mycobacterial survival under oxidative stress. We demonstrate that CmtR functions as a novel redox sensor and that its expression can be significantly induced under H2O2 stress. CmtR can physically interact with the negative regulator Zur and de-represses the expression of the esx-3 operon, which leads to Zn2+ accumulation and promotion of reactive oxygen species detoxication in mycobacterial cells. Zn2+ can also act as an effector molecule of the CmtR regulator, using which the latter can de-repress its own expression for further inducing bacterial antioxidant adaptation. Consistently, CmtR can induce the expression of EsxH, a component of esx-3 operon involved in Zn2+ transportation that has been reported earlier, and inhibit phagosome maturation in macrophages. Lastly, CmtR significantly contributes to bacterial survival in macrophages and in the lungs of infected mice. Our findings reveal the existence of an antioxidant regulatory pathway in mycobacteria and provide novel information on stress-triggered gene regulation and its association with host–pathogen interaction.
Highlights
Reactive oxygen species (ROS) are an unavoidable host environmental cue for intracellular pathogens such as Mycobacterium tuberculosis and Mycobacterium bovis; the signaling pathway in mycobacteria for sensing and responding to environmental stress remains largely unclear
We report that CmtR, usually regarded as a Cd/ Pb sensor [36,37,38], is a novel redox sensor in M. bovis that is essential for mycobacterial growth under oxidative stress
In a previous screening of the transcriptional factor library of M. tuberculosis, we preliminarily characterized CmtR as a potential regulator that contributes to H2O2 resistance of M. bovis Bacillus CalmetteGuérin (BCG) (Fig. S1A)
Summary
In a previous screening of the transcriptional factor library of M. tuberculosis, we preliminarily characterized CmtR as a potential regulator that contributes to H2O2 resistance of M. bovis BCG (Fig. S1A). In the absence of H2O2 stress, no obvious growth difference was observed between the WT strain and the overexpressing or deletion strains (Fig. 1, A and C) These results indicate that cmtR expression enhances the resistance of M. bovis BCG to H2O2. No obvious effect was observed for MabR, an unrelated protein, under the same experimental conditions (lanes 8 and 9), which indicates that CmtR inhibits the DNAbinding ability of Zur. We further studied the integrated effect of H2O2 and CmtR on the DNA-binding activity of Zur using EMSA. The expression of the control gene fbpB remained unaffected under the same experimental conditions These results indicate that Zn21 inhibits the DNA-binding activity of CmtR and induces the expression of cmtR in mycobacterial strains. Our data suggest that CmtR enhances mycobacterial survival in macrophages in vitro as well as in mice
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