DevR-mediated adaptive response in Mycobacterium tuberculosis H37Ra: links to asparagine metabolism

Abstract

The DevR transcriptional switch that defines the response of Mycobacterium tuberculosis to the lack of oxygen is now well established and likely helps the bacteria shift to a state of persistence. The M. tuberculosis two component signal transduction system (TCS), DevR–DevS, implicated in this transition to latency, is differentially expressed in H37Ra and H37Rv strains. Despite originating from the H37 ancestral strain, H37Ra and H37Rv have significant differences in their growth, physiology, and virulence. To further dissect the role of DevR in growth adaptive processes of M. tuberculosis, we investigated the hypoxic response of the avirulent H37Ra strain. Our results show that the DevR–DevS TCS in H37Ra is responsive to hypoxia and capable of target gene regulation, indicating similar DevR–DevS signaling pathways in H37Ra and H37Rv. A key finding of this study was the constitutive expression of the Rv3134c–devR–devS operon and a subset of sentinel DevR-regulated genes in aerobic cultures of H37Ra but not H37Rv grown in Dubos–Tween–albumin medium. Asparagine and/or catabolites of asparagine metabolism were implicated in aerobic induction of the DevR–DevS TCS in H37Ra. This is the first report of medium-specific constitutive expression of the DevR regulon in an avirulent strain and suggests a potential role for metabolite(s) in the activation of the DevR–DevS TCS.