Clinically-relevant mutations in the PhoR sensor kinase of host-adapted Mycobacterium abscessus isolates impact response to acidic pH and virulence

Functional genomics analysis of Mycobacterium abscessus clinical isolates from chronically-infected patients to identify genes under strong evolutionary pressure during lung adaptation identified phoR as one of the most frequently mutated. phoR encodes the histidine kinase (HK) of the two-component regulatory system (TCS) PhoPR. While PhoPR has been extensively studied in Mycobacterium tuberculosis for its role in virulence, little is known about the function of this TCS and the signals governing its activation in M. abscessus. We here show that acidic pH leads to the upregulation of phoP in M. abscessus and that clinically-relevant nonsynonymous mutations identified in PhoR exacerbate this response. PhoR appears to modulate the ability of its cognate response regulator, PhoP, to autoregulate itself by controlling its dephosphorylation. At low pH, the phosphatase activity of PhoR is reduced and the build-up of phospho-PhoP that ensues results in the upregulation of phoP that accompanies the induction of a defined set of genes, many of which are thought to play a role in virulence and host adaptation. In line with the idea that M. abscessus isolates expressing clinically-relevant PhoR variants may be better prepared for survival within the host, we find these strains to be less efficiently internalized by macrophages and to display enhanced intracellular survival.