Deletion of Two-Component Regulatory Systems Increases the Virulence of Mycobacterium tuberculosis

Abstract

ABSTRACT Two-component regulatory signal transduction systems are widely distributed among bacteria and enable the organisms to make coordinated changes in gene expression in response to a variety of environmental stimuli. The genome sequence of Mycobacterium tuberculosis contains 11 complete two-component systems, four isolated homologous regulators, and three isolated homologous sensors. We have constructed defined mutations in six of these genes and measured virulence in a SCID mouse model. Mice infected with four of the mutants (deletions of devR , tcrXY , trcS , and kdpDE ) died more rapidly than those infected with wild-type bacteria. The other two mutants ( narL and Rv3220c ) showed no change compared to the wild-type H37Rv strain. The most hypervirulent mutant ( devR Δ) also grew more rapidly in the acute stage of infection in immunocompetent mice and in gamma interferon-activated macrophages. These results define a novel class of genes in this pathogen whose presence slows down its multiplication in vivo or increases its susceptibility to host killing mechanisms. Thus, M. tuberculosis actively maintains a balance between its own survival and that of the host.