VapBC22 toxin-antitoxin system from <i>Mycobacterium tuberculosis</i> is required for pathogenesis and modulation of host immune response

Abstract

Virulence-associated protein B and C toxin-antitoxin (TA) systems are widespread in prokaryotes, but their precise role in physiology is poorly understood. We have functionally characterized the VapBC22 TA system from <i>Mycobacterium tuberculosis</i>. Transcriptome analysis revealed that overexpression of VapC22 toxin in <i>M. tuberculosis</i> results in reduced levels of metabolic enzymes and increased levels of ribosomal proteins. Proteomics studies showed reduced expression of virulence-associated proteins and increased levels of cognate antitoxin, VapB22 in the Δ<i>vapC22</i> mutant strain. Furthermore, both the Δ<i>vapC22</i> mutant and VapB22 overexpression strains of <i>M. tuberculosis</i> were susceptible to killing upon exposure to oxidative stress and showed attenuated growth in guinea pigs and mice. Host transcriptome analysis suggests upregulation of the transcripts involved in innate immune responses and tissue remodeling in mice infected with the Δ<i>vapC22</i> mutant strain. Together, we demonstrate that the VapBC22 TA system belongs to a key regulatory network and is essential for <i>M. tuberculosis</i> pathogenesis.