The XXXX VprA-VprB Two-Component System Controls Virulence through Endotoxin Modification.

@entity1 @entity3275 @entity1522 @entity3081 @entity66 @entity2228 @entity1838 @entity28656 @entity3793 @entity281
The bacterial cell surface is the first structure the host immune system targets to prevent @entity281 . Cationic antimicrobial peptides of the innate immune system bind to the membrane of Gram-negative pathogens via conserved, surface-exposed lipopolysaccharide (LPS) molecules. We recently reported that modern strains of the global intestinal pathogen @entity1838 modify the anionic @entity3275 domain of LPS with a novel moiety, @entity1522 . Remarkably, @entity2228 or @entity28656 addition to @entity3275 alters the surface charge of the bacteria to help evade the cationic antimicrobial peptide polymyxin. However, the regulatory mechanisms of @entity3275 modification in @entity1838 are unknown. Here, we identify a novel two-component system that regulates @entity3275 glycine modification by responding to important biological cues associated with pathogenesis, including bile, mildly acidic pH, and cationic antimicrobial peptides. The @entity3793 kinase Vc1319 (VprB) and the response regulator Vc1320 (VprA) respond to these signals and are required for the expression of the almEFG operon that encodes the genes essential for @entity2228 modification of @entity3275 . Importantly, both the newly identified two-component system and the @entity3275 modification machinery are required for colonization of the @entity1 host. This study demonstrates how @entity1838 uses a previously unknown regulatory network, independent of well-studied @entity1838 virulence factors and regulators, to respond to the host environment and cause @entity281 . IMPORTANCE: @entity1838 , the etiological agent of @entity66 , infects millions of @entity1 every year. @entity1838 El Tor and classical biotypes have been responsible for all @entity3081 pandemics. The El Tor biotype responsible for the current seventh pandemic has displaced the classical biotype worldwide and is highly resistant to cationic antimicrobial peptides, like polymyxin B. This resistance arises from the attachment of one or two @entity2228 residues to the @entity3275 domain of lipopolysaccharide, a major surface component of Gram-negative bacteria. Here, we identify the VprAB two-component system that regulates the charge of the bacterial surface by directly controlling the expression of genes required for @entity2228 addition to @entity3275 . The VprAB-dependent @entity3275 modification confers polymyxin B resistance and contributes significantly to pathogenesis. This finding is relevant for understanding how @entity1838 has evolved mechanisms to facilitate the evasion of the host immune system and increase bacterial fitness.
