title: The lipopolysaccharide modification regulator PmrA limits Salmonella virulence by repressing the type three-secretion system Spi/Ssa.
abstract: The regulatory protein PmrA controls expression of lipopolysaccharide (LPS) modification genes in Salmonella enterica serovar Typhimurium, the etiologic agent of human gastroenteritis and murine typhoid fever. PmrA-dependent LPS modifications confer resistance to serum, Fe(3+), and several antimicrobial peptides, suggesting that the pmrA gene is required for Salmonella virulence. We now report that, surprisingly, a pmrA null mutant is actually hypervirulent when inoculated i.p. into C3H/HeN mice. We establish that the PmrA protein binds to the promoter and represses transcription of ssrB, a virulence regulatory gene required for expression of the Spi/Ssa type three-secretion system inside macrophages. The pmrA mutant displayed heightened expression of SsrB-dependent genes and faster Spi/Ssa-dependent macrophage killing than wild-type Salmonella. A mutation in the ssrB promoter that abolished repression by the PmrA protein rendered Salmonella as hypervirulent as the pmrA null mutant. The antivirulence function of the PmrA protein may limit the acute phase of Salmonella infection, thereby enhancing pathogen persistence in host tissues.
authors.affiliation: Department of Microbial Pathogenesis, Yale School of Medicine, New Haven, CT 06536-0812, USA.
authors.forename: Jeongjoon
authors.initials: J
authors.lastname: Choi
authors.forename: Eduardo A
authors.initials: EA
authors.lastname: Groisman
mesh_terms: D000818:Animals; D001426:Bacterial Proteins / Q000378:metabolism*; D058947:Bacterial Secretion Systems / Q000235:genetics / Q000502:physiology*; D047369:Chromatin Immunoprecipitation; D024202:Electrophoretic Mobility Shift Assay; D005260:Female; D015964:Gene Expression Regulation, Bacterial / Q000235:genetics*; D008070:Lipopolysaccharides / Q000378:metabolism; D008264:Macrophages / Q000378:metabolism; D051379:Mice; D010957:Plasmids / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D012486:Salmonella typhimurium / Q000235:genetics* / Q000472:pathogenicity*; D014157:Transcription Factors / Q000378:metabolism*
chemical_list: D001426:Bacterial Proteins; D058947:Bacterial Secretion Systems; D008070:Lipopolysaccharides; C119761:SsrB protein, Salmonella typhimurium; D014157:Transcription Factors; C081902:pmrA protein, Bacteria
keywords: Salmonella pathogenicity island 2; cytotoxicity