Natural mutations in a Staphylococcus aureus virulence regulator attenuate cytotoxicity but permit bacteremia and abscess formation.
Sudip DasClaudia LindemannBernadette C YoungJulius MullerBabett ÖsterreichNicola TernetteAnn-Cathrin WinklerKerstin PaprotkaRichard ReinhardtKonrad U FörstnerElizabeth AllenAmy FlaxmanYuko YamaguchiChristine S RollierPauline van DiemenSebastian BlättnerChristian W RemmeleMartina SelleMarcus DittrichTobias MüllerJörg VogelKnut OhlsenDerrick W CrookRuth MasseyDaniel J WilsonThomas RudelDavid H WyllieMartin J FraunholzPublished in: Proceedings of the National Academy of Sciences of the United States of America (2016)
Staphylococcus aureus is a major bacterial pathogen, which causes severe blood and tissue infections that frequently emerge by autoinfection with asymptomatically carried nose and skin populations. However, recent studies report that bloodstream isolates differ systematically from those found in the nose and skin, exhibiting reduced toxicity toward leukocytes. In two patients, an attenuated toxicity bloodstream infection evolved from an asymptomatically carried high-toxicity nasal strain by loss-of-function mutations in the gene encoding the transcription factor repressor of surface proteins (rsp). Here, we report that rsp knockout mutants lead to global transcriptional and proteomic reprofiling, and they exhibit the greatest signal in a genome-wide screen for genes influencing S. aureus survival in human cells. This effect is likely to be mediated in part via SSR42, a long-noncoding RNA. We show that rsp controls SSR42 expression, is induced by hydrogen peroxide, and is required for normal cytotoxicity and hemolytic activity. Rsp inactivation in laboratory- and bacteremia-derived mutants attenuates toxin production, but up-regulates other immune subversion proteins and reduces lethality during experimental infection. Crucially, inactivation of rsp preserves bacterial dissemination, because it affects neither formation of deep abscesses in mice nor survival in human blood. Thus, we have identified a spontaneously evolving, attenuated-cytotoxicity, nonhemolytic S. aureus phenotype, controlled by a pleiotropic transcriptional regulator/noncoding RNA virulence regulatory system, capable of causing S. aureus bloodstream infections. Such a phenotype could promote deep infection with limited early clinical manifestations, raising concerns that bacterial evolution within the human body may contribute to severe infection.
Keyphrases
- transcription factor
- staphylococcus aureus
- genome wide
- hydrogen peroxide
- escherichia coli
- long noncoding rna
- endothelial cells
- oxidative stress
- genome wide identification
- pseudomonas aeruginosa
- gene expression
- dna methylation
- gram negative
- genetic diversity
- nitric oxide
- ejection fraction
- poor prognosis
- end stage renal disease
- newly diagnosed
- soft tissue
- klebsiella pneumoniae
- copy number
- cystic fibrosis
- candida albicans
- peripheral blood
- wound healing
- patient reported outcomes
- heat shock
- patient reported
- label free
- binding protein