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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.

Original publication

DOI

10.1073/pnas.1520255113

Type

Journal article

Journal

Proceedings of the national academy of sciences of the united states of america

Publication Date

16/05/2016

Volume

113

Pages

E3101 - E3110

Addresses

Biocenter, Chair of Microbiology, University of Würzburg, D-97074 Wuerzburg, Germany;

Keywords

Hela Cells, Animals, Mice, Inbred BALB C, Humans, Mice, Staphylococcus aureus, Bacteremia, Staphylococcal Infections, Abscess, Hemolysis, Bacterial Proteins, RNA, Messenger, RNA, Untranslated, Virulence Factors, Reverse Transcriptase Polymerase Chain Reaction, Proteomics, Virulence, Apoptosis, Gene Expression Regulation, Bacterial, Mutation, Female, Real-Time Polymerase Chain Reaction