Natural mutations in a Staphylococcus aureus virulence regulator attenuate cytotoxicity but permit bacteremia and abscess formation

Abstract

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.

In or out: Phagosomal escape ofStaphylococcus aureus

“…By contrast, studies making use of PMNs from the peripheral blood of human donors report on S . aureus replication within these PMNs (Blättner et al, ; Das et al, ; Voyich et al, ). In neutrophils, S .…”

“…However, these bacteria were not found to replicate intracellularly. By contrast, studies making use of PMNs from the peripheral blood of human donors report on S. aureus replication within these PMNs (Blättner et al, 2016;Das et al, 2016;Voyich et al, 2005). In neutrophils, S. aureus also was bound by a phagosomal membrane until host cell lysis and only few bacteria were found in the cytosol of murine PMNs (Gresham et al, 2000;Kobayashi et al, 2010) thereby again supporting survival of the bacteria within vesicles of the host cell.…”

Evolutionary Constraints Shaping Streptococcus pyogenes –Host Interactions

“…Staphylococcus aureus) and -negative bacteria (e.g. Pseudomonas aeruginosa ) [8,18,23–26]. However, as most animal models of pathogenesis bypass natural routes of infection, they fail to recapitulate the primary modes of GAS colonization, infection and transmission in and from the human nasopharynx.…”

Genomic Landscape of Intrahost Variation in Group A Streptococcus: Repeated and Abundant Mutational Inactivation of the fabT Gene Encoding a Regulator of Fatty Acid Synthesis

“…For example, sequence analysis of the genomes of 95 colonies of Staphylococcus aureus cultured at one time point from a human patient with a perinephric abscess found an average pairwise distance between the genomes of 7.4 SNPs (61). Similarly, in related work (62)(63)(64), several investigators have studied bacterial genome-scale intrahost evolution over time, but in these studies, generally only a single colony at each time point has been analyzed (65)(66)(67)(68)(69).…”