Abstract
Staphylococcus aureus
is a major cause of life-threatening bacterial infection. A significant risk factor for infection is nasal carriage. Previously, we reported spontaneous mutations during carriage associated with infection, including loss-of-function of the gene
repressor of surface proteins
(
rsp
). Here we use genomic screens, experimental assays, and molecular examination of
rsp
mutants from patients to understand how
rsp
is involved in infection; we find it has far-reaching effects on gene regulation. Paradoxically,
rsp
mutants exhibited attenuated toxicity and reduced disease severity early in experimental infection, without sacrificing the ability to cause abscesses and bloodstream infection. This work reveals a complex relationship between correlates of disease in the laboratory and in patients, demonstrating that life-threatening disease can be associated with reduced severity early in infection.
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
SSR
42, a long-noncoding RNA. We show that
rsp
controls
SSR
42 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.