Description:
<jats:title>ABSTRACT</jats:title>
<jats:p>
<jats:named-content content-type="genus-species">Staphylococcus aureus</jats:named-content>
is an important human pathogen that employs a large repertoire of secreted virulence factors to promote disease pathogenesis. Many strains of
<jats:named-content content-type="genus-species">S. aureus</jats:named-content>
possess a
<jats:italic>plc</jats:italic>
gene that encodes a phosphatidylinositol (PI)-specific phospholipase C (PI-PLC) capable of hydrolyzing PI and cleaving glycosyl-PI (GPI)-linked proteins from cell surfaces. Despite being secreted by virulent staphylococci, the contribution of PI-PLC to the capacity of
<jats:named-content content-type="genus-species">S. aureus</jats:named-content>
to cause disease remains undefined. Our goal in these studies was to understand PI-PLC in the context of
<jats:named-content content-type="genus-species">S. aureus</jats:named-content>
biology. Among a collection of genetically diverse clinical isolates of
<jats:named-content content-type="genus-species">S. aureus</jats:named-content>
, community-associated methicillin-resistant
<jats:named-content content-type="genus-species">S. aureus</jats:named-content>
(CA-MRSA) USA300 secreted the most PI-PLC. Screening a collection of two-component system (TCS) mutants of
<jats:named-content content-type="genus-species">S. aureus</jats:named-content>
, we identified both the
<jats:italic>agr</jats:italic>
quorum-sensing system and the SrrAB TCS to be positive regulators of
<jats:italic>plc</jats:italic>
gene expression. Real-time PCR and PI-PLC enzyme assays of the TCS mutants, coupled with SrrA promoter binding studies, demonstrated that SrrAB was the predominant transcriptional activator of
<jats:italic>plc</jats:italic>
. Furthermore,
<jats:italic>plc</jats:italic>
regulation was linked to oxidative stress both
<jats:italic>in vitro</jats:italic>
and
<jats:italic>in vivo</jats:italic>
in a SrrAB-dependent manner. A Δ
<jats:italic>plc</jats:italic>
mutant in a CA-MRSA USA300 background exhibited a survival defect in human whole blood and in isolated neutrophils. However, the same mutant strain displayed no survival defect in murine models of infection or murine whole blood. Overall, these data identify potential links between bacterial responses to the host innate immune system and to oxidative stress and suggest how PI-PLC could contribute to the pathogenesis of
<jats:named-content content-type="genus-species">S. aureus</jats:named-content>
infections.
</jats:p>