Thepsmα Locus Regulates Production of Staphylococcus aureus Alpha-Toxin during Infection

Abstract

ABSTRACTStaphylococcus aureusis a leading cause of human bacterial infection, causing a wide spectrum of disease ranging from skin and soft tissue infections to life-threatening pneumonia and sepsis.S. aureustoxins play an essential role in disease pathogenesis, contributing to both immunomodulation and host tissue injury. Prominent among these toxins are the membrane-active pore-forming cytolysin alpha-toxin (Hla) and the amphipathic α-helical phenol-soluble modulin (PSM) peptides. As deletion of either thehlaorpsmlocus leads to a phenotypically similar virulence defect in skin and soft tissue infection, we sought to determine the relative contribution of each locus to disease pathogenesis. Here we show that production of Hla can be modulated by PSM expression. AnS. aureusmutant lacking PSM expression exhibits a transcriptional delay inhlamRNA production and therefore fails to secrete normal levels of Hla at early phases of growth. This leads to attenuation of virulencein vitroand in murine skin and lung models of infection, correlating with reduced recovery of Hla from host tissues. Production of Hla and restoration of staphylococcal virulence can be achieved in thepsmmutant by plasmid-driven overexpression ofhla. Our study suggests the coordinated action of Hla and PSMs in host tissue during early pathogenesis, confirming a major role for Hla in epithelial injury duringS. aureusinfection. These findings highlight the possibility that therapeutics targeting PSM production may simultaneously prevent Hla-mediated tissue injury.