The psm α Locus Regulates Production of Staphylococcus aureus Alpha-Toxin during Infection

Abstract

Staphylococcus aureus is 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. aureus toxins play an essential role in disease pathogenesis, contributing to both immunomodulation and host tissue injury. Prominent among these toxins are the membrane-active poreforming cytolysin alpha-toxin (Hla) and the amphipathic ␣-helical phenol-soluble modulin (PSM) peptides. As deletion of either the hla or psm locus 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. An S. aureus mutant lacking PSM expression exhibits a transcriptional delay in hla mRNA production and therefore fails to secrete normal levels of Hla at early phases of growth. This leads to attenuation of virulence in vitro and 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 the psm mutant by plasmid-driven overexpression of hla. 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 during S. aureus infection. These findings highlight the possibility that therapeutics targeting PSM production may simultaneously prevent Hla-mediated tissue injury.

CD36 Is Essential for Regulation of the Host Innate Response to Staphylococcus aureus α-Toxin–Mediated Dermonecrosis

“…To determine whether Hla is necessary for increased dermonecrosis in the absence of CD36, we infected wild-type and CD36 −/− mice with a LAC isogenic hla -deletion mutant (LAC Δhla ) (31). At the same inoculum used for LAC (8 × 10 6 CFU), mice infected with LAC Δhla failed to develop dermonecrosis, consistent with previous reports (data not shown) (4, 32). However, at a higher inoculum (1.1 ×10 7 CFU), LACΔ hla infected CD36 −/− mice showed small, but increased abscess formation and dermonecrosis on day three post-infection compared to wild-type mice (Fig.…”

Bacterial Abscess Formation Is Controlled by the Stringent Stress Response and Can Be Targeted Therapeutically

“…The stringently regulated S. aureus phenol soluble modulin (PSM) toxins have been shown to be the major virulence factors contributing to abscess lesion formation and deletion of the psm locus results in the attenuation of virulence in several disease models (Berube et al, 2014). Therefore, using a S. aureus USA300 luminescent reporter strain, we measured the expression of the psm α operon when subjected to DJK-5.…”

“…PSMs recruit, activate and subsequently lyse neutrophils, the key effectors and first responders against bacterial infections (Berube et al, 2014). Previous studies have shown that upon uptake of S. aureus in neutrophils, the stringent response is elicited resulting in increased PSM synthesis, which contributes to survival after phagocytosis by mediating neutrophil lysis (Geiger et al, 2012).…”

Staphylococcusaureusα-Toxin Response Distinguishes Respiratory Virus–Methicillin-ResistantS. aureusCoinfection in Children

“…Seven-week-old female C57BL/6J mice (Jackson Laboratories, Bar Harbor, ME) were infected with 2-4 × 10 8 colony-forming units of S. aureus in 30 µL of PBS delivered via intranasal inoculation, with inoculum preparation and animal monitoring performed as previously described [17].…”