Phenol-soluble modulin alpha and beta display divergent roles in mice with staphylococcal septic arthritis

Phenol-soluble modulin alpha (PSM alpha) is identified as potent virulence factors in Staphylococcus aureus (S. aureus) infections. Very little is known about the role of PSM beta which belongs to the same toxin family. Here we compared the role of PSMs in S. aureus-induced septic arthritis in a murine model using three isogenic S. aureus strains differing in the expression of PSMs (Newman, Delta psm alpha, and Delta psm beta). The effects of PSMs on neutrophil NADPH-oxidase activity were determined in vitro. We show that the PSM alpha activates neutrophils via the formyl peptide receptor (FPR) 2 and reduces their NADPH-oxidase activity in response to the phorbol ester PMA. Despite being a poor neutrophil activator, PSM beta has the ability to reduce the neutrophil activating effect of PSM alpha and to partly reverse the effect of PSM alpha on the neutrophil response to PMA. Mice infected with S. aureus lacking PSM alpha had better weight development and lower bacterial burden in the kidneys compared to mice infected with the parental strain, whereas mice infected with bacteria lacking PSM beta strain developed more severe septic arthritis accompanied with higher IL-6 and KC. We conclude that PSM alpha and PSM beta play distinct roles in septic arthritis: PSM alpha aggravates systemic infection, whereas PSM beta protects arthritis development. Phenol-soluble modulin alpha and beta display divergent roles in staphylococcal infection and its associated septic arthritis - whereas PSM alpha is a virulence factor for neutrophils that worsens infection, PSM beta protects from the development of septic arthritis.