Shedding of Tumor Necrosis Factor Receptor 1 Induced by Protein A Decreases Tumor Necrosis Factor Alpha Availability and Inflammation during Systemic Staphylococcus aureus Infection

Abstract

ABSTRACTStaphylococcus aureusinfections are an important public health concern due to their increasing incidence and high rates of mortality. The success ofS. aureusas a pathogen is highly related to its enormous capacity to evade the host immune response. The critical role of tumor necrosis factor alpha (TNF-α) in the initial host defense against systemic staphylococcal infection has been demonstrated in experimental models and may partially explain the lack of significant benefits observed in clinical trials attempting to neutralize this cytokine in septic patients.S. aureusprotein A plays a key role in regulating inflammation through its ability to bind and signal through the TNF-α receptor 1 (TNFR1). In this study, we demonstrate thatS. aureus, via protein A-mediated signaling, induces early shedding of TNFR1, which precedes the secretion of TNF-αin vitroandin vivo. The results obtained using a protein A-deficient mutant andtnfr1−/−mice strongly suggest that the increased levels of soluble TNFR1 present during experimentalS. aureusinfection may neutralize circulating TNF-α and impair the host inflammatory response. Early shedding of TNFR1 induced by protein A may constitute a novel mechanism by whichS. aureussubverts the host immune response.