Staphylococcus aureus infections are an important public health concern due to their increasing incidence and high rates of mortality. The success of S. aureus as a pathogen is highly related to its enormous capacity to evade the host immune response. The critical role of tumor necrosis factor alpha (TNF-␣) 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. aureus protein A plays a key role in regulating inflammation through its ability to bind and signal through the TNF-␣ receptor 1 (TNFR1). In this study, we demonstrate that S. aureus, via protein A-mediated signaling, induces early shedding of TNFR1, which precedes the secretion of TNF-␣ in vitro and in vivo. The results obtained using a protein A-deficient mutant and tnfr1 ؊/؊ mice strongly suggest that the increased levels of soluble TNFR1 present during experimental S. aureus infection may neutralize circulating TNF-␣ and impair the host inflammatory response. Early shedding of TNFR1 induced by protein A may constitute a novel mechanism by which S. aureus subverts the host immune response.
Staphylococcus aureus protein A (SpA) plays a critical role in the induction of inflammation. This study was aimed to determine whether the number of short sequence repeats (SSRs) present in the polymorphic region modulates the inflammatory response induced by SpA. We demonstrated that there is a dose-response effect in the activation of interferon (IFN)-β signaling in airway epithelial and immune cells, depending on the number of SSRs, which leads to differences in neutrophil recruitment. We also determined that a significant proportion of isolates from patients with chronic infections such as osteomyelitis and cystic fibrosis carry fewer SSRs than do isolates from patients with acute infections or healthy carriers and that there was an inverse correlation between the number of SSRs and the length of disease course. Given the importance of IFN signaling in eradication of S. aureus, loss of SSRs may represent an advantageous mechanism to adapt to and persist in the host.
Interleukin 1 (IL-1) β is a critical cytokine that orchestrates host defenses against Staphylococcus aureus and is crucial for the eradication of bacteria. The production and action of IL-1β are regulated by multiple control pathways. Among them, IL-1RII (the type II IL-1 receptor) acts as a decoy receptor and has been shown to regulate the biological effects of IL-1β. High levels of soluble IL-1RII are present in septic patients; however, the stimuli that regulate the expression and release of IL-1RII in pathological conditions are incompletely elucidated. In the present study, we demonstrated the ability of S. aureus and protein A to induce IL-1RII shedding in myeloid cells. The positive modulation of IL-1RII expression and cleavage was associated with the failure to detect IL-1β in response to S. aureus both in vitro and in vivo, suggesting that the soluble form of the receptor could be masking the availability of IL-1β. The absence of detectable IL-1β was associated with low levels of inflammatory cytokines and chemokines known to be regulated by IL-1β and with increased bacterial persistence. Modulation of decoy receptors during systemic S. aureus infection is proposed as a new strategy used by this bacterium to evade the immune response.
Staphylococcus aureus is an important human pathogen that causes infections that may present high morbidity and mortality. Among its many virulence factors protein A (SpA) and Staphylococcal binding immunoglobulin protein (Sbi) bind the Fc portion of IgG interfering with opsonophagocytosis. We have previously demonstrated that SpA interacts with the TNF-α receptor (TNFR) 1 through each of the five IgG binding domains and induces the production of pro-inflammatory cytokines and chemokines. The IgG binding domains of Sbi are homologous to those of SpA, which allow us to hypothesize that Sbi might also have a role in the inflammatory response induced by S. aureus. We demonstrate that Sbi is a novel factor that participates in the induction of the inflammatory response during staphylococcal infections via TNFR1 and EGFR mediated signaling as well as downstream MAPKs. The expression of Sbi significantly contributed to IL-6 production and modulated CXCL-1 expression as well as neutrophil recruitment to the site of infection, thus demonstrating for the first time its relevance as a pro-inflammatory staphylococcal antigen in an in vivo model.
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