The Length of the Staphylococcus aureus Protein A Polymorphic Region Regulates Inflammation: Impact on Acute and Chronic Infection

Abstract

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.

<b><i>Staphylococcus aureus</i></b> Induces Shedding of IL-1RII in Monocytes and Neutrophils

“…5c), as has been previously described for the regulation of these inflammatory molecules [27,28,29,30]. We have previously reported that protein A induces CXCL10 production in macrophages [31]. The critical role of protein A in the induction of this chemokine in vivo was further confirmed in this study.…”

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

“…TNFR1 signaling triggered by protein A initiates the production of interleukin 8 (IL-8) and the recruitment of neutrophils to the site of infection (26). Protein A induces other proinflammatory cytokines and chemokines, such as type I interferon (IFN) and CXCL10, in airway epithelial cells and macrophages, which also contribute to neutrophil recruitment and bacterial clearance (27)(28)(29).…”

“…A clinical isolate of Escherichia coli (isolate 515; generously provided by D. Centron, IMPaM, UBA-CONICET, Buenos Aires, Argentina) and Pseudomonas aeruginosa PAO-1 (31) were grown in Luria-Bertani agar (Britania, Buenos Aires, Argentina) and were suspended in RPMI 1640 medium (Life Technologies, Grand Island, NY) at a concentration of 1 ϫ 10 9 CFU/ml. Lactococcus lactis MG1363 carrying the pKS80 vector containing full-length spa or an empty-vector control (provided by Tim Foster, Trinity College, Dublin, Ireland) was grown in M17 medium supplemented with 0.5% glucose and 5 g/ml erythromycin at 30°C without agitation (29,32,33). Cells were harvested by centrifugation at 10,000 rpm for 10 min, and the pellet was suspended in RPMI 1640 medium (Life Technologies, Grand Island, NY) at a concentration of 5 ϫ 10 8 CFU/ml.…”

“…Breeding colonies were established at the animal facility of the National University of San Luis (San Luis, Argentina). Mice were inoculated intraperitoneally with 200 l of either recombinant protein A (at a dose of 0.125 nmol/g, based on a mouse model of LPS-induced endotoxemia [34] and our previous studies [29]), wild-type S. aureus, a protein A-deficient mutant (2 ϫ 10 8 CFU/ml), E. coli 515 (2 ϫ 10 8 CFU/ ml), or PBS as control. Blood samples were obtained by puncture of the retro-orbital plexus at different times after inoculation.…”

Expression of CXCR1 (Interleukin-8 Receptor) in Murine Macrophages After Staphylococcus aureus Infection and its Possible Implication on Intracellular Survival Correlating with Cytokines and Bacterial Anti-Oxidant Enzymes

“…Studies evaluating the role of S. aureus infectioninduced CXCR1 expression in murine macrophages of Swiss albino mice have not been described. It was reported that staphylococcal protein A initiates the production of IL-8 and the recruitment of neutrophils to the site of infection [16,17]. However, even typical extracellular pathogens, S. aureus, may occasionally become intracellular, at least within macrophages, monocytes, and polymorphonuclear neutrophil (PMN) when host defense mechanisms are activated.…”