Differential effects of antibiotics on neutrophils exposed to lipoteichoic acid derived from Staphylococcus aureus
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als of Clinical Microbiology and Antimicrobials Open Access
RESEARCH
Differential effects of antibiotics on neutrophils exposed to lipoteichoic acid derived from Staphylococcus aureus Marquerita Algorri and Annie Wong‑Beringer*
Abstract Background: Persistent bacteremia occurs in at least 30% of patients with Staphylococcus aureus bloodstream infec‑ tion (SAB) and may be attributable to a dysregulated host immune response. Neutrophils interact with a variety of S. aureus microbial factors, including lipoteichoic acid (LTA), to activate phagocytic function in a concentration-depend‑ ent manner. Antibiotics have been shown to exert both direct antimicrobial action as well as immunomodulatory effects. In this study, we compared the effects of different anti-staphylococcal antibiotics on LTA-mediated immune activation of neutrophils. Methods: Neutrophils obtained from healthy volunteers were exposed to two levels of LTA (1 and 10 μg/ml) with or without addition of antibiotics from different pharmacologic classes (vancomycin, daptomycin, ceftaroline). Neutro‑ phil function was assessed by examining phagocytic response, activation (CD11b, CD62L expression), Toll-like recep‑ tor-2 expression, cell survival and apoptosis, and CXCL8 release. Results: Differential LTA-mediated antibiotic effects on neutrophil function were observed primarily at the high LTA exposure level. Ceftaroline in the presence of 10 μg/ml LTA had the most prominent effects on phagocytosis and CD11b and CD62L expression, with trends towards increased neutrophil survival and preservation of CXCL8 release when compared to daptomycin and vancomycin with the latter significantly dampening PMN CXCL8 release. Conclusions: Select antimicrobial agents, such as ceftaroline, exert immunostimulatory effects on neutrophils exposed to S. aureus LTA, which when confirmed in vivo, could be leveraged for its dual immunomodulatory and antibacterial actions for the treatment of persistent SAB mediated by a dysregulated host response. Keywords: Antibiotics, Immunomodulation, Staphylococcus aureus bacteremia, Lipoteichoic acid, Ceftaroline Introduction Staphylococcus aureus is a leading cause of bacteremia and gram-positive sepsis in the United States, affecting 80 per 100,000 individuals annually [1, 2]. We and others have shown that persistent bacteremia (SAB) despite receipt of antibiotics with in vitro activity, affects approximately 1 in 3 patients and is a strong risk factor for mortality [3–7]. Specifically, each day of persistence causes a *Correspondence: [email protected] University of Southern California, School of Pharmacy, 1985 Zonal Avenue, Los Angeles, CA 90089, USA
16% increase in the risk of 30-day mortality [7]. Recent evidence points to a dysregulated host immune response contributing to the development of persistence [3, 8–10]. S. aureus possesses a variety of virulence factors that can contribute to immune dysfunction by modulating targeted pro-inflammatory responses. Importantly, S. aureus can subvert the phagocytic actions of neutrophils (PMNs)
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