Differential effects of antibiotics on neutrophils exposed to lipoteichoic acid derived from Staphylococcus aureus

Marquerita Algorri,Annie Wong-Beringer

doi:10.1186/s12941-020-00392-w

Marquerita Algorri, Annie Wong-Beringer

Open Access

https://doi.org/10.1186/s12941-020-00392-w

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Abstract

BackgroundPersistent bacteremia occurs in at least 30% of patients with Staphylococcus aureus bloodstream infection (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-dependent 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.MethodsNeutrophils 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). Neutrophil function was assessed by examining phagocytic response, activation (CD11b, CD62L expression), Toll-like receptor-2 expression, cell survival and apoptosis, and CXCL8 release.ResultsDifferential 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.ConclusionsSelect 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.

Highlights

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]
Our results indicate that the pro-inflammatory effect of lipoteichoic acid (LTA) is concentration-dependent and that ceftaroline strongly promotes polymorphonuclear leukocytes (PMNs) activation and phagocytosis while preserving cell survival and CXCL8 release, relative to other commonly used drugs, such as vancomycin, which impairs CXCL8 secretion
Neutrophil activation, phagocytosis, and cell survival is differentially affected by LTA exposure level and antibiotics We used two different exposure levels of LTA in combination with anti-staphylococcal antibiotics to stimulate PMNs isolated from healthy human donors

Summary

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 [3,4,5,6,7]. Recent evidence points to a dysregulated host immune response contributing to the development of persistence [3, 8,9,10]. 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. We compared the effects of different anti-staphylococcal antibiotics on LTA-mediated immune activation of neutrophils

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