Antibiotics Differentially Modulate Lipoteichoic Acid-Mediated Host Immune Response

Marquerita Algorri,Annie Wong-Beringer

doi:10.3390/antibiotics9090573

Abstract

In Staphylococcus aureus bacteremia, our group has shown that a dysregulated balance of pro- and anti-inflammatory cytokine response biased towards an immunoparalysis phenotype is predictive of persistence and mortality, despite receipt of antibiotics. Certain antibiotics, as well as lipoteichoic acid (LTA) released from S. aureus, can modulate immune response ex vivo. Here, we evaluated the effects of three anti-staphylococcal antibiotics (vancomycin, tedizolid, and daptomycin) on the expression of cytokines and cell surface markers of immune activation (TNFα, HLA-DR) and immunoparalysis (IL-10, PD-L1) in human peripheral blood mononuclear cells (PBMC) exposed to high (10 μg) and low (1 μg) doses of LTA. Results suggested a dose-dependent relationship between LTA and induction of anti- and pro-inflammatory immune responses. Differential antibiotic effects were prominently observed at high but not low LTA condition. Vancomycin significantly induced IL-10 and TNFα expression, whereas daptomycin had no effects on cytokine response or expression of cell surface receptors. Tedizolid increased TNFα and modestly increased HLA-DR expression, suggesting a stimulatory effect. These findings suggest that anti-staphylococcal agents differentially alter LTA-mediated immune cell activation status and cytokine response, providing support for future clinical studies to better elucidate the complexities of host–microbial–antibiotic interaction that can help direct precision therapy for S. aureus bacteremia.

Highlights

The majority of sepsis-related deaths occur more than five days after onset of sepsis [1]
Tedizolid increased TNFα and modestly increased human leukocyte antigen DR-isotype (HLA-DR) expression, suggesting a stimulatory effect. These findings suggest that anti-staphylococcal agents differentially alter lipoteichoic acid (LTA)-mediated immune cell activation status and cytokine response, providing support for future clinical studies to better elucidate the complexities of host–microbial–antibiotic interaction that can help direct precision therapy for S. aureus bacteremia
We examined four relevant sepsis markers to assess host immune response phenotype: IL-10, TNFα, HLA-DR, and programmed cell death ligand 1 (PD-L1) (Figure 1)

Summary

Introduction

The majority of sepsis-related deaths occur more than five days after onset of sepsis [1]. HLA-DR is a major histocompatibility (MHC) class II cell surface receptor present on monocytes and dendritic cells that is responsible for presenting antigens to CD4+ T cells, thereby initiating and activating the adaptive immune response. An additional marker of interest that has been shown previously to be strongly associated with increased risk of mortality in patients with sepsis is programmed cell death ligand 1 (PD-L1) on monocytes, which communicates with the inhibitory program cell death receptor (PD-1) and initiates T cell apoptosis [5]. Despite receipt of antibiotic therapy, persistent growth of the bacterium in blood for at least three days after start of antibiotic therapy occurs in 37% of patients and is associated with 16% increased risk of death for Antibiotics 2020, 9, 573; doi:10.3390/antibiotics9090573 www.mdpi.com/journal/antibiotics

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