The Impact of Rubella Virus Infection on a Secondary Inflammatory Response in Polarized Human Macrophages.

Erik Schilling,Claudia Claus,Ulrike Koehl,Lukas Pfeiffer,Anja Grahnert,Sunna Hauschildt

doi:10.3389/fimmu.2021.772595

Abstract

Macrophages (MΦ) are known to exhibit distinct responses to viral and bacterial infection, but how they react when exposed to the pathogens in succession is less well understood. Accordingly, we determined the effect of a rubella virus (RV)-induced infection followed by an LPS-induced challenge on cytokine production, signal transduction and metabolic pathways in human GM (M1-like)- and M (M2-like)-MΦ. We found that infection of both subsets with RV resulted in a low TNF-α and a high interferon (IFN, type I and type III) release whereby M-MΦ produced far more IFNs than GM-MΦ. Thus, TNF-α production in contrast to IFN production is not a dominant feature of RV infection in these cells. Upon addition of LPS to RV-infected MΦ compared to the addition of LPS to the uninfected cells the TNF-α response only slightly increased, whereas the IFN-response of both subtypes was greatly enhanced. The subset specific cytokine expression pattern remained unchanged under these assay conditions. The priming effect of RV was also observed when replacing RV by IFN-β one putative priming stimulus induced by RV. Small amounts of IFN-β were sufficient for phosphorylation of Stat1 and to induce IFN-production in response to LPS. Analysis of signal transduction pathways activated by successive exposure of MΦ to RV and LPS revealed an increased phosphorylation of NFκB (M-MΦ), but different to uninfected MΦ a reduced phosphorylation of ERK1/2 (both subtypes). Furthermore, metabolic pathways were affected; the LPS-induced increase in glycolysis was dampened in both subtypes after RV infection. In conclusion, we show that RV infection and exogenously added IFN-β can prime MΦ to produce high amounts of IFNs in response to LPS and that changes in glycolysis and signal transduction are associated with the priming effect. These findings will help to understand to what extent MΦ defense to viral infection is modulated by a following exposure to a bacterial infection.

Highlights

Macrophages (MF) are a vital part of the innate immune response
While M1-MF triggered by interferon (IFN)-g in combination with Tolllike receptor (TLR) agonist lipopolysaccharide (LPS) promote proinflammatory and tumoricidal properties, M2-MF generated in response to IL-4 and IL-13 show anti-inflammatory and protumoral properties and serve key roles in wound healing and tissue repair
Based on recent findings, showing that after rubella virus (RV)-infection neither the amount of extracellular virus particles nor the number of RV-positive cells varied between GM- and M-MF [11], we here examined the cellular morphology of both subsets after infection with RV by staining of F-actin

Summary

Introduction

Macrophages (MF) are a vital part of the innate immune response. They comprise different activation states that have been generally categorized into two broad but distinct subsets termed M1-MF (classically activated) and M2-MF (alternatively activated). While M1-MF triggered by interferon (IFN)-g in combination with Tolllike receptor (TLR) agonist lipopolysaccharide (LPS) promote proinflammatory and tumoricidal properties, M2-MF generated in response to IL-4 and IL-13 show anti-inflammatory and protumoral properties and serve key roles in wound healing and tissue repair. These classes are generally accepted to be at the opposite extremes of a spectrum of intermediate phenotypes [1]. As MF developed in the presence of CSFs do not exactly mirror those of the activated M1- and M2-MF we will refer to the two subsets used here as GM- and M-MF, respectively [2]

Methods

Results

Conclusion