Naïve Human Macrophages Are Refractory to SARS-CoV-2 Infection and Exhibit a Modest Inflammatory Response Early in Infection.

Ziyun Zhang,Efstathios S Giotis,Rebecca Penn,Wendy S Barclay

doi:10.3390/v14020441

Ziyun Zhang, Efstathios S Giotis + Show 2 more

Open Access

https://doi.org/10.3390/v14020441

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Journal: Viruses	Publication Date: Feb 21, 2022
Citations: 11	License type: CC BY 4.0

Affiliation: Imperial College London, University of Essex

Abstract

Involvement of macrophages in the SARS-CoV-2-associated cytokine storm, the excessive secretion of inflammatory/anti-viral factors leading to the acute respiratory distress syndrome (ARDS) in COVID-19 patients, is unclear. In this study, we sought to characterize the interplay between the virus and primary human monocyte-derived macrophages (MDM). MDM were stimulated with recombinant IFN-α and/or infected with either live or UV-inactivated SARS-CoV-2 or with two reassortant influenza viruses containing external genes from the H1N1 PR8 strain and heterologous internal genes from a highly pathogenic avian H5N1 or a low pathogenic human seasonal H1N1 strain. Virus replication was monitored by qRT-PCR for the E viral gene for SARS-CoV-2 or M gene for influenza and TCID50 or plaque assay, and cytokine levels were assessed semiquantitatively with qRT-PCR and a proteome cytokine array. We report that MDM are not susceptible to SARS-CoV-2 whereas both influenza viruses replicated in MDM, albeit abortively. We observed a modest cytokine response in SARS-CoV-2 exposed MDM with notable absence of IFN-β induction, which was instead strongly induced by the influenza viruses. Pre-treatment of MDM with IFN-α enhanced proinflammatory cytokine expression upon exposure to virus. Together, the findings concur that the hyperinflammation observed in SARS-CoV-2 infection is not driven by macrophages.

Highlights

The ongoing COVID-19 pandemic has generated many urgent questions on the diverse clinical manifestations of the causative agent severe acute respiratory syndrome coronavirus2 (SARS-CoV-2)
This study provides further evidence that macrophages ogenesis and in particular in triggering the cytokine storm that mediates the severity of are refractory to SARS-CoV-2
We report that SARS-CoV-2 failed to trigger excessive proARDS in COVID-19 patients’ lungs

Summary

Introduction

The ongoing COVID-19 pandemic has generated many urgent questions on the diverse clinical manifestations of the causative agent severe acute respiratory syndrome coronavirus2 (SARS-CoV-2). One of the perplexing hallmarks of SARS-CoV-2 infection is the exacerbated inflammatory response in severe COVID-19 patients resulting in excessive release of pro-inflammatory cytokines known as “cytokine storm”, leading in turn to detrimental alveolar damage and fibrosis, progressive respiratory failure and multiple organ dysfunction [10]. The prototypical influenza virus-induced cytokine storm has been described to originate from several cell types such as tissue macrophages, mast, endothelial, and epithelial cells [15]. These cells upon virus stimulation release initially TNF-α and IL-1ß, which in turn stimulate the release of other cytokines mainly

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