FcγRs mediated antibody-dependent enhancement of SARS-CoV-2 infection in human monocyte derived macrophages

Abstract

Macrophages play a central role in innate immunity but can facilitate viral dissemination through antibody-dependent mechanisms. Although considered non permissive to SARS-CoV-2, anti-Spike antibodies may mediate virus-cell interactions via Fc gamma receptors, enabling antibody-dependent enhancement (ADE) of infection. Whether anti-Spike antibodies can mediate FcγRs dependent SARS-CoV-2 infection in macrophages remains to be clarified. We explored the capacity of SARS-CoV-2 Spike directed antibodies to mediate ADE in human monocyte derived macrophages (hMDMs). SARS-CoV-2 entry and replication were assessed using Spike pseudotyped lentiviral vectors and SARS-CoV-2 expressing GFP or luciferase. ADE was assessed using three human IgG1 anti-Spike antibodies: DH1047 and COVA1-16, neutralizing class 1 antibodies targeting the receptor binding domain, and DH1052, a non-neutralizing targeting the N-terminal domain as well as sera from five severe COVID-19 patients. An FcγRII expressing cell line was used to confirm FcγR dependent infection and to screen a panel of patient sera. Viral replication was quantified by luciferase activity, GFP fluorescence, immunostaining and infectivity assays. Lentiviral particles were internalized by hMDMs but failed to establish infection. SARS-CoV-2 failed to replicate in hMDMs unless preincubated with mAb DH1047, which mediated FcγR dependent infection in hMDMs and FcγRII expressing cells. Sera from patients with COVID-19 did not promote ADE, instead, dose dependently inhibited DH1047 mediated infection. SARS-CoV-2 replication can occur via FcγR in the presence of specific mAb and defined antibody to virus ratios. Polyclonal antibody responses suppress this mechanism, providing an explanation for the lack of convincing clinical evidence of ADE of infection in COVID-19 patients.