FcγRIIa-mediated antibody-dependent uptake of SARS-CoV-2 enhances IL-6 expression of monocytes

This work aimed to investigate interactions between antibody-opsonized SARS-CoV-2 and monocytes enriched from human peripheral blood mononuclear cells (PBMC) to determine whether antibody dependent enhancement might contribute to the pathophysiology of COVID-19. Pre-incubation of SARS-CoV-2 with sera from hospitalized COVID-19 patients led to significantly increased virus uptake and viral replication in monocytes. Remarkably, SARS-CoV-2 pre-incubated with sera from patients with severe COVID-19 but not those with mild disease or post vaccination strongly increased IL-6 secretion by monocytes. Antibody dependent viral uptake was partially inhibited by monoclonal anti-FcγRIIa antibody whereas IL-6 secretion was completely abolished. FcγRIIa preferentially binds IgG2, and sera from patients with severe COVID-19 contained lower IgG2 levels as compared to mild COVID-19 cases whereas IgG1 levels were increased. These data suggests that FcγRIIa-mediated binding of antibody-opsonized SARS-CoV-2 critically impacts monocytic inflammatory cytokine release and COVID-19 pathophysiology.