Antibody-Dependent Heterotypic Syncytia Drive COVID-19 Inflammation and Disease Progression

Abstract Severe COVID-19 is characterized by profound immune dysregulation and excessive inflammation. Aberrant myeloid responses drive hyperinflammation, yet the precise mechanisms remain elusive. Here, we demonstrate that certain spike antibodies promote the formation of heterotypic syncytia between monocytes/macrophages and virus-infected pneumocytes, leading to excessive inflammatory cytokine release. This antibody-dependent syncytium formation requires FcγRI (CD64) and ADAM10, as well as the assembly of the six-helix bundle by the spike S2 subunit. Notably, these syncytia exhibit a stronger proinflammatory signature compared to virus-infected epithelial cells. In vivo , sub-neutralizing antibody concentrations amplified inflammation and exacerbated disease in SARS-CoV-2-infected mice without increasing viral burden. Furthermore, scRNA-seq of postmortem lung tissues from COVID-19 patients implicated the monocyte/macrophage-derived syncytia as a key cellular source of inflammatory cytokines. Together, these findings define a novel mechanism of antibody-dependent enhancement of inflammation that helps explain the hyperinflammatory responses in severe COVID-19 and suggest new therapeutic opportunities targeting this pathway.