ABSTRACT
Despite more than 90% of total plasma fucosylated IgG, specific IgGs with low core fucosylation are found sporadically in response to enveloped virus infections and to alloantigens on blood cells. IgG responses with low core fucosylation are directly pathogenic in SARS-CoV-2 and dengue infections. In COVID-19, formation of IgG with low core fucosylation (afucosylated IgG) against spike protein (S) predicts and directly mediates disease progression to severe form. Low fucosylation of IgG causes increased antibody-dependent cellular toxicity mediated by intense Fc{gamma}R-mediated stimulation of platelets, monocytes, macrophages, and natural killer cells. The mechanism of afucosylated IgG formation has remained elusive thus far in COVID-19, dengue infection, and other disorders. This study demonstrates that infection of megakaryocytes by SARS-CoV-2 drives the formation of pathogenic anti-S afucosylated IgGs, causing pulmonary vascular thrombosis, acute lung injury, and death in Fc{gamma}-expressing mice.