Afucosylated IgG Promote Thrombosis in Mouse Injected with SARS-CoV-2 Spike Expressing Megakaryocytes

TL;DR

This study shows that afucosylated IgG antibodies, produced in response to SARS-CoV-2 in megakaryocytes, cause dangerous blood clots and severe outcomes in mice.

Contribution

The novel finding is that SARS-CoV-2 infection of megakaryocytes leads to afucosylated IgGs that promote thrombosis and severe disease in mice.

Findings

Afucosylated IgGs targeting SARS-CoV-2 spike protein cause pulmonary thrombosis and lung injury in mice.

Virus-infected megakaryocytes trigger platelet activation and increased thrombus formation in mice.

Inhibitors targeting FcγRIIa, serotonin, or complement anaphylatoxins prevent thrombosis and bleeding issues in infected mice.

Abstract

Despite the prevalence of fucosylated IgG in plasma, specific IgGs with low core fucosylation sporadically emerge in response to virus infections and blood cell alloantigens. This low fucosylation of IgG is implicated in the pathogenesis of SARS-CoV-2 and dengue infections. In COVID-19, the presence of IgGs with low core fucosylation (afucosylated IgGs) targeting spike protein predicts disease progression to a severe form and actively mediates this progression. This study reveals that SARS-CoV-2 infection of megakaryocytes promotes the generation of pathogenic afucosylated anti-spike IgGs, leading to outcomes, such as pulmonary vascular thrombosis, acute lung injury, and mortality in FcγRIIa-transgenic mice. Platelets from mice injected with virus-infected human megakaryocytes express significant activation biomarkers, indicating a direct link between the immune response and platelet activation. Mice injected with virus-infected human megakaryocytes demonstrate an elevated rate of thrombus formation induced by FeCl3 (4%) and a reduction in bleeding time, emphasizing the intricate interplay of viral infection, immune response, and hemostatic complications. Treatment with inhibitors targeting FcγRIIa, serotonin, or complement anaphylatoxins of mice injected with spike-expressing MKs successfully prevents observed platelet activation, thrombus formation, and bleeding abnormalities, offering potential therapeutic strategies for managing severe outcomes associated with afucosylated IgGs in COVID-19 and related disorders.

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