Remnant virus proteins sustain vascular inflammation post coronavirus infection in mice and humans

SARS-CoV-2 coronavirus infections are associated with long-term vascular dysfunction, yet the drivers remain unclear. We hypothesized that remnant Betacoronavirus antigens remain in circulation and organs, act as danger-associated molecular patterns (DAMPs), and sustain inflammation. We used human patient samples, mouse virus infection models, and in vitro techniques to define the role of remnant virus proteins after coronavirus infection. In patients, both coronavirus-derived S- and N-proteins persisted months after infection even with S- and N-specific antibodies present in circulation. A high-N-protein subgroup exhibited increased vWF and vWF/ADAMTS13 ratio and elevated IL-6/IFN-γ plasma levels indicative of endothelial activation and low-grade inflammation. Extracellular vesicles bearing VCAM-1/PDGFR were increased 4-6 months after infection. In animal models, virus infection was resolved within ten days after pulmonary infection in the lung. Remnant virus proteins accumulated in organs after full virus resolution and were linked to localized inflammation and endothelial cell activation 17 days post infection. Virus tropism was not required for virus protein presence in organs. Prednisolone treatment after viral clearance reduced remnant protein-associated vascular inflammation. In vitro, N- and S-proteins directly induced a proinflammatory NF-κB response in liver spheroids and endothelial cells, with N-protein signaling being TLR4-dependent. Together, these data identify remnant coronavirus proteins as active inflammatory DAMPs that promote post-infectious endothelial activation and might define an antigen-linked vascular inflammatory phenotype after SARS-CoV-2 infection.