SARS-CoV-2 nucleocapsid protein forms complexes with soluble complement regulatory proteins that can bind to the virion

The SARS-CoV-2 nucleocapsid protein has been detected in the plasma of COVID-19 patients, and its levels in the plasma correlate with the severity of the disease. It is also an immunomodulatory protein, triggering the release of proinflammatory cytokines. Complement system dysregulation in COVID-19 patients led us to hypothesize that either nucleocapsid protein or spike protein might interact with the proteins of the complement system, mainly complement regulatory proteins (CRPs). We demonstrate that the nucleocapsid protein, but not the spike protein, binds to multiple CRPs, including C1-inhibitor, C4-binding protein, factor H, and vitronectin. The nucleocapsid protein binds to both the recombinant spike protein and the SARS-CoV-2 virions. We further demonstrated that the virion-nucleocapsid-CRP complex could be formed. Recruitment of the CRPs on SARS-CoV-2 virion mediated by nucleocapsid protein deserves further investigation to reveal complement modulation strategies of SARS-CoV-2.