Activation of classical complement pathway through SARS-CoV2 Nucleocapsid attachment to the surface of uninfected cells

The complement system plays an important role in the immune defense against pathogens, either by direct elimination of the pathogen or by attacking the infected cells to limit viral spread. However, an unregulated increase in the activity of the complement may cause harmful, exaggerated tissue damage. Instances of such adverse complement hyper-activation were reported in acute COVID-19 cases, however, the underlying mechanisms yet remain vague.

We have revealed the ability of SARS-CoV-2 nucleocapsid protein (NP) to attract anti-NP antibodies and the complement system via binding to healthy epithelial cells. Because soluble heparin analogs compete with NP binding to the plasma membrane of healthy host cells, we conclude that NP and the NP-antibody complexes are tethered through a putative heparin-sulfate proteoglycan receptor (HSPG). We demonstrate that such tethering may cause the activation of the classical complement pathway, leading to the formation of membrane attack complexes. The presence of both NP from SARS-CoV-2 and anti-NP antibodies from patients’ sera was necessary and sufficient for complement deposition on a variety of uninfected cells. We further show that soluble heparin analogs are protective by preventing NP binding to uninfected cells, suggesting future therapeutic possibilities. We propose a mechanism where NP-driven accrual of antibodies may damage healthy cells and tissues in COVID-19.