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

## TL;DR

The SARS-CoV-2 nucleocapsid protein binds to complement regulatory proteins, potentially modulating immune responses during infection.

## Contribution

Discovery that nucleocapsid protein, not spike protein, interacts with multiple complement regulatory proteins and forms complexes with the virion.

## Key findings

- Nucleocapsid protein binds to complement regulatory proteins like C1-inhibitor, C4-binding protein, factor H, and vitronectin.
- Nucleocapsid protein binds to recombinant spike protein and SARS-CoV-2 virions.
- A virion-nucleocapsid-complement regulatory protein complex can be formed.

## Abstract

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.

The online version contains supplementary material available at 10.1038/s41598-026-37866-4.