Highly pathogenic coronavirus N protein aggravates lung injury by MASP-2-mediated complement over-activation

TLDR

Excessive immune responses drive SARS‑CoV, MERS‑CoV, and SARS‑CoV‑2 pathogenesis and lethality, yet the underlying mechanism is unclear. The study shows that coronavirus N proteins bind MASP‑2, triggering lectin‑pathway complement over‑activation that worsens lung injury, and that blocking this interaction or inhibiting complement—e.g., with anti‑C5a antibody—significantly reduces injury, suggesting complement suppression as a common therapeutic strategy.

Abstract

Abstract An excessive immune response contributes to SARS-CoV, MERS-CoV and SARS-CoV-2 pathogenesis and lethality, but the mechanism remains unclear. In this study, the N proteins of SARS-CoV, MERS-CoV and SARS-CoV-2 were found to bind to MASP-2, the key serine protease in the lectin pathway of complement activation, resulting in aberrant complement activation and aggravated inflammatory lung injury. Either blocking the N protein:MASP-2 interaction or suppressing complement activation can significantly alleviate N protein-induced complement hyper-activation and lung injury in vitro and in vivo . Complement hyper-activation was also observed in COVID-19 patients, and a promising suppressive effect was observed when the deteriorating patients were treated with anti-C5a monoclonal antibody. Complement suppression may represent a common therapeutic approach for pneumonia induced by these highly pathogenic coronaviruses. One Sentence Summary The lectin pathway of complement activation is a promising target for the treatment of highly pathogenic coronavirus induced pneumonia.