Volume 7 Issue 10, Oct 2022:
Article
Highly pathogenic coronavirus N protein aggravates inflammation by MASP-2-mediated lectin complement pathway overactivation
Ting Gao,Lin Zhu
ORCID: orcid.org/0000-0001-5772-9482,Hainan Liu,Xiaopeng Zhang,Tingting Wang,Yangbo Fu,Hongzhen Li,Qincai Dong,Yong Hu,Zhang Zhang,Jing Jin,Zijing Liu,Weihong Yang,Yaoning Liu,Yanwen Jin,Kaitong Li,Yongjiu Xiao,Junli Liu,Huailong Zhao,Yue Liu,Ping Li,Jibo Song,Lu Zhang,Yuwei Gao,Sisi Kang,Shoudeng Chen
ORCID: orcid.org/0000-0002-7634-2141,Qingjun Ma,Xiuwu Bian
ORCID: orcid.org/0000-0003-4383-0197,Wei Chen
ORCID: orcid.org/0000-0001-5805-2469,Xuan Liu
ORCID: orcid.org/0000-0001-6369-9259,Qing Mao &…Cheng Cao
ORCID: orcid.org/0000-0001-7981-6114
Excessive inflammatory responses contribute to the pathogenesis and lethality of highly pathogenic human coronaviruses, but the underlying mechanism remains unclear. In this study, the N proteins of highly pathogenic human coronaviruses, including severe acute respiratory syndrome coronavirus (SARS-CoV), middle east respiratory syndrome coronavirus (MERS-CoV) and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), were found to bind MASP-2, a key serine protease in the lectin pathway of complement activation, resulting in excessive complement activation by potentiating MBL-dependent MASP-2 activation, and the deposition of MASP-2, C4b, activated C3 and C5b-9. Aggravated inflammatory lung injury was observed in mice infected with adenovirus expressing the N protein. Complement hyperactivation was also observed in SARS-CoV-2-infected patients. Either blocking the N protein:MASP-2 interaction, MASP-2 depletion or suppressing complement activation can significantly alleviate N protein-induced complement hyperactivation and lung injury in vitro and in vivo. Altogether, these data suggested that complement suppression may represent a novel therapeutic approach for pneumonia induced by these highly pathogenic coronaviruses.
