Highly pathogenic coronavirus N protein aggravates inflammation by MASP-2-mediated lectin complement pathway overactivation.

Signal transduction and targeted therapy 2022 Sep 14

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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. © 2022. The Author(s).

Citation

Ting Gao, Lin Zhu, 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, Qingjun Ma, Xiuwu Bian, Wei Chen, Xuan Liu, Qing Mao, Cheng Cao. Highly pathogenic coronavirus N protein aggravates inflammation by MASP-2-mediated lectin complement pathway overactivation. Signal transduction and targeted therapy. 2022 Sep 14;7(1):318