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

  • Signal Transduct Target Ther. 2022 Sep 14;7(1):318. doi: 10.1038/s41392-022-01133-5.
Ting Gao  #  1 ,  Lin Zhu  #  1  2 ,  Hainan Liu  #  1 ,  Xiaopeng Zhang  #  1 ,  Tingting Wang  2 ,  Yangbo Fu  1 ,  Hongzhen Li  3 ,  Qincai Dong  1 ,  Yong Hu  1 ,  Zhang Zhang  1 ,  Jing Jin  2 ,  Zijing Liu  1 ,  Weihong Yang  2 ,  Yaoning Liu  2 ,  Yanwen Jin  1 ,  Kaitong Li  3 ,  Yongjiu Xiao  4 ,  Junli Liu  1 ,  Huailong Zhao  1 ,  Yue Liu  1 ,  Ping Li  1 ,  Jibo Song  5 ,  Lu Zhang  4 ,  Yuwei Gao  6 ,  Sisi Kang  7 ,  Shoudeng Chen  7 ,  Qingjun Ma  1 ,  Xiuwu Bian  8 ,  Wei Chen  1 ,  Xuan Liu  9 ,  Qing Mao  10 ,  Cheng Cao  11
Affiliations
  • 1. Institute of Biotechnology, Academy of Military Medical Sciences, Beijing, 100850, China.
  • 2. Institute of Physical Science and Information Technology, Anhui University, Hefei, Anhui, 230601, China.
  • 3. Beijing Key Laboratory of Bio-products Safety Assessment, Joinn Laboratories (China) Co. Ltd, Beijing, 100176, China.
  • 4. The 940th Hospital of the People's Liberation Army, Lanzhou, Gansu, 730050, China.
  • 5. Department of Gastroenterology, the 960th Hospital of the People's Liberation Army, Zibo, Shandong, 255300, China.
  • 6. Academy of Military Medical Science of PLA, 666 Liuyingxi St, Changchun, 130122, China.
  • 7. Molecular Imaging Center, Guangdong Provincial Key Laboratory of Biomedical Imaging, The Fifth Affiliated Hospital, Sun Yat-sen University, Zhuhai, 519000, China.
  • 8. First Affiliated Hospital, Army Medical University, Chongqing, 400038, China.
  • 9. Institute of Biotechnology, Academy of Military Medical Sciences, Beijing, 100850, China. [email protected].
  • 10. First Affiliated Hospital, Army Medical University, Chongqing, 400038, China. [email protected].
  • 11. Institute of Biotechnology, Academy of Military Medical Sciences, Beijing, 100850, China. [email protected].
  • # Contributed equally.
PMID: 36100602 DOI: 10.1038/s41392-022-01133-5
Abstract

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.

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