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

Ting Gao; Mingdong Hu; Xiaopeng Zhang; Hongzhen Li; Lin Zhu; Hainan Liu; Qincai Dong; Zhang Zhang; Zhongyi Wang; Yong Hu; Yangbo Fu; Yanwen Jin; Kaitong Li; Songtao Zhao; Yongjiu Xiao; Shuping Luo; Lufeng Li; Lingfang Zhao; Junli Liu; Huailong Zhao; Yue Liu; Weihong Yang; Jing Peng; Xiaoyu Chen; Ping Li; Yaoning Liu; Yonghong Xie; Jibo Song; Lu Zhang; Qingjun Ma; Xiuwu Bian; Wei Chen; Xuan Liu; Qing Mao; Cheng Cao

Severe acute respiratory syndrome (SARS), that was initially reported in Guangdong, China, in November 2002, is a highly contagious and deadly respiratory disease (1, 2). Severe acute respiratory syndrome coronavirus (SARS-CoV) was identified as the novel etiological agent of this disease. Nearly a decade after the SARS outbreak, a new zoonotic coronavirus, 5 Middle East respiratory syndrome (MERS) coronavirus (MERS-CoV), was identified as the etiological agent of MERS (3) . Recently, a new coronavirus, SARS-CoV-2 was first identified in Wuhan, China and spread rapidly to other provinces in china and all over the world. As of 19 March 2020, SARS-CoV-2 has infected more than 230000 people with a fatality rate of 4.2% (https://www.who.int/emergencies/diseases/novel-coronavirus-2019/situation-reports/). Infection 10 of the virus caused severe atypical pneumonia similar to SARS-CoV infection (4). Although the pathogenesis of these diseases are being intensively investigated, it is still not well understood why the viral infections lead to respiratory failure with a high fatality rate (5) . The SARS-CoV nucleocapsid (N) protein is a 46-kDa viral RNA-binding protein sharing only 20-30% homology with the N proteins of other known coronaviruses (6) , whereas N proteins of the highly 15 pathogenic coronaviruses are more similar, including SARS-CoV-2 (91%) and MERS-CoV (51%) by BLASTP (5, 7, 8) . The N protein is one of the most abundant viral structural proteins in patient sera during SARS-CoV infection (9). Potentially N protein plays a role in the virus pathogenesis as the pre-administration of N protein, but not other viral proteins, via recombinant vaccinia virus or Venezuelan equine encephalitis virus replicon particles resulted in severe 20 pneumonia in aged mice challenged with SARS-CoV (10, 11) .