The ORF8 Protein of SARS-CoV-2 Mediates Immune Evasion through Potently Downregulating MHC-I

Zhang, Yiwen; Zhang, Junsong; Chen, Yingshi; Luo, Baohong; Yuan, Yaochang; Huang, Feng; Yang, Tao; Yu, Fei; Liu, Jun; Liu, Bingfen; Song, Zheng; Chen, Jingliang; Pan, Ting; Zhang, Xu; Li, Yuzhuang; Li, Rong; Huang, Wenjing; Xiao, Fei; Zhang, Hui

SARS-CoV-2 infection have caused global pandemic and claimed over 5,000,000 tolls1–4. Although the genetic sequences of their etiologic viruses are of high homology, the clinical and pathological characteristics of COVID-19 significantly differ from SARS5,6. Especially, it seems that SARS-CoV-2 undergoes vast replication in vivo without being effectively monitored by anti-viral immunity7. Here, we show that the viral protein encoded from open reading frame 8 (ORF8) of SARS-CoV-2, which shares the least homology with SARS-CoV among all the viral proteins, can directly interact with MHC-I molecules and significantly down-regulates their surface expression on various cell types. In contrast, ORF8a and ORF8b of SARS-CoV do not exert this function. In the ORF8-expressing cells, MHC-I molecules are selectively target for lysosomal degradation by an autophagy-dependent mechanism. As a result, CTLs inefficiently eliminate the ORF8-expressing cells. Our results demonstrate that ORF8 protein disrupts antigen presentation and reduces the recognition and the elimination of virus-infected cells by CTLs8. Therefore, we suggest that the inhibition of ORF8 function could be a strategy to improve the special immune surveillance and accelerate the eradication of SARS-CoV-2 in vivo.