Proc Natl Acad Sci U S A . The ORF8 protein of SARS-CoV-2 mediates immune evasion through down-regulating MHC-?

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Proc Natl Acad Sci U S A


. 2021 Jun 8;118(23):e2024202118.
doi: 10.1073/pnas.2024202118.
The ORF8 protein of SARS-CoV-2 mediates immune evasion through down-regulating MHC-?


Yiwen Zhang ¹ , Yingshi Chen ¹ , Yuzhuang Li ¹ , Feng Huang ² , Baohong Luo ¹ , Yaochang Yuan ¹ , Baijin Xia ¹ , Xiancai Ma ¹ , Tao Yang ¹ , Fei Yu ¹ , Jun Liu ¹ , Bingfeng Liu ¹ , Zheng Song ¹ , Jingliang Chen ¹ , Shumei Yan ¹ , Liyang Wu ¹ , Ting Pan ¹ , Xu Zhang ¹ , Rong Li ¹ , Wenjing Huang ³ , Xin He ¹ , Fei Xiao ⁴ , Junsong Zhang ⁵ , Hui Zhang ⁶



Affiliations

• PMID: 34021074
• DOI: 10.1073/pnas.2024202118

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Abstract

COVID-19, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has become a global pandemic and has claimed over 2 million lives worldwide. Although the genetic sequences of SARS-CoV and SARS-CoV-2 have high homology, the clinical and pathological characteristics of COVID-19 differ significantly from those of SARS. How and whether SARS-CoV-2 evades (cellular) immune surveillance requires further elucidation. In this study, we show that SARS-CoV-2 infection leads to major histocompability complex class ? (MHC-?) down-regulation both in vitro and in vivo. The viral protein encoded by open reading frame 8 (ORF8) of SARS-CoV-2, which shares the least homology with SARS-CoV among all viral proteins, directly interacts with MHC-? molecules and mediates their down-regulation. In ORF8-expressing cells, MHC-? molecules are selectively targeted for lysosomal degradation via autophagy. Thus, SARS-CoV-2-infected cells are much less sensitive to lysis by cytotoxic T lymphocytes. Because ORF8 protein impairs the antigen presentation system, inhibition of ORF8 could be a strategy to improve immune surveillance.

Keywords: MHC-?; ORF8; SARS-CoV-2; immune evasion.