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Proc Natl Acad Sci U S A ; 118(23)2021 06 08.
Article in English | MEDLINE | ID: covidwho-1238060

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 Ι (MHC-Ι) 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-Ι molecules and mediates their down-regulation. In ORF8-expressing cells, MHC-Ι 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.


Subject(s)
Antigen Presentation , COVID-19/immunology , Down-Regulation/immunology , Histocompatibility Antigens Class I/immunology , Immune Evasion , SARS-CoV-2/immunology , Viral Proteins/immunology , Animals , Autophagy/genetics , Autophagy/immunology , COVID-19/genetics , Chlorocebus aethiops , HEK293 Cells , Histocompatibility Antigens Class I/genetics , Humans , Lysosomes/genetics , Lysosomes/immunology , Lysosomes/virology , Mice , Mice, Transgenic , SARS-CoV-2/genetics , Vero Cells , Viral Proteins/genetics
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