Abstract
The MHC class I-mediated antigen presentation pathway plays a critical role in antiviral immunity. Here we show that the MHC class I pathway is targeted by SARS-CoV-2. Analysis of the gene expression profile from COVID-19 patients as well as SARS-CoV-2 infected epithelial cell lines reveals that the induction of the MHC class I pathway is inhibited by SARS-CoV-2 infection. We show that NLRC5, an MHC class I transactivator, is suppressed both transcriptionally and functionally by the SARS-CoV-2 ORF6 protein, providing a mechanistic link. SARS-CoV-2 ORF6 hampers type II interferon-mediated STAT1 signaling, resulting in diminished upregulation of NLRC5 and IRF1 gene expression. Moreover, SARS-CoV-2 ORF6 inhibits NLRC5 function via blocking karyopherin complex-dependent nuclear import of NLRC5. Collectively, our study uncovers an immune evasion mechanism of SARS-CoV-2 that targets the function of key MHC class I transcriptional regulators, STAT1-IRF1-NLRC5.
Highlights
The major histocompatibility complex (MHC) class I-mediated antigen presentation pathway plays a critical role in antiviral immunity
We showed that the induction of MHC class I gene expression is impaired by SARS-CoV-2 infection
Our data indicate that impaired upregulation of the MHC class I gene expression in the airway and intestinal epithelial cells during SARS-CoV-2 infection interferes with the CD8 T celldependent cellular immunity, causing a higher risk of exacerbation of viral loads and prolonged infection[4,5,6,50,51]
Summary
The MHC class I-mediated antigen presentation pathway plays a critical role in antiviral immunity. SARS-CoV-2 ORF6 hampers type II interferon-mediated STAT1 signaling, resulting in diminished upregulation of NLRC5 and IRF1 gene expression. The underlying mechanism by which SARS-CoV-2 inhibits host antiviral programs to eliminate virus-infected cells is poorly understood. Studies using Nlrc5-deficient mice demonstrated that NLRC5 plays a critical role in CD8 cytotoxic T cell activation and protection against infection of intracellular pathogens such as Listeria monocytogenes or influenza A virus[14,15]. Induction of MHC class I genes is inhibited in the airway epithelial cells of COVID-19 patients, as well as in the epithelial cell lines infected with SARSCoV-2 We found that both transcriptional upregulation and functional CITA activity of NLRC5 are suppressed by the ORF6 protein of SARS-CoV-2, which exerts its suppressive activity by inhibiting the interferon-mediated signaling as well as karyopherin complex-dependent nuclear import. Our discovery reveals an immune evasion mechanism by SARS-CoV-2 to escape the MHC class I pathway and may provide a potential therapeutic intervention for COVID-19
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
