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First Author:   Martin-Sancho et al. 

Journal/preprint name: Biorxiv 

Paper DOI https://doi.org/10.1101/2020.09.29.319566.  

Tags:  Bioinformatics, Cell Biology, Immunology/Immunity, Molecular biology, Proteomics, Virology 

Summary  

Martin-Sancho et al. identify 65 interferon-stimulated genes (ISGs) that mediate host cell restriction of SARS-CoV-2 infection in a large-scale gain-of-function (overexpression) study. These ISGs include endosomal factors inhibiting viral entry and nucleic acid binding proteins supressing viral RNA synthesis. Furthermore, many are ER or Golgi resident proteins that inhibit viral protein translation, regulate lipid membrane composition and vesicle transport. Among the 65 ISGs, BST2 was identified, a known restriction factor that tethers newly synthesized viruses to the cell plasma membrane and impairs viral release. Here, the authors describe BST2 as a restriction factor for SARS-CoV-2 and found that it is counteracted by the viral accessory protein ORF7a.   

Research Highlights 

  1. Identification of antiviral restriction factors through a large-scale analysis of ISGs: a subset of 65 ISGs restricts SARS-CoV-2 viral replication. 

  1. ISGs controlling viral entry impact on endo-lysosomal function, probably impairing low-pH dependent entry. 

  1. ISGs inhibiting RNA replication detect viral RNA and prevent its active replication.  

  1. ER- and Golgi resident ISGs inhibit late stage replication. 

  1. BST2 inhibits SARS-CoV-2 release and it is counteracted by ORF7a, that is incorporated in the viral particle.  

Impact for COVID-19 research:  

  • This study makes an important contribution to our understanding of how cells control SARS-CoV-2 infection, and some results may be extrapolated to other viral infections. 

Methodologies: 

  • Study Typein vitro. 

Important cell lines/viral models used: SARS-CoV-2 USA-WA1/2020, isolated from an oropharyngeal swab from a patient with a respiratory illness who developed clinical disease (COVID-19) in January 2020 in Washington, USA, was obtained from BEI Resources (NR-52281) 

  • Key Techniques: lentiviral transduction, RNA-seq, CRISPR/Cas9, immunofluorescence 

Limitations: 

  • Assays are conducted in cell lines expressing ISGs by lentiviral transduction and their expression might differ compared to endogenous protein levels. Also, the levels of upregulation in their expression after SARS-CoV-2 infection as ISGs is not addressed. 

  • Some of the results are a bit vague since as it is a large-scale screen the authors don’t investigate all the 65 ISGs. 

  • Loss-of-function experiments of the 65 ISGs identified would be very interesting. 

  • It is conceivable that some restriction factors of SARS-CoV-2 are not ISGs.