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Genome-wide CRISPR Screens Reveal Host Factors Critical for SARS-CoV-2 Infection

Jin Wei1, Mia Madel Alfajaro1, Peter C DeWeirdt2

  • 1Department of Laboratory Medicine, Yale School of Medicine, New Haven, CT 06520, USA; Department of Immunobiology, Yale School of Medicine, New Haven, CT 06520, USA.

Cell
|November 4, 2020
PubMed

Insights

Researchers identified key host genes for SARS-CoV-2 infection using CRISPR screens. These findings reveal new therapeutic targets and pathways critical for coronaviruses, including HMGB1 and the SWI/SNF complex.

Area of Science:

  • Virology
  • Genetics
  • Immunology

Background:

  • Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causes COVID-19, necessitating identification of host factors for therapeutic development.
  • Understanding host-pathogen interactions is crucial for combating viral infections and pathogenesis.

Purpose of the Study:

  • To identify host genes essential for SARS-CoV-2 infection using genome-wide CRISPR screens.
  • To discover novel therapeutic targets and understand coronavirus disease 2019 (COVID-19) pathogenesis.
  • To explore SARS lineage-specific and pan-coronavirus host factors.

Main Methods:

  • Genome-wide CRISPR screens were performed in Vero-E6 cells using SARS-CoV-2, MERS-CoV, and engineered viruses.
  • Functional validation of identified host factors, including HMGB1, was conducted.
  • Small-molecule antagonists were tested for their efficacy against SARS-CoV-2 infection.

Main Results:

  • Known host factors like ACE2 and Cathepsin L were identified.
  • Novel pro-viral genes, including HMGB1 and the SWI/SNF complex, were discovered.
  • HMGB1 was shown to regulate ACE2 expression and be critical for entry of multiple coronaviruses.
  • Small-molecule inhibitors targeting identified genes reduced SARS-CoV-2 infection in primate and human cells.

Conclusions:

  • The study identifies essential host genes for SARS-CoV-2 and other coronaviruses, offering potential therapeutic targets.
  • HMGB1 and the SWI/SNF complex represent key SARS lineage-specific and pan-coronavirus factors, respectively.
  • Inhibiting identified host factors demonstrates a viable therapeutic strategy against SARS-CoV-2.
Keywords:
COVID-19CRISPR screenEpigeneticsHMGB1MERS-CoVMiddle East Respiratory SyndromeSARS-CoV-2SWI/SNF complexSevere Acute Respiratory Syndrome

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