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A CRISPR/Cas9 genetically engineered organoid biobank reveals essential host factors for coronaviruses

Joep Beumer1, Maarten H Geurts1, Mart M Lamers2

  • 1Oncode Institute, Hubrecht Institute, Royal Netherlands Academy of Arts and Sciences and University Medical Center, Utrecht, Netherlands.

Nature Communications
|September 18, 2021
PubMed

Insights

This study identifies TMPRSS2 as a key target for pan-coronavirus therapies using intestinal organoids. These organoid models offer a more accurate approach to discovering effective antiviral treatments.

Area of Science:

  • Virology
  • Genetics
  • Human Disease Modeling

Background:

  • Genetic screens in transformed cell lines poorly mimic in vivo viral targets.
  • Intestinal organoids offer a more relevant, genetically engineerable model for human disease.
  • Identifying host genes critical for virus replication can accelerate therapeutic development.

Purpose of the Study:

  • To identify reliable host factors for anti-coronavirus therapeutic targeting.
  • To generate and utilize mutant clonal intestinal organoids (IOs) for coronavirus research.
  • To assess the role of specific host genes in SARS-CoV-2, SARS-CoV, and MERS-CoV replication.

Main Methods:

  • Generated mutant clonal intestinal organoids (IOs) for 19 host genes.
  • Verified ACE2 and DPP4 as entry receptors for SARS-CoV/SARS-CoV-2 and MERS-CoV.
  • Assessed the dependence of viral replication on specific proteases, including TMPRSS2 and Cathepsin B/L.

Main Results:

  • ACE2 and DPP4 confirmed as entry receptors for SARS-CoV/SARS-CoV-2 and MERS-CoV, respectively.
  • SARS-CoV-2 replication in IOs depends on cell surface protease TMPRSS2, not Cathepsin B/L.
  • TMPRSS2 is essential for SARS-CoV-2, B.1.1.7 variant, SARS-CoV, and MERS-CoV replication.

Conclusions:

  • Non-transformed human organoid models are crucial for relevant coronavirus research.
  • TMPRSS2 is a promising pan-coronavirus therapeutic target.
  • An organoid knockout biobank is valuable for studying current and emerging coronaviruses.

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