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Identification and targeting of regulators of SARS-CoV-2-host interactions in the airway epithelium

Brooke Dirvin1,2, Heeju Noh3,4,5, Lorenzo Tomassoni3,4,6

  • 1Columbia Center for Human Development, Columbia University Irving Medical Center, New York, NY 10032, USA.

Science Advances
|May 16, 2025
PubMed

Insights

This study identifies key proteins controlling SARS-CoV-2 reprogramming in human airway cells. It also reveals 11 drugs that may reverse the virus

Area of Science:

  • Molecular biology
  • Virology
  • Cell biology

Background:

  • The impact of SARS-CoV-2 on lung tissue is well-documented, but the molecular mechanisms by which the virus manipulates host cells in different human airway epithelial cell types are not fully understood.
  • Existing research often relies on transcriptomic profiling and non-primary cell models, limiting insights into specific cellular responses.

Purpose of the Study:

  • To identify master regulator (MR) proteins that control SARS-CoV-2-induced cellular reprogramming in distinct human airway epithelial cell populations.
  • To explore potential therapeutic interventions by identifying drugs that can counteract the viral host response.

Main Methods:

  • Network-based analysis of single-cell transcriptomic profiles from human ciliated, secretory, and basal cells.
  • CRISPR assays to identify proviral factors.
  • Large-scale drug perturbation screens on primary human airway cells.

Main Results:

  • Identified master regulator proteins involved in chromatin remodeling, endosomal sorting, and ubiquitin pathways as key components of the SARS-CoV-2 host response.
  • Discovered 11 candidate drugs capable of reversing the master regulator signature induced by SARS-CoV-2.
  • Highlighted the role of proviral factors identified through CRISPR assays.

Conclusions:

  • Master regulator analysis combined with perturbational profiles of primary human cells offers an innovative strategy for studying pathogen-host interactions.
  • This approach facilitates drug prioritization for various airway conditions, including those affected by SARS-CoV-2.

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