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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 USA 10032.
Abstract:
Although the impact of SARS-CoV-2 in the lung has been extensively studied, the molecular regulators and targets of the host-cell programs hijacked by the virus in distinct human airway epithelial cell populations remain poorly understood. This is in part ascribed to the use of nonprimary cell systems, overreliance on single-cell gene expression profiling that does not ultimately reflect protein activity, and bias toward the downstream effects rather than their mechanistic determinants. Here we address these issues by network-based analysis of single cell transcriptomic profiles of pathophysiologically relevant human adult basal, ciliated and secretory cells to identify master regulator (MR) protein modules controlling their SARS-CoV-2-mediated reprogramming. This uncovered chromatin remodeling, endosomal sorting, ubiquitin pathways, as well as proviral factors identified by CRISPR analyses as components of the host response collectively or selectively activated in these cells. Large-scale perturbation assays, using a clinically relevant drug library, identified 11 drugs able to invert the entire MR signature activated by SARS-CoV-2 in these cell types. Leveraging MR analysis and perturbational profiles of human primary cells represents a novel mechanism-based approach and resource that can be directly generalized to interrogate signatures of other airway conditions for drug prioritization.
Insights
This study identifies key protein modules controlling host cell reprogramming by SARS-CoV-2 in distinct airway cells. It also found 11 drugs that can reverse the virus
Area of Science:
- Molecular biology
- Virology
- Cell biology
Background:
- SARS-CoV-2 lung impact is known, but host cell reprogramming mechanisms in specific airway cells are unclear.
- Previous studies relied on non-primary cells and gene expression, not protein activity or mechanistic drivers.
Purpose of the Study:
- Identify master regulator protein modules controlling SARS-CoV-2-mediated host cell reprogramming in distinct human airway epithelial cells.
- Investigate the host response to SARS-CoV-2 at the protein activity level.
- Discover potential therapeutic interventions targeting these host-virus interactions.
Main Methods:
- Network-based analysis of single-cell transcriptomic profiles from human adult basal, ciliated, and secretory cells.
- CRISPR-based screening to identify proviral factors.
- Large-scale drug perturbation assays using a clinically relevant library.
Main Results:
- Identified chromatin remodeling, endosomal sorting, ubiquitin pathways, and proviral factors as key components of the host response.
- These pathways were collectively or selectively activated in different cell types.
- Discovered 11 drugs capable of reversing the master regulator signature induced by SARS-CoV-2.
Conclusions:
- This study provides a novel mechanism-based approach to understand SARS-CoV-2 host-cell interactions.
- The findings offer a valuable resource for drug prioritization in airway diseases.
- The identified master regulator modules and drug candidates can guide future therapeutic strategies.
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