Single-cell susceptibility to viral infection is driven by variable cell states
Sam Reffsin1, Jesse Miller2, Kasirajan Ayyanathan2
1Department of Bioengineering, School of Engineering and Applied Sciences, University of Pennsylvania, Philadelphia, PA, USA.
Cell
|November 15, 2025
Summary
Cell susceptibility to viral infection, including SARS-CoV-2, depends on intrinsic cellular states and host factors. Identifying these states helps understand viral entry and control mechanisms in vivo.
Area of Science:
- Virology
- Cell Biology
- Immunology
Background:
- Viral infection efficiency relies on host factors, but cellular susceptibility varies.
- Understanding cell-specific vulnerabilities is key to identifying novel therapeutic targets.
Purpose of the Study:
- To identify host factors and cellular states that determine susceptibility to SARS-CoV-2 infection.
- To investigate the role of these factors in viral entry and cellular infectability.
Main Methods:
- Single-cell clone tracing to retrospectively identify highly susceptible cells.
- Depletion experiments to determine the function of identified host factors.
- Analysis of patient lung samples to assess in vivo factor expression.
Main Results:
- Identified host factors involved in viral entry and regulation of cellular infectability.
- Discovered heterogeneous expression of these factors in patient lungs, particularly in inflammatory conditions.
- Characterized a distinct cell state susceptible to influenza A virus.
Conclusions:
- Intrinsic cellular state variability is a primary determinant of viral susceptibility.
- Profiling susceptible cell subsets reveals crucial host factors for viral life cycles.
- Findings have implications for understanding viral pathogenesis and developing targeted interventions.
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