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Updated: Jun 21, 2025
Infection of Primary Nasal Epithelial Cells Grown at an Air-Liquid Interface to Characterize Human Coronavirus-Host Interactions
Published on: September 22, 2023
Initiator cell death event induced by SARS-CoV-2 in the human airway epithelium
Kaixin Liang1,2,3,4,5, Katherine C Barnett1,2,3,4, Martin Hsu1,2,3,4
1Department of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
Abstract:
Virus-induced cell death is a key contributor to COVID-19 pathology. Cell death induced by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is well studied in myeloid cells but less in its primary host cell type, angiotensin-converting enzyme 2 (ACE2)-expressing human airway epithelia (HAE). SARS-CoV-2 induces apoptosis, necroptosis, and pyroptosis in HAE organotypic cultures. Single-cell and limiting-dilution analysis revealed that necroptosis is the primary cell death event in infected cells, whereas uninfected bystanders undergo apoptosis, and pyroptosis occurs later during infection. Mechanistically, necroptosis is induced by viral Z-RNA binding to Z-DNA-binding protein 1 (ZBP1) in HAE and lung tissues from patients with COVID-19. The Delta (B.1.617.2) variant, which causes more severe disease than Omicron (B1.1.529) in humans, is associated with orders of magnitude-greater Z-RNA/ZBP1 interactions, necroptosis, and disease severity in animal models. Thus, Delta induces robust ZBP1-mediated necroptosis and more disease severity.
Insights
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection triggers necroptosis in airway cells via Z-RNA/ZBP1 interactions. The Delta variant exacerbates this cell death pathway, leading to increased COVID-19 severity.
Area of Science:
- Virology
- Immunology
- Pathology
Background:
- Virus-induced cell death significantly contributes to COVID-19 pathology.
- Cell death mechanisms in primary host cells, human airway epithelia (HAE), infected by SARS-CoV-2 are less understood compared to myeloid cells.
- SARS-CoV-2 infection induces multiple cell death pathways including apoptosis, necroptosis, and pyroptosis in HAE.
Purpose of the Study:
- To investigate the specific cell death pathways induced by SARS-CoV-2 in human airway epithelia (HAE).
- To elucidate the molecular mechanisms driving SARS-CoV-2-induced cell death in HAE.
- To compare the impact of different SARS-CoV-2 variants on cell death and disease severity.
Main Methods:
- Utilized organotypic HAE cultures infected with SARS-CoV-2.
- Employed single-cell and limiting-dilution analyses to quantify cell death events.
- Investigated the role of viral Z-RNA and Z-DNA-binding protein 1 (ZBP1) interactions in necroptosis induction.
- Compared disease severity and ZBP1 activation between SARS-CoV-2 Delta and Omicron variants in animal models.
Main Results:
- Necroptosis was identified as the primary cell death pathway in SARS-CoV-2 infected HAE cells.
- Uninfected bystander cells predominantly underwent apoptosis, while pyroptosis occurred later in infection.
- Viral Z-RNA binding to ZBP1 was mechanistically linked to necroptosis induction in HAE and patient lung tissues.
- The SARS-CoV-2 Delta variant showed significantly higher Z-RNA/ZBP1 interactions and induced more severe necroptosis and disease compared to the Omicron variant.
Conclusions:
- SARS-CoV-2 infection triggers distinct cell death pathways in HAE, with necroptosis being dominant in infected cells.
- Z-RNA/ZBP1 interaction is a critical mechanism driving necroptosis in SARS-CoV-2 infected airway epithelia.
- The increased severity associated with the Delta variant is linked to its potent induction of ZBP1-mediated necroptosis.
