2. Academic Validation
  3. Initiator cell death event induced by SARS-CoV-2 in the human airway epithelium

Initiator cell death event induced by SARS-CoV-2 in the human airway epithelium

  • Sci Immunol. 2024 Jul 12;9(97):eadn0178. doi: 10.1126/sciimmunol.adn0178.
Kaixin Liang 1 2 3 4 5,  Katherine C Barnett 1 2 3 4,  Martin Hsu 1 2 3 4,  Wei-Chun Chou 1 2 3 4,  Sachendra S Bais 6,  Kristina Riebe 7,  Yuying Xie 8 9,  Tuong Thien Nguyen 10,  Thomas H Oguin 3rd 7,  Kevin M Vannella 11 12,  Stephen M Hewitt 13,  Daniel S Chertow 11 12,  Maria Blasi 7 14,  Gregory D Sempowski 7,  Amelia Karlsson 7,  Beverly H Koller 1 2,  Deborah J Lenschow 6 15 16,  Scott H Randell 10,  Jenny P-Y Ting 1 2 3 4
Affiliations

Affiliations

  • 1 Department of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
  • 2 Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
  • 3 Department of Microbiology and Immunology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
  • 4 Center for Translational Immunology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
  • 5 Oral and Craniofacial Biomedicine Program, Adams School of Dentistry, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
  • 6 Department of Medicine, Washington University School of Medicine, Saint Louis, MO 63130, USA.
  • 7 Duke Human Vaccine Institute, Durham, NC 27701, USA.
  • 8 Department of Computational Mathematics, Science and Engineering, Michigan State University, East Lansing, MI 48824, USA.
  • 9 Department of Statistics and Probability, Michigan State University, East Lansing, MI 48824, USA.
  • 10 Marsico Lung Institute, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
  • 11 Emerging Pathogens Section, Critical Care Medicine Department, Clinical Center, National Institutes of Health, Bethesda, MD 20892, USA.
  • 12 Laboratory of Virology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Hamilton, MT 59840, USA.
  • 13 Laboratory of Pathology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA.
  • 14 Department of Medicine, Duke University School of Medicine, Durham, NC 27701, USA.
  • 15 Department of Pathology and Immunology, Washington University School of Medicine, Saint Louis, MO 63110, USA.
  • 16 Department of Molecular Microbiology, Washington University School of Medicine, Saint Louis, MO 63110, USA.
PMID: 38996010 DOI: 10.1126/sciimmunol.adn0178
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.

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