An epithelial-immune circuit amplifies inflammasome and IL-6 responses to SARS-CoV-2

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  • Barnett, Katherine C.
    • Affiliation: School of Medicine, Department of Genetics
  • Xie, Yuying
    • Other Affiliation: Michigan State University
  • Asakura, Takanori
    • Affiliation: School of Medicine, Marsico Lung Institute/UNC Cystic Fibrosis Center
  • Song, Dingka
    • Affiliation: School of Medicine, Department of Genetics
  • Liang, Kaixin
    • Affiliation: School of Medicine, Department of Genetics
  • Taft-Benz, Sharon A.
    • Affiliation: School of Medicine, Department of Genetics
  • Guo, Haitao
    • Affiliation: School of Medicine, Department of Genetics
  • Yang, Shuangshuang
    • Affiliation: School of Medicine, Department of Genetics
  • Okuda, Kenichi
    • Affiliation: School of Medicine, Marsico Lung Institute/UNC Cystic Fibrosis Center
  • Gilmore, Rodney C.
    • Affiliation: School of Medicine, Marsico Lung Institute/UNC Cystic Fibrosis Center
  • Loome, Jennifer F.
    • Affiliation: School of Medicine, Department of Microbiology and Immunology
  • Oguin III, Thomas H.
    • Other Affiliation: Duke Human Vaccine Institute
  • Sempowski, Gregory D.
    • Other Affiliation: Duke Human Vaccine Institute
  • Randell, Scott H.
    • Other Affiliation: Michigan State University
  • Heise, Mark T.
    • Affiliation: School of Medicine, Department of Genetics
  • Lei, Yu Leo
    • Other Affiliation: University of Michigan
  • Boucher, Richard C.
    • Affiliation: School of Medicine, Marsico Lung Institute/UNC Cystic Fibrosis Center
  • Ting, Jenny P.-Y.
    • Affiliation: School of Medicine, Department of Genetics
Abstract
  • Elevated levels of cytokines IL-1β and IL-6 are associated with severe COVID-19. Investigating the underlying mechanisms, we find that while primary human airway epithelia (HAE) have functional inflammasomes and support SARS-CoV-2 replication, they are not the source of IL-1β released upon infection. In leukocytes, the SARS-CoV-2 E protein upregulates inflammasome gene transcription via TLR2 to prime, but not activate, inflammasomes. SARS-CoV-2-infected HAE supply a second signal, which includes genomic and mitochondrial DNA, to stimulate leukocyte IL-1β release. Nuclease treatment, STING, and caspase-1 inhibition but not NLRP3 inhibition blocked leukocyte IL-1β release. After release, IL-1β stimulates IL-6 secretion from HAE. Therefore, infection alone does not increase IL-1β secretion by either cell type. Rather, bi-directional interactions between the SARS-CoV-2-infected epithelium and immune bystanders stimulates both IL-1β and IL-6, creating a pro-inflammatory cytokine circuit. Consistent with these observations, patient autopsy lungs show elevated myeloid inflammasome gene signatures in severe COVID-19., IL-1β and IL-6 are increased in severe COVID-19. Examining the underlying mechanisms, Barnett et al. show that SARS-CoV-2 E protein primes, and DNA from infected epithelial cells activates, inflammasome-dependent IL-1β secretion from leukocytes, which in turn stimulates IL-6 release from epithelial cells.
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  • Article
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  • In Copyright
Journal title
  • Cell Host & Microbe
Language
  • English
Version
  • Postprint
ISSN
  • 1931-3128
Publisher
  • Cell Press

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