1. An epithelial-immune circuit amplifies inflammasome and IL-6 responses to SARS-CoV-2.
- Author
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Barnett, Katherine C., Xie, Yuying, Asakura, Takanori, Song, Dingka, Liang, Kaixin, Taft-Benz, Sharon A., Guo, Haitao, Yang, Shuangshuang, Okuda, Kenichi, Gilmore, Rodney C., Loome, Jennifer F., Oguin III, Thomas H., Sempowski, Gregory D., Randell, Scott H., Heise, Mark T., Lei, Yu Leo, Boucher, Richard C., and Ting, Jenny P.-Y.
- 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. [Display omitted] • SARS-CoV-2-infected epithelial cells stimulate IL-1β secretion in co-cultured PBMCs • SARS-CoV-2 E protein primes and DNA DAMPs activate inflammasomes in leukocytes • IL-1β stimulates IL-6 secretion from epithelial and immune cells • Intensified inflammasome priming is observed in BALF from severe COVID-19 patients 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. [ABSTRACT FROM AUTHOR]
- Published
- 2023
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