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An epithelial-immune circuit amplifies inflammasome and IL-6 responses to SARS-CoV-2
Barnett, K. C., Xie, Y., Asakura, T., Song, D., Liang, K., Taft-Benz, S. A., Guo, H., Yang, S., Okuda, K., Gilmore, R. C., Loome, J. F., Oguin Iii, T. H., Sempowski, G. D., Randell, S. H., Heise, M. T., Lei, Y. L., Boucher, R. C., & Ting, J. P.-Y. (2023). An epithelial-immune circuit amplifies inflammasome and IL-6 responses to SARS-CoV-2. Cell Host and Microbe, 31(2), 243-259.e6. https://doi.org/10.1016/j.chom.2022.12.005
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.
