Student and Faculty Publications
Publication Date
2-8-2023
Journal
Cell Host & Microbe
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.
Keywords
Humans, Inflammasomes, NLR Family, Pyrin Domain-Containing 3 Protein, Interleukin-6, SARS-CoV-2, COVID-19, Cytokines, Interleukin-1beta, inflammasome, SARS-CoV-2, IL-6, IL-1β, NLRP3, NLRP1, AIM2, STING, TLR2
Included in
Bioinformatics Commons, Biomedical Informatics Commons, COVID-19 Commons, Epidemiology Commons, Medical Sciences Commons, Oncology Commons
Comments
Supplementary Materials
Data Availability Statement
PMID: 36563691