An Epithelial-Immune Circuit Amplifies Inflammasome and Il-6 Responses to SARS-CoV-2

Authors

Katherine C Barnett
Yuying Xie
Takanori Asakura
Dingka Song
Kaixin Liang
Sharon A Taft-Benz
Haitao Guo
Shuangshuang Yang
Kenichi Okuda
Rodney C Gilmore
Jennifer F Loome
Thomas H Oguin Iii
Gregory D Sempowski
Scott H Randell
Mark T Heise
Yu Leo Lei
Richard C Boucher
Jenny P-Y Ting

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

Comments

Supplementary Materials

Data Availability Statement

PMID: 36563691