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

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

doi:10.1016/j.chom.2022.12.005

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

Cell Host Microbe. 2023 Feb 8;31(2):243-259.e6. doi: 10.1016/j.chom.2022.12.005. Epub 2022 Dec 9.

Authors

Katherine C Barnett¹, Yuying Xie², Takanori Asakura³, Dingka Song¹, Kaixin Liang⁴, Sharon A Taft-Benz⁵, Haitao Guo¹, Shuangshuang Yang¹, Kenichi Okuda³, Rodney C Gilmore³, Jennifer F Loome⁶, Thomas H Oguin Iii⁷, Gregory D Sempowski⁷, Scott H Randell⁸, Mark T Heise⁹, Yu Leo Lei¹⁰, Richard C Boucher³, Jenny P-Y Ting¹¹

Affiliations

¹ Department of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA; Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA; Department of Microbiology and Immunology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
² Department of Computational Mathematics, Science and Engineering, Michigan State University, East Lansing, MI 48824, USA; Department of Statistics and Probability, Michigan State University, East Lansing, MI 48824, USA.
³ Marsico Lung Institute, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
⁴ Department of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA; Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA; Department of Microbiology and Immunology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA; Oral and Craniofacial Biomedicine Program, Adams School of Dentistry, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
⁵ Department of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
⁶ Department of Microbiology and Immunology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
⁷ Duke Human Vaccine Institute, Durham, NC 27701, USA.
⁸ Department of Statistics and Probability, Michigan State University, East Lansing, MI 48824, USA.
⁹ Department of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA; Department of Microbiology and Immunology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
¹⁰ Department of Periodontics and Oral Medicine, Rogel Cancer Center, University of Michigan, Ann Arbor, MI 48104, USA; Department of Otolaryngology-Head and Neck Surgery, Rogel Cancer Center, University of Michigan, Ann Arbor, MI 48109, USA.
¹¹ Department of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA; Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA; Department of Microbiology and Immunology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA. Electronic address: jenny_ting@med.unc.edu.

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: AIM2; IL-1β; IL-6; NLRP1; NLRP3; SARS-CoV-2; STING; TLR2; inflammasome.

MeSH terms

COVID-19*
Cytokines / metabolism
Humans
Inflammasomes* / metabolism
Interleukin-1beta / metabolism
Interleukin-6
NLR Family, Pyrin Domain-Containing 3 Protein / genetics
NLR Family, Pyrin Domain-Containing 3 Protein / metabolism
SARS-CoV-2

Substances

Inflammasomes
NLR Family, Pyrin Domain-Containing 3 Protein
Interleukin-6
Cytokines
Interleukin-1beta

Abstract

MeSH terms

Substances

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