Surface Proteins of SARS-CoV-2 Drive Airway Epithelial Cells to Induce IFN-Dependent Inflammation

SARS-CoV-2, the virus that has caused the COVID-19 pandemic, robustly activates the host immune system in critically ill patients. Understanding how the virus engages the immune system will facilitate the development of needed therapeutic strategies. In this study, we demonstrate both in vitro and i...

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Bibliographic Details
Published in:The Journal of immunology (1950) 2021-06, Vol.206 (12), p.3000-3009
Main Authors: Anand, Gautam, Perry, Alexandra M, Cummings, Celeste L, St Raymond, Emma, Clemens, Regina A, Steed, Ashley L
Format: Article
Language:English
Subjects:
Animals
Cell Line, Tumor
Coronavirus Envelope Proteins - immunology
Epithelial Cells - immunology
Epithelial Cells - virology
Female
Humans
Inflammation - immunology
Innate Immunity and Inflammation
Interferon Type I - immunology
Male
Mice
Spike Glycoprotein, Coronavirus - immunology
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Summary:SARS-CoV-2, the virus that has caused the COVID-19 pandemic, robustly activates the host immune system in critically ill patients. Understanding how the virus engages the immune system will facilitate the development of needed therapeutic strategies. In this study, we demonstrate both in vitro and in vivo that the SARS-CoV-2 surface proteins spike (S) and envelope (E) activate the key immune signaling IFN pathway in both human and mouse immune and epithelial cells independent of viral infection and replication. These proteins induce reactive oxidative species generation and increases in human- and murine-specific, IFN-responsive cytokines and chemokines, similar to their upregulation in critically ill COVID-19 patients. Induction of IFN signaling is dependent on canonical but discrepant inflammatory signaling mediators, as the activation induced by S is dependent on IRF3, TBK1, and MyD88, whereas that of E is largely MyD88 independent. Furthermore, these viral surface proteins, specifically E, induced peribronchial inflammation and pulmonary vasculitis in a mouse model. Finally, we show that the organized inflammatory infiltrates are dependent on type I IFN signaling, specifically in lung epithelial cells. These findings underscore the role of SARS-CoV-2 surface proteins, particularly the understudied E protein, in driving cell specific inflammation and their potential for therapeutic intervention.
ISSN:0022-1767
1550-6606
1550-6606
DOI:10.4049/jimmunol.2001407