Specialized interferon action in COVID-19

Matthew D. Galbraith(University of Colorado Anschutz Medical Campus), Kohl T. Kinning(University of Colorado Anschutz Medical Campus), Kelly D. Sullivan(University of Colorado Anschutz Medical Campus), Paula Araya(University of Colorado Anschutz Medical Campus), Keith P. Smith(University of Colorado Anschutz Medical Campus), Ross E. Granrath(University of Colorado Anschutz Medical Campus), Jessica R. Shaw(University of Colorado Anschutz Medical Campus), Ryan M. Baxter(University of Colorado Anschutz Medical Campus), Kimberly R. Jordan(University of Colorado Anschutz Medical Campus), Seth Russell(University of Colorado Anschutz Medical Campus), Monika Dzieciątkowska(University of Colorado Anschutz Medical Campus), Julie A. Reisz(University of Colorado Anschutz Medical Campus), Fabia Gamboni(University of Colorado Anschutz Medical Campus), Francesca Cendali(University of Colorado Anschutz Medical Campus), Tusharkanti Ghosh(Colorado School of Public Health), Kejun Guo(University of Colorado Anschutz Medical Campus), Cara C. Wilson(University of Colorado Anschutz Medical Campus), Mario L. Santiago(University of Colorado Anschutz Medical Campus), Andrew A. Monte(University of Colorado Anschutz Medical Campus), Tellen D. Bennett(University of Colorado Anschutz Medical Campus), Kirk C. Hansen(University of Colorado Anschutz Medical Campus), Elena W.Y. Hsieh(University of Colorado Anschutz Medical Campus), Angelo D’Alessandro(University of Colorado Anschutz Medical Campus), Joaquı́n M. Espinosa(University of Colorado Anschutz Medical Campus)
Proceedings of the National Academy of Sciences
February 25, 2022
10.1073/pnas.2116730119
Cited by 93Open Access
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Abstract

The impacts of interferon (IFN) signaling on COVID-19 pathology are multiple, with both protective and harmful effects being documented. We report here a multiomics investigation of systemic IFN signaling in hospitalized COVID-19 patients, defining the multiomics biosignatures associated with varying levels of 12 different type I, II, and III IFNs. The antiviral transcriptional response in circulating immune cells is strongly associated with a specific subset of IFNs, most prominently IFNA2 and IFNG. In contrast, proteomics signatures indicative of endothelial damage and platelet activation associate with high levels of IFNB1 and IFNA6. Seroconversion and time since hospitalization associate with a significant decrease in a specific subset of IFNs. Additionally, differential IFN subtype production is linked to distinct constellations of circulating myeloid and lymphoid immune cell types. Each IFN has a unique metabolic signature, with IFNG being the most associated with activation of the kynurenine pathway. IFNs also show differential relationships with clinical markers of poor prognosis and disease severity. For example, whereas IFNG has the strongest association with C-reactive protein and other immune markers of poor prognosis, IFNB1 associates with increased neutrophil to lymphocyte ratio, a marker of late severe disease. Altogether, these results reveal specialized IFN action in COVID-19, with potential diagnostic and therapeutic implications.

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