Specialized interferon action in COVID-19

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.

Beyond GWAS—Could Genetic Differentiation within the Allograft Rejection Pathway Shape Natural Immunity to COVID-19?

“…CD80 is also a ligand for cytotoxic T-lymphocyte antigen 4 (CTLA-4, also known as CD152), which remains constitutively expressed on most of the T cells, for example, on Tregs, in which CTLA-4 expression increases upon activation [ 25 , 27 , 29 ]. CD28 competes with CTLA-4 for binding to CD80 and CD86 [ 26 , 29 , 31 ]. Interestingly, CD80 and CD86 proteins may act as receptors for some adenoviruses [ 22 ].…”

“…One SNP on chromosome 12 pointed out interferon IFN-gamma, which is a cytokine produced mostly by activated T cells and NK cells and that can induce MHC expression, which makes it an important factor in transplantation. IFN plays a dual role in COVID-19 infections, on one side aggravating the symptoms, and on the other alleviating the disease course, depending on the disease stage and types of the interferon involved and on the personal predispositions [ 31 ]. This occurred in some patients shown to be associated with higher mortality [ 31 ], whereas in others poor IFN responses were associated with a more severe disease course [ 32 , 33 ].…”

“…IFN plays a dual role in COVID-19 infections, on one side aggravating the symptoms, and on the other alleviating the disease course, depending on the disease stage and types of the interferon involved and on the personal predispositions [ 31 ]. This occurred in some patients shown to be associated with higher mortality [ 31 ], whereas in others poor IFN responses were associated with a more severe disease course [ 32 , 33 ]. In immunosuppressed patients, IFN has a beneficial effect and was applied as an adjuvant treatment [ 34 ].…”

Cross-talk between red blood cells and plasma influences blood flow and omics phenotypes in severe COVID-19

“…Particularly interesting due to its association with higher mortality risk is kynurenine, which decreases upon suspension of healthy control RBCs in COVID-19 plasma. Kynurenine levels are associated with hypoxia markers and interferon signaling (IFNG) (27, 41). The restoration of proteins and metabolites levels is acute and immediate and occurs at the expense of RBC shapes.…”

An open-label randomized, controlled trial of the effect of lopinavir and ritonavir, lopinavir and ritonavir plus interferon-β-1a, and hydroxychloroquine in hospitalized patients with COVID-19: final results

“…Here, results suggest a detrimental effect of IFN-ß-1a treatment: participants assigned to the lopinavir/ritonavir plus IFN-β-1a arm had significantly longer time to hospital discharge (alone or combined in composite endpoints) and higher 90-day mortality than untreated controls, whereas these outcomes were not significantly different between participants assigned to lopinavir/ritonavir alone or to the control arm. Overall, this suggests that IFN-ß-1a administration is not always appropriate, and that screening of IFN signalling pathways may be required to identify patients who would most benefit from IFN treatment [ 4 ].…”