Systemic Multi-Omics Analysis Reveals Interferon Response Heterogeneity and Links Lipid Metabolism to Immune Alterations in Severe COVID-19
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The immune response to SARS-CoV-2 is highly heterogeneous, with interferon (IFN)-stimulated gene (ISG) expression playing a dual role in antiviral defense and immune dysregulation. To understand the broader implications of IFN-driven immune responses, we analyzed whole-blood transcriptomics, plasma proteomics, metabolomics, and immune cell profiling in COVID-19 patients and uninfected controls. Patients were stratified into low (LIS), moderate (MIS), and high (HIS) ISG expression clusters, independent of acute disease severity. HIS patients exhibited elevated inflammatory mediators (S100A8/A9, Neopterin) and altered metabolic profiles, yet immune activation patterns varied. Plasma from HIS cases induced differential activation in healthy neutrophils and monocytes, with severe HIS plasma showing reduced activation, suggesting the presence of suppressive soluble factors. Metabolomic analysis revealed widespread lipid metabolism dysregulation, including reductions in phospholipids, sphingolipids, and plasmalogens, which correlated with impaired immune activation. Branched-chain lipids and tryptophan metabolism products correlated strongly with monocyte and neutrophil activation, linking metabolic shifts to immune regulation. Despite IFN autoantibody detection in a subset of patients, no direct association with ISG expression was observed. These findings suggest that IFN-driven immune-metabolic dysregulation may persist beyond acute infection, contributing to post-viral inflammation, immune dysfunction, and susceptibility to long COVID or autoimmune-like sequelae. The interplay between IFN signaling, mitochondrial function, and lipid metabolism highlights novel therapeutic targets for immune modulation in viral infections and chronic inflammatory conditions. Understanding these immune signatures may inform precision medicine approaches in post-viral syndromes and immunometabolic disorders.
