Preprint Systemic Multi-Omics … Reveals Interferon Response Heterogeneity & Links Lipid Metabolism to Immune Alterations in Severe COVID, 2025, Lira-Junior+

SNT Gatchaman · Mar 18, 2025

Systemic Multi-Omics Analysis Reveals Interferon Response Heterogeneity and Links Lipid Metabolism to Immune Alterations in Severe COVID-19
Ronaldo Lira-Junior; Anoop Ambikan; Axel Cederholm; Ssefanit Rezene; Flora Mikaeloff; Sara Svensson Akusjarvi; Ahmet Yalcinkaya; Xi Chen; Maike Sperk; Maribel Aranda Guillen; Hampus Nordqvist; Carl Johan Treutiger; Nils Landegren; Ujjwal Neogi; Soham Gupta

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.

Link | PDF (Preprint: BioRxiv) [Open Access]

SNT Gatchaman · Mar 18, 2025

I'd encourage people to read this preprint. For a summary I ran this through the recently released Gemma3:12b LLM.

AI Summary said:

Okay, this is a very detailed and complex study. Here's a breakdown of the key findings, organized for clarity, along with a summary of the limitations and future directions. I'm aiming to capture the essence of the research in a digestible format. I'll also highlight the most significant implications.

I. Core Findings & Key Themes

ISG Expression Isn't Destiny: The study challenges the simple assumption that high interferon-stimulated gene (ISG) expression automatically equates to severe COVID-19. While ISG expression is present, it's not the sole determinant of disease severity.

Multilayered Immune Response: The study reveals a complex interplay between inflammation, immune activation, and metabolic reprogramming in COVID-19.

Metabolic Dysfunction as a Driver of Severity: A significant finding is that metabolic dysfunction, particularly in lipid and amino acid metabolism, is strongly linked to disease severity in patients with high ISG expression. This isn't just a consequence of inflammation; it appears to be a driver of severity.

Specific Metabolic Alterations:

TCA Cycle Suppression: Reduced levels of citrate and aconitate, indicating mitochondrial dysfunction and impaired energy metabolism.

Lipid Depletion: Significant reductions in plasmalogens, phosphatidylcholines, and sphingolipids – crucial for membrane stability and immune signaling.

Impact on Immune Cell Function: These metabolic alterations correlate with reduced immune cell activation (neutrophils and monocytes).

Citrate/Aconitate Connection: The study highlights the potential importance of citrate and aconitate, which are involved in anti-inflammatory and IFN-regulatory functions, and may also inhibit SARS-CoV-2 replication. Their depletion could be contributing to the severity.

Unique Metabolic Profiles in Clusters: The HIS and MIS clusters (defined by ISG expression) show distinct metabolic profiles, suggesting different underlying mechanisms.

Viral Hijacking of Metabolism: The study reinforces the concept that viruses, including SARS-CoV-2, can hijack cellular metabolic pathways for their own replication, potentially leading to metabolic depletion in infected cells.

Immune Cell Refractoriness: The study suggests that immune cells in severe cases may be "refractory" – less responsive – due to prior overstimulation or suppressive factors in circulation.

II. Detailed Breakdown of Findings by Category

Immunology:

High ISG expression is present, but not the sole determinant of severity.

Immune cells in severe cases may be less responsive due to prior overstimulation or suppressive factors.

Metabolomics:

Significant alterations in amino acid and lipid metabolism.

TCA cycle suppression (citrate, aconitate depletion).

Reduced levels of plasmalogens, phosphatidylcholines, and sphingolipids.

Viral-Host Interaction:

Viruses hijack cellular metabolic pathways for replication.

Lower lipid levels are associated with disease severity.

III. Limitations

Plasma vs. Intracellular Metabolism: The study focused on plasma metabolites. Intracellular metabolic changes in immune cells weren't assessed.

Correlation vs. Causation: Associations were observed, but causal relationships weren't established.

Limited Cohort Size: The study had a relatively small cohort, requiring validation in larger, multi-center studies.

IV. Future Directions & Implications

Single-Cell Metabolomics: Investigate intracellular metabolic changes in individual immune cells.

Functional Assays: Use functional assays to determine if metabolic interventions can modulate immune responses.

Longitudinal Studies: Conduct larger, longitudinal studies to validate findings and track metabolic changes over time.

Therapeutic Potential:

Metabolic Replenishment: Explore strategies to replenish TCA cycle intermediates.

Lipid Supplementation: Investigate the potential benefits of lipid supplementation.

Immuno-Metabolic Therapies: Develop therapies that target both immune responses and metabolic pathways.

Broader Applications: The findings may have implications for understanding and treating other viral infections, autoimmune diseases, and chronic inflammatory conditions.

V. The "Big Picture" Significance

This study moves beyond a simple "inflammation = bad" narrative in COVID-19. It highlights the critical, often overlooked, role of metabolism in shaping the immune response and influencing disease severity. It suggests that restoring metabolic homeostasis could be a novel therapeutic strategy, not just for COVID-19, but for a range of immune-related disorders. The study's emphasis on the interplay between viral hijacking of cellular processes and the host's metabolic response is a significant contribution to our understanding of viral pathogenesis.
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Preprint Systemic Multi-Omics … Reveals Interferon Response Heterogeneity & Links Lipid Metabolism to Immune Alterations in Severe COVID, 2025, Lira-Junior+

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Preprint Systemic Multi-Omics … Reveals Interferon Response Heterogeneity & Links Lipid Metabolism to Immune Alterations in Severe COVID, 2025, Lira-Junior+

SNT Gatchaman Senior Member (Voting Rights) Staff Member

SNT Gatchaman Senior Member (Voting Rights) Staff Member

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