Biology subjects

Ambikan, A.

Publications and source records attributed to Ambikan, A..

7 recordsLinked to original sources

bioRxiv2026

IFN-driven lipid synthesis shutdown in CD4⁺ T cells during acute SIV infection and persistent OXPHOS with ART initiation

Cellular metabolism regulates HIV/SIV replication and reservoir establishment, yet how infection and antiretroviral therapy initiation (ARTi) shape CD4 T cell metabolism in vivo remains poorly defined. Using the SIVmac239 macaque model, we integrated single-cell metabolic profiling (MIST), transcriptomics, lipidomics and genome-scale metabolic modeling to characterize their metabolic remodeling. At peak viremia, CD4 T cells exhibited shutdown of de novo fatty-acid (FA) synthesis, reflected by acetyl-CoA carboxylase-1 (ACC1) downregulation, inhibition of lipid-anabolic reactions, and depletion of membrane phospholipids. This state was driven by type I interferon (IFN-I) responses, and IFN-I suppressed ACC1 in vitro. Pharmacologic inhibition of FA synthesis enhanced T cell activation and exerted direct antiviral effects. Following ARTi, most metabolic pathways in CD4+ T cells were suppressed, whereas oxidative phosphorylation (OXPHOS) remained elevated and its levels in effector memory cells correlated with cell-associated-vDNA These findings identify IFN-driven FA synthesis suppression as a novel effector mechanism during acute viral infection, and persistent OXPHOS in effector CD4 T cells as a metabolic correlate of early reservoir establishment.

immunology↗

bioRxiv2025

Integrated Systems Vaccinology Reveals Distinct Metabolic Responses to SARS-CoV-2 Infection and DNA-Based Vaccines in Ferrets

Understanding systemic effects of vaccination and infection is central to defining correlates of protection against SARS-CoV-2. We used untargeted serum metabolomics to profile the immunometabolic landscape of ferrets after SARS-CoV-2 infection and DNA-/protein-based vaccination. Ferrets were vaccinated with either a multigenic DNA vaccine encoding SARS-CoV-2 RBD, M, and N (OC2), an N-only DNA vaccine (OC12), a recombinant spike protein with QS-21 adjuvant (S+QS21), or a hepatitis B/D control construct (Hep-B/D), and subsequently challenged with SARS-CoV-2. Serum was analyzed longitudinally at baseline, post-vaccination, and post-challenge. SARS-CoV-2 infection induced broad metabolic reprogramming, involving TCA cycle, glutathione metabolism, and nucleotide turnover, reflecting inflammation and cellular activation. OC2 vaccination induced strong metabolic shifts in amino acid and mitochondrial pathways despite low pre-challenge anti-S antibodies. Post-challenge, these shifts extended to redox and nucleotide pathways, correlating with robust anti-S and very strong anti-N antibody responses and complete viral clearance in BAL, but with marked airway pathology, consistent with T cell-mediated clearance of infected cells. S+QS21 and OC12 induced distinct, immunogen-specific signatures with partial protection, while Hep-B/D showed minimal systemic engagement. Metabolite-antibody correlations revealed vaccine-specific associations, highlighting lipid and amino acid pathways as potential immunogenicity biomarkers. Overlap and heatmap analyses showed that metabolic trajectories reflect both the magnitude and quality of immune training. These findings underscore the value of systems vaccinology in resolving mechanistic differences in vaccine responses and support metabolic profiling as a tool for evaluating immune efficacy in preclinical vaccine studies.

immunology↗

bioRxiv2025

Systemic Multi-Omics Analysis Reveals Interferon Response Heterogeneity and Links Lipid Metabolism to Immune Alterations in Severe COVID-19

The immune response to SARS-CoV-2 infection is highly heterogeneous, and interferon (IFN)-stimulated genes (ISGs) play a central but context-dependent role in antiviral defense and immune dysregulation. To investigate how ISG heterogeneity relates to immune and metabolic states, we performed an integrated analysis of whole-blood transcriptomics, plasma proteomics, metabolomics, and immune activation markers in hospitalized COVID-19 patients and COVID-negative healthy controls and covalescent individuals. Patients segregated into low (LIS), moderate (MIS), and high (HIS) ISG expression endotypes, largely independent of clinical severity. While high ISG expression was associated with systemic inflammation and innate immune activation, severe disease within the HIS endotype was characterized by marked metabolic perturbations, including depletion of tricarboxylic acid cycle intermediates and multiple lipid classes involved in membrane integrity and immunometabolic signaling. Plasma-transfer assays demonstrated that plasma from severe HIS patients impaired neutrophil and monocyte activation ex vivo, indicating functional attenuation of innate immune responses despite elevated ISG expression. These metabolic alterations correlated with reduced immune activation, supporting the existence of an interferon-associated immune-metabolic axis that constrains immune functionality in severe disease. Although type I IFN neutralization was detected in a subset of patients with IFN antigen reactivity, these samples did not account for ISG heterogeneity or disease severity. Together, these findings show that high ISG expression defines a transcriptional endotype permissive for inflammation but insufficient for effective immune function, highlighting the importance of immune-metabolic context in shaping COVID-19 disease outcomes.

immunology↗

bioRxiv2025

Immune-Coagulation Dynamics in Severe COVID-19: Insights from Autoantibody Profiling and Transcriptomics

Severe COVID-19 is characterized by immune dysregulation and coagulation abnormalities, leading to complications such as thromboembolism and multi-organ failure. This study explores the relationship between autoantibodies targeting coagulation-related factors and gene expression in severe COVID-19. Whole-blood transcriptomics revealed upregulation of coagulation-related genes, including VWF and Factor V, in severe patients compared to mild cases and healthy controls. Autoantibody profiling against seven coagulation-related proteins (ADAMTS13, Factor V, Protein S, SERPINC1, Apo-H, PROC1, and Prothrombin) showed reactivities below established positivity thresholds, but mean-fluorescent intensities were elevated numerically in severe (Protein S) and convalescent (SERPINC1) patients. Correlation analysis revealed trends of negative associations between autoantibody reactivities and coagulation gene expression in severe cases, suggesting a potential role for autoantibodies in modulating immune-coagulation interactions warranting further orthogonal validation. Furthermore, age-dependent increases in subthreshold autoantibody reactivities were observed in severe cases, highlighting the potential impact of immunosenescence on disease severity. These findings do not exclude the possibility that subthreshold autoantibodies may contribute indirectly to immune-coagulation dynamics in severe COVID-19 through mechanisms beyond direct transcriptional regulation. This study highlights the complexity of immune-coagulation interactions and provides foundation for future research into their biological and clinical relevance, particularly for identifying biomarkers and therapeutic targets in thromboinflammatory diseases.

immunology↗

bioRxiv2025

Disrupted α-ketoglutarate homeostasis trains monocyte-derived macrophages towards M2-like phenotype in long-term treated HIV-infection

Cells of the myeloid lineage, particularly monocytes and macrophages, are central to HIV pathogenesis, contributing to viral persistence and immune regulation during suppressive therapy. We hypothesized that metabolic reprogramming and altered chemokine signaling in people with HIV (PWH) on long-term ART impair monocyte trafficking and macrophage polarization. Using single-cell RNA sequencing, immunophenotyping, and metabolic modeling, we identified altered receptor expression and disrupted metabolic flux linked to reduced monocyte migration. Plasma secretome profiling revealed a nonclassical inflammatory microenvironment, while integrative multi-omics and single-cell proteomics of monocyte-derived macrophages (MDMs) demonstrated metabolic rewiring of the Glycolysis-TCA Anaplerosis Axis, orchestrated in part by elevated -ketoglutarate (AKG). Differentiation with PWH serum or AKG, skewed MDMs toward an M2-like phenotype, and enhanced HIV susceptibility. Together, these systems-level and mechanistic analyses reveal that metabolic training drives macrophage dysfunction in well-treated PWH, sustaining low-grade inflammation and highlighting potential therapeutic targets.

systems biology↗

bioRxiv2024

TISSUE-SPECIFIC METABOLOMIC REPROGRAMMING DETERMINES THE DISEASE PATHOPHYSIOLOGY OF SARS-COV-2 VARIANTS IN HAMSTER MODEL

Despite significant effort, a clear understanding of host tissue-specific responses and their implications for immunopathogenicity against the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variant infection has remained poorly defined. To shed light on the interaction between organs and specific SARS-CoV-2 variants, we sought to characterize the complex relationship among acute multisystem manifestations, dysbiosis of the gut microbiota, and the resulting implications for SARS-CoV-2 variant-specific immunopathogenesis in the Golden Syrian Hamster (GSH) model using multi-omics approaches. Our investigation revealed increased viremia in diverse tissues of delta-infected GSH compared to the omicron variant. Multi-omics analyses uncovered distinctive metabolic responses between the delta and omicron variants, with the former demonstrating dysregulation in synaptic transmission proteins associated with neurocognitive disorders. Additionally, delta-infected GSH exhibited an altered fecal microbiota composition, marked by increased inflammation-associated taxa and reduced commensal bacteria compared to the omicron variant. These findings underscore the SARS-CoV-2-mediated tissue insult, characterized by modified host metabolites, neurological protein dysregulation, and gut dysbiosis, highlighting the compromised gut-lung-brain axis during acute infection. TeaserIn hamsters at acute infection, SARS-CoV-2 variant-specific metabolic responses and gut dysbiosis dysregulate synaptic transmission proteins.

systems biology↗

bioRxiv2020

Metabolic reprogramming and host-immune response against Crimean-Congo Hemorrhagic Fever Viruses

The pathogenesis and host-viral interactions of the Crimean-Congo hemorrhagic fever orthonairovirus (CCHFV) are convoluted and not well evaluated. Application of the multi-omics system biology approaches including biological network analysis in elucidating the complex host-viral response, allow for interrogating the viral pathogenesis. The present study aimed to fingerprint the system-level alterations during acute CCHFV-infection and the cellular immune responses during productive CCHFV-replication in vitro. We used system-wide network-based system biology analysis of peripheral blood mononuclear cells (PBMCs) from a longitudinal cohort of CCHF patients during the acute phase of infection and after one year of recovery (convalescent phase) and untargeted quantitative proteomics analysis of the most permissive CCHFV-infected Huh7 and SW13 cells. In the RNAseq analysis of the PBMCs, comparing the acute and convalescent-phase, we observed system-level hosts metabolic reprogramming towards central carbon and energy metabolism (CCEM) with distinct upregulation of oxidative phosphorylation (OXPHOS) during CCHFV-infection. Upon application of network-based system biology methods, negative coordination of the biological signaling systems like FOXO/Notch axis and Akt/mTOR/HIF-1 signaling with metabolic pathways during CCHFV-infection were observed. The temporal quantitative proteomics in Huh7 showed a dynamic change in the CCEM over time and was in agreement with the cross-sectional proteomics in SW13 cells. By blocking the two key CCEM pathways, glycolysis and glutaminolysis, viral replication was inhibited in vitro. Activation of key interferon stimulating genes during infection suggested the role of type I and II interferon-mediated antiviral mechanisms both at system-level and during progressive replication. Significance StatementA combination of multi-modal systems-wide host-immune response and in vitro temporal analysis identified molecular re-arrangement in CCEM and fingerprinting the interferon-mediated antiviral mechanism during CCHFV-infection. Using the newly gained insights, we then modulated the key pathways of CCEM by drugs and inhibited the productive CCHFV-replication in in vitro infection models. Our study thus provides a comprehensive, system-level picture of the regulation of cellular and metabolic pathways during productive CCHFV-infection for the first time that aids in identifying novel therapeutic targets and treatment strategies.

microbiology↗