Biology subjects

Rezene, S.

Publications and source records attributed to Rezene, S..

4 recordsLinked to original sources

bioRxiv2026

ISG15-USP18 signaling restrains viperin-dependent metabolic antiviral restriction

Type I interferon (IFN-I) responses are tightly regulated to balance antiviral defense with cellular homeostasis. In humans, interferon-stimulated gene 15 (ISG15) functions as a critical negative regulator of IFN-I signaling by stabilizing the IFN negative regulator USP18, yet the functional consequences of ISG15 deficiency remain elusive. Here, we show that the loss of ISG15 exaggerates the JAK-STAT activation and, downstream, amplifies multiple ISGs including the nucleotide-modifying enzyme RSAD2 (viperin). Our quantitative proteomics, genetic reconstitution, and signaling analyses establish that defective USP18 stabilization skews the IFN response towards viperin expression. This amplified ISG network promotes viperin-catalyzed accumulation of the antiviral nucleotide analog ddhCTP, resulting in enhanced inhibition of viral RNA synthesis and the replication of Crimean-Congo hemorrhagic fever virus and SARS-CoV-2. Together, these findings demonstrate an ISG15-USP18-viperin axis that can be targeted to boost the metabolic antiviral restriction.

microbiology↗

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↗