Biology subjects

Naval, P.

Publications and source records attributed to Naval, P..

3 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

Self-driven Biological Discovery through Automated Hypothesis Generation and Experimental Validation

Automation is transforming scientific discovery by enabling systematic exploration of complex hypotheses. Large language models (LLMs) perform well across diverse tasks and promise to accelerate research, but often struggle to interact with logical structures. Here we present a framework integrating LLM-based agents with laboratory automation, guided by a logical scaffold incorporating symbolic relational learning, structured vocabularies, and experimental constraints. This integration reduces output incoherence and improves reliability in automated workflows. We couple this AI-driven approach to automated cell-culture and metabolomics platforms, enabling hypothesis validation and refinement, yielding a flexible system for scientific discovery. We validate the system in Saccharomyces cerevisiae, identifying novel interactions, including glutamate-induced synergistic growth inhibition in spermine-treated cells and aminoadipates partial rescue of formic-acid stress. All hypotheses, experiments, and data are captured in a graph database employing controlled vocabularies. Existing ontologies are extended, and a novel representation of scientific hypotheses is presented using description logics. This work enables a more reliable, machine-driven discovery process in systems biology.

systems biology↗

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↗