Project leader: Doc. Marko Šestan

Duration of the project: 15.10.2026. – 14.10.2029.

Project code: IP-2026-4887
Funding: Croatian Science Foundation (HRZZ)

Goals: Infection makes us feel sick, but the biology behind that familiar sensation is far more intricate than we tend to assume. The metabolic shifts triggered by infection—often dismissed as harmful side effects—are actually a tightly coordinated, evolutionarily conserved defense program. Once immune cells sense a pathogen, they broadcast signals that deliberately reset systemic homeostasis, reshaping how metabolically active organs produce, release, and use nutrients. In essence, the feeling of being sick is the body’s adaptive metabolic reprogramming in action. These changes carry profound clinical consequences. When this sickness metabolism becomes dysregulated, patients can develop hypoglycemia, hypertriglyceridemia, muscle wasting, and organ dysfunction. Conversely, if the metabolic response is insufficient, the host may struggle to control pathogens. Deciphering how the immune system rewires whole‑body metabolism is therefore crucial for predicting disease trajectories, identifying metabolic biomarkers, and designing host‑directed therapies. Despite extensive work on infection‑driven glucose and lipid remodeling, the influence of viral infection on amino acid (AA) metabolism remains surprisingly underexplored. This gap matters: AA lie at the heart of host–pathogen competition. Viruses rely on host AA pools for protein synthesis; immune cells need them for clonal expansion, cytokine production, and effector function; tissues depend on them for repair. AA availability may thus represent a critical bottleneck in antiviral immunity — yet the functional relevance and multiorgan coordination of infection‑induced AA remodeling remain largely unknown. Therefore, this project will map how unconventional, multi‑organ immune–metabolic circuits regulate AA metabolism during viral infection and test whether targeted activation of these circuits can suppress viral replication. Using cutting‑edge immunological and metabolic technologies across mouse infection models, in vitro viral assays, and ex vivo organ co‑culture systems, we aim to uncover a new dimension of the immune–metabolomic interactome and lay the foundation for metabolic interventions that improve outcomes across diverse viral diseases.

Immune triggered changes in amino acid metabolism fuel a potent antiviral response