THE ROLE OF KYNURENINE METABOLISM IN IMMUNE-MEDIATED NEURODEVELOPMENTAL PATHOLOGYAFTER CYTOMEGALOVIRUS INFECTION

Ongoing Projects, Projects

 

Call title: Research Projects / Swiss – Croatian research projects

Call code: IPCH-2023-10

Competent authority:  Croatian Science Foundation

Project title: The role of kynurenine metabolism in immune-mediated neurodevelopmental pathology after cytomegalovirus infection

Applicant name: University of Rijeka Faculty of Medicine

Coordinator: Prof. Stipan Jonjic, MD, PhD

Research Team, University of Rijeka Faculty of Medicine:

  • Prof. Astrid Krmpotic, MD, PhD
  • Prof. Ilija Brizić, PhD
  • Tina Ruzic, PhD
  • Marko Sustic, PhD
  • Jelena Materljan, PhD student

Project implementation period: 01.10.2024 – 30.09.2028

Total project value: 198.245,00

Brief description:

Congenital cytomegalovirus (CMV) infection is the most common intrauterine viral infection in the world. Approximately one-third of symptomatic infants, and to a lesser extent asymptomatic infants, develop long-term CNS manifestations. The molecular mechanisms driving CNS damage and subsequent neurologic deficits after CMV infection are ill-understood. Mouse CMV (MCMV) infection of newborn mice phenocopies many facets of CMV pathogenesis in the brain of congenitally infected infants. Our recent findings demonstrated that IFN-γ derived from NK/ILC1 cells mediated microglial activation and delayed cerebellar development in MCMV-infected newborn mice. Tryptophan catabolism along the kynurenine pathway generates quinolinic acid, which is used for de novo NAD synthesis. Kynurenine and its metabolites are also immune- and neuro-modulatory molecules that bind glutamatergic receptors, G-protein coupled receptors, and aryl hydrocarbon receptor (Ahr). Transcription of the first enzyme in the kynurenine pathway, Ido1, is mediated by IFN-γ signalling, demonstrating that kynurenine pathway activation is directly linked to inflammation. However, potential role of Kynurenine pathway in linking inflammation to neurodevelopmental pathology during CMV infection has not been explored. In this project, we are exploring the impact of NK cell-derived IFN-γ on kynurenine pathway induction in microglia from MCMV infected brain, as well as the role of kynurenine pathway activation in modulating early postnatal cerebellar development and in driving neurofunctional deficits.