Receptor-Focused Interventions Against Orthoflavivirus Neuroinvasion and Entry

REFINE confronts the escalating challenge of mosquito-borne orthoflavivirus infections, focusing on West Nile and Usutu viruses as emergent threats to European public health. The overall goal is to identify novel targets for therapeutics and to deliver a suite of validated models to assess efficacy and safety of novel compounds (antibodies, inhibitors, and vaccine candidate targets) for Phase I clinical trials. In the first of its six experimental objectives, REFINE characterizes genomic diversity of orthoflaviviruses to select representative clinically relevant strains. A unique strength of the proposal is the extensive suite of model assays (objective 2) designed to unravel the complex dynamics of virus-host interactions at each step of the infection pathway. These assays form a basis for receptor and pathway characterisation (objective 3). Objective 4 aims to asses both efficacy and safety of novel intervention strategies targeting these receptors and pathways, based on nanobodies, peptides and monoclonal antibodies. Objective 5 studies the key infection steps and putative receptors in humans, utilizing previously collected patient samples to ensure real-world applicability of developed strategies. Ultimately, objective 6 is to integrate knowledge gained to establish a robust and sustainable platform capable of rapid validation of new therapeutic interventions. The overall mission of REFINE is to significantly enhance Europe's preparedness and response abilities against the expected wave of mosquito-borne viral diseases. The team members share a lifelong commitment to advancing our understanding of the molecular mechanisms underlying various aspects of host-pathogen interactions at the human-animal-environment interface. Together, the REFINE team embodies a comprehensive approach to address one of the priority health security concerns of our time by delivering effective and safe countermeasures against emergent viral pathogens in Europe.