Exploring innovative model systems of virus replication to unravel virus tropism and pathogenesis.

Viral infections are responsible for great morbidity and mortality around the world, particularly due to lower respiratory and diarrheal diseases. In addition, emerging and re-emerging viruses pose a serious threat, which is well illustrated by the ongoing COVID-19 pandemic. Understanding the fine details of how a virus infects its host, replicates and causes disease is a fundamental step towards the conceptualization and development of efficient countermeasures for the control, prevention and treatment of viral diseases. The use of robust and physiologically relevant cultivation systems is thus essential to generate solid and comprehensive knowledge on virus biology and pathogenesis.

This research program will focus on exploring two innovative model systems in virology, zebrafish larvae and stem-cell derived organoids as virus infection models with the purpose of illuminating details in their biology. We will take advantage of the optical transparency of zebrafish larvae, including transgenic lines (with fluorescent cell types and/ or gene knockouts), to study the viral mechanisms of pathogenesis, characterize cell tropism, virus dissemination and interactions with the microbiome. Stem cell derived organoid systems constitute another importance advance that can complement this approach and will become the go-to in vitro system, since a more in-depth knowledge of physiologically

relevant processes can be generated. The major focus will be on human gut viruses, particularly on human norovirus, the most common cause of gastroenteritis worldwide. We are (and will continue) developing additional infection models of emerging viruses. Two examples are for the arthropod-borne Rift Valley fever virus and for the respiratory influenza virus (including in co-infection with Aspergillus). Bringing this knowledge forward will make a definite contribution to the design of innovative ways to combat viral infections.