Ontrafeling van het in vivo cel tropisme en de verspreiding van het humaan norovirus.

Human norovirus (HuNoV) is a major cause of viral gastroenteritis worldwide, leading to significant morbidity and mortality, particularly in low-income regions. Despite its impact, no specific antiviral treatments or vaccines exist due to the historical challenges of culturing the virus and studying its infection mechanisms. This PhD thesis addresses key knowledge gaps in HuNoV research by using a zebrafish larval model to investigate the virus's cellular tropism, pathogenesis, and potential antiviral treatments. Through advanced techniques such as single-cell RNA sequencing, confocal microscopy, and flow cytometry, the study identifies HuNoV infection in macrophages, hepatocytes, enterocytes, and goblet cells, with macrophages playing a central role in immune response regulation. Beyond immune cells, intestinal epithelial cells also mount a strong antiviral response, accompanied by metabolic changes to limit viral replication. Interestingly, goblet cells, responsible for mucus production, were found to be infected by HuNoV, with increased mucus secretion potentially aiding viral persistence. The study also evaluates the antiviral efficacy of favipiravir and nitazoxanide in the zebrafish model, demonstrating their ability to inhibit HuNoV replication. Favipiravir induces polymerase mispriming, leading to a loss of viral infectivity, while nitazoxanide enhances innate immune responses. These findings highlight the potential of these drugs for treating chronic norovirus infections in immunocompromised patients, marking a significant step toward addressing a critical unmet need in antiviral therapy. The research presented in this thesis not only advances our understanding of HuNoV infection and host responses but also offers promising avenues for the development of antiviral treatments, addressing a critical unmet need in global health.