The unexplored desert of Enterovirus C and the search for antivirals Insights from human organotypic models

Enteroviruses (EVs) are ubiquitous pathogens causing a spectrum of symptoms in humans, ranging from mild to severe. While much attention is given to well-known genotypes like poliovirus, understanding the less-studied non-polio genotypes within the Enterovirus C (EV-C) species is essential for unravelling their molecular epidemiology, tropism, and pathogenesis. Despite predominantly affecting African children, the occurrence of severe cases among immunocompromised patients in Europe underscores the necessity for deeper comprehension. Utilizing human-based organotypic models of the airway, gut, and brain provides promising tools for studying host-pathogen interactions and conducting preclinical investigations with enhanced translational potential. The thesis begins with a global overview of EV prevalence, elucidating genotype distribution variations. EV-C tropism is then explored using organotypic cultures to delineate replication dynamics and infection patterns across respiratory and intestinal models. A clinical case of severe chronic diarrhea in an immunocompromised patient highlights the urgency for effective treatment strategies. The latter part of the thesis explores the utility of diverse organoid models for antiviral testing. A novel method for generating airway organoids with reversed polarity is introduced. Furthermore, we assess the broad-spectrum antiviral efficacy of Halofuginone Hydrobromide against various viruses, including EV-A71, using human organoid models. Finally, discussions on the potential of human-based organotypic models in EV-C research and antiviral testing, drawing parallels with poliovirus animal research, underscore the importance of standardized models and cautious result interpretation. This thesis provides valuable insights into EV-C pathogenesis and emphasizes the significance of innovative and relevant methodologies in testing treatment efficacy against viral diseases.