Understanding genotype dependent infection of Parechovirus A Using human-based models

Genotypes belonging to the Parechovirus A (PeV-A) species are picornaviruses causing disease in infants. While their infection is usually asymptomatic or mild, some genotypes, especially PeV-A3, can cause severe diseases. Despite their clinical relevance, there is no explanation of the differential disease caused by the different genotypes. In this thesis, we investigate the pathogenesis of PeV-As using human based organotypic models.
In Chapter 2, we describe the use of intestinal organoids or enteroids for the modelling of viral infection. In Chapter 3, we use one of those models to study PeV-A infection. The model is permissive to infection of both lab-adapted and clinical isolates of PeV-A1, but only to clinical isolates of PeV-A3. The cell tropism was different, PeV-A1 infected enterocytes and Paneth cells, and PeV-A3 goblet cells. In Chapter 4, we analyze the infection of PeV-A1 and PeV-A3 in brain organoids. Both genotypes are also able to infect UNOs with similar cell tropism. However, the inflammatory response following PeV-A3 infection is more upregulated than with PeV-A1.
In Chapter 5, we explore the role of new host factors during PeV-A infection using a genome-wide CRISPR-Cas9 screening. We identify SPPL3 and MYADM as important host factors for PeV-A1 infection and confirm their importance for PeV-A3 and PeV-A4 infection with silencing RNA and knock-out on HT-29 cells.
Finally, in Chapter 6 we investigate the antiviral activity of halofuginone hydrobromide against viruses from different families employing organotypic models. Halofuginone hydrobromide shows potent antiviral activity against SARS-CoV-2 in the airway epithelium, but not against any of the other viruses.