**2.1 Culturing the unculturable**

At almost all stages of replication, viruses associate closely with the host cell, and therefore the cell model used to research virus infection is crucial. Primary cells better represent the phenotype of healthy cells *in vivo* but have a short lifetime, are difficult to culture, and are heterogeneous and thereby renders manipulating them difficult. The widespread use of immortalized cell lines for culturing diverse virus strains is a common practice, but the induction of interferon-stimulated genes and other antiviral defenses is defective in many tumor-derived and artificially immortalized cell lines. These flaws can interfere with virus replication, particularly when cells are infected at lower, more physiologically important multiplicities. Moreover, there are some challenging cases where the virus fails to adapt in man-made culture conditions, like, norovirus or other enteric viruses, which remain unculturable to date in any kind of cell line system. Luckily for us, stem-cell-derived human intestinal organoids have successfully grown and studied these viral cultures up to one round of infection [28]. Similarly, respiratory viruses which are challenging to grow in cell lines like human coronavirus HKU1, human bocavirus, and human rhinovirus C could be successfully isolated from clinical specimens using Human airway epithelial (HAE) cultures [29–31]. These data prove that there is room for discovering unknown viruses and their mechanism of infection, pathogenesis, and immune escape through the fine-tuning of crucial features of the organoid platform [32].
