Neuroinvasive EV-D68 infection in cerebral organoids mimics human pathology

Abstract

Abstract Emerging viruses with the capacity to cause neurological disease remain a global health threat. One such virus, Enterovirus-D68 (EV-D68), has recently received attention due to an associative rise in cases of a polio-like paralytic disease called acute flaccid myelitis (AFM) in some children. Although EV-D68 was identified in the 1960s (prototypic strain Fermon), circulating neuroinvasive EV-D68 strains have evolved to infect cells of the central nervous system. AFM remains a rare infection outcome, suggesting that host immune responses may play a role in limiting disease. Studies of such immune responses as well as tools to examine these responses remain limited. To this end, we seek to understand how neuroinvasive and non-neuroinvasive EV-D68 differentially modulate immune responses using both neuronal cultures and cerebral organoids. We infected neuroblastoma cells (SH-SY5Y cells) with Fermon and neuroinvasive EV-D68 and found that both viruses were able to replicate in these cells, which is different from what is observed during human disease. Thus, to better dissect strain differences and model human disease, we generated cerebral organoids and infected with our EV-D68 strains. We now found that cerebral organoids were more permissive to neuroinvasive EV-D68 infection compared to Fermon. Further, we found that neuroinvasive EV-D68 infection led to a global increase in the interferon-stimulated gene IFIT1 activation, whereas Fermon infection led to modest IFIT1 activation in bystander cells. These data suggest that immune responses can better control Fermon infection compared to neuroinvasive EV-D68, and also highlight the utility of using cerebral organoids to examine neurotropic virus regulation of immune responses. Supported by grants from the Burroughs Wellcome Fund and the Office of the University of the Provost