Parechovirus infections in human brain organoids: host immune response and not neuro-infectivity as a correlate of neuropathology

Parechovirus A (PeV-A) is a species in the Picornaviridae family that can cause a variety of diseases, mainly in children.The most prevalent genotype, PeV-A1, can causes mild respiratory and gastrointestinal symptoms while the second most prevalent genotype, PeV-A3 can elicit severe neurological disease such as meningoencephalitis in infants. The factors determining differential outcomes between genotypes are poorly understood. In this study, we investigated the viral dynamics and tropism of PeV-A1 and PeV-A3 infection in human induced pluripotent stem cell (hiPSC)-derived unguided neural organoids (UNOs). UNOs supported PeV-A1 and PeV-A3 replication, as measured by RT-qPCR and confirmed by TCID50. Both genotypes showed similar cell tropism and infected neurons and astrocytes. Despite replicating up to a higher titre as compared to PeV-A3, PeV-A1 infection showed no significant cytokine upregulation while PeV-A3 infection resulted in an increased production of IFN-λ1 and CXCL10. This effect was also seen for Echovirus 11, another picornaviruses resulting in neurological disease. Blocking the IFN-pathway with Ruxolitinib resulted in enhanced replication of PeV-A3 indicating IFN-mediated restriction of PeV-A3 replication. This genotype-specific immune response could explain the exacerbated PeV-A3 associated severe clinical neuropathology.