Mapping the journey of a neuro-invasive virus in zebrafish larvae: contrasted viral spread and type I interferon responses in periphery and central nervous system

Organ-to-organ dissemination of viruses is a critical feature of host-virus interactions. Neuroinvasive viruses can enter the central nervous systems (CNS), which often results in death or permanent neurological impairment. The complex mechanisms underpinning this spread are poorly understood, as they depend on a variety of parameters, including initial site of entry, route of access to the CNS, and immune responses. To better understand these phenomena, we analyzed the spatial dynamics of Sindbis virus (SINV) dissemination in the transparent zebrafish larva. Using fluorescent reporter viruses, we observed that SINV readily invaded the CNS after inoculation at various peripheral sites. Both sensory and motor neurons were gateways to the CNS, with 2 to 3 occurrences of CNS entry par larva. While peripheral infection was transient, CNS infection was persistent and more variable. Within the CNS, viral dissemination resulted both from long-distance axonal transport and short distance shedding. Type I interferon (IFN) response was systemic in the periphery, and local in the CNS; nevertheless, it played a key role in controlling the infection in both compartments, as shown by IFN receptor knockdown or with IFN triple mutants. We built a mathematical model of the infection based on our quantitative imaging, providing additional insight. The rate of new virion production was estimated around 1 to 2 infective virions per productively infected cell per hour. The model also found that IFN did not only prevent new infections but accelerated the death of infected cells, and had a stronger effect in periphery than CNS. This study paves the way for a deeper understanding of the mechanisms at play in pathogen- and host response- mediated neurological damage during viral encephalitis.