Spatial dynamics of peripheral and central nervous system infection by an interferon-inducing neuroinvasive virus

Abstract

AbstractOrgan-to-organ dissemination of viruses is a critical feature of host-virus interactions. In particular, neuroinvasive viruses are able to enter the central nervous systems (CNS), which may result 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 transparent zebrafish larvae. Using fluorescent reporter viruses, we observed that SINV readily invaded the CNS after inoculation at various peripheral sites. From tail muscle, the virus used dorsal root ganglia (DRG) sensory neurons as a gateway to the spinal cord and further propagation to the brain. While peripheral infection was systematically transient, due to the key protective role of the strong and rapid type I interferon (IFN) response, CNS infection was persistent and more variable. Within the CNS, viral dissemination resulted both from long-distance axonal transport and short distance shedding, and IFN response was local, while it was systemic in the periphery. A mathematical model was built on this quantitative imaging foundation, that provided additional insight on the parameters of this infection, such as the rate of new virion production, estimated around 1 to 2 infective virions per productively infected cell per hour; the occurrences of CNS entry events, which was 2 to 3 per larva; or the impact of the IFN response, which did not only prevent new infections but accelerated the death of infected cells.