Pseudovirus rVSVΔG-ZEBOV-GP Infects Neurons in Retina and CNS, Causing Apoptosis and Neurodegeneration in Neonatal Mice

摘要

Zaire Ebola virus (ZEBOV) survivors experience visualand CNS sequelae that suggests the ZEBOVglycoprotein can mediate neurotropism. Replication-competentrVSVDG-ZEBOV-GP vaccine candidateis generally well tolerated; however, its potentialneurotropism requires careful study. Here, we showthat a single inoculation of rVSVDG-ZEBOV-GP virusin neonatal C57BL/6 mice results in transient viremia,neurological symptoms, high viral titers in eyes andbrains, and death. rVSVDG-ZEBOV-GP infects the innerlayers of the retina, causing severe retinitis. In thecerebellum, rVSVDG-ZEBOV-GP infects neurons inthe granular and Purkinje layers, resulting in progressivefoci of apoptosis and neurodegeneration. Thesusceptibility to infection is not due to impairedtype I IFN responses, although MDA5 / , IFNb / ,and IFNAR1 / mice have accelerated mortality.However, boosting interferon levels by co-administeringpoly(I:C) reduces viral titers in CNS and improvessurvival. Although these data should not bedirectly extrapolated to humans, they challengethe hypothesis that VSV-based vaccines are nonneurotropic.