Pseudovirus rVSVdeltaG-ZEBOV-GP infects murine neurons in the retina and CNS causing apoptosis and neurodegeneration

Authors

• IL MacWilliams
• JL Kielczewski
• D Ireland
• J Sykes
• A Lewkowicz
• B Xu
• CC Chan
• R Caspi
• M Manangeeswaran
• D Verthelyi

Abstract

Administration of replication competent vesicular stomatitis virus (VSV) expressing Zaire Ebola glycoprotein (ZEBOV GP), also known as rVSVdeltaG-ZEBOV-GP, to adult immunocompetent mice, non-human primates, and human patients produces GP neutralizing antibodies. Ebola can persist in the eyes and central nervous system of convalescent patients suggesting that GP can mediate neurotropic infection. Although rVSVdeltaG-ZEBOV-GP is generally well-tolerated in adult populations, the expression of GP in a pseudotyped virus raises the possibility of neurotropism in susceptible populations. Here, we show that virally susceptible neonatal C57BL/6 mice inoculated with rVSVdeltaG-ZEBOV-GP develop neurological symptoms and die, despite controlling viremia. Mice developed high viral titers in eye and brain where the virus primarily localizes to neurons of retina and cerebellum. Within cerebellum, viral foci localize to the neuron-dense granular layer and associate with neurodegeneration and apoptosis. Impairment in type-I interferon responses (MDA5-/-, IFNb-/-, and IFNAR1-/- mice) increase mortality, while boosting interferon responses at challenge with Poly(I:C) reduced viral titers in CNS and improved survival. This study shows that rVSVdeltaG-ZEBOV-GP infects neurons in the brain and eye, causes apoptosis and neurodegeneration, and is ultimately lethal. Although the data cannot be directly extrapolated to adults, this challenges the hypothesis that replacing VSV-G with Ebola GP eliminates neurotropism.

Scientific Focus Area: Microbiology and Infectious Diseases

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