Pseudovirus rVSVΔG-ZEBOV-GP Infects Neurons in Retina and CNS, Causing Apoptosis and Neurodegeneration in Neonatal Mice
Ian L. McWilliams,
Jennifer L. Kielczewski,
Derek D.C. Ireland,
Jacob S. Sykes,
Aaron P. Lewkowicz,
Krishnamurthy Konduru,
Biying C. Xu,
Chi-Chao Chan,
Rachel R. Caspi,
Mohanraj Manangeeswaran,
Daniela Verthelyi
Affiliations
Ian L. McWilliams
Division of Biotechnology Review and Research-III, Office of Biotechnology Products, Center for Drug Evaluation and Research, Food and Drug Administration, Silver Spring, MD 20993, USA
Jennifer L. Kielczewski
Laboratory of Immunology, National Eye Institute, NIH, Bethesda, MD 20892, USA
Derek D.C. Ireland
Division of Biotechnology Review and Research-III, Office of Biotechnology Products, Center for Drug Evaluation and Research, Food and Drug Administration, Silver Spring, MD 20993, USA
Jacob S. Sykes
Division of Biotechnology Review and Research-III, Office of Biotechnology Products, Center for Drug Evaluation and Research, Food and Drug Administration, Silver Spring, MD 20993, USA
Aaron P. Lewkowicz
Division of Biotechnology Review and Research-III, Office of Biotechnology Products, Center for Drug Evaluation and Research, Food and Drug Administration, Silver Spring, MD 20993, USA
Krishnamurthy Konduru
Laboratory of Emerging Pathogens, Division of Emerging and Transfusion Transmitted Diseases, Office of Blood Research and Review, Center for Biologics Evaluation and Research, Food and Drug Administration, Silver Spring, MD 20993, USA
Biying C. Xu
Laboratory of Immunology, National Eye Institute, NIH, Bethesda, MD 20892, USA
Chi-Chao Chan
Laboratory of Immunology, National Eye Institute, NIH, Bethesda, MD 20892, USA
Rachel R. Caspi
Laboratory of Immunology, National Eye Institute, NIH, Bethesda, MD 20892, USA
Mohanraj Manangeeswaran
Division of Biotechnology Review and Research-III, Office of Biotechnology Products, Center for Drug Evaluation and Research, Food and Drug Administration, Silver Spring, MD 20993, USA; Corresponding author
Daniela Verthelyi
Division of Biotechnology Review and Research-III, Office of Biotechnology Products, Center for Drug Evaluation and Research, Food and Drug Administration, Silver Spring, MD 20993, USA; Corresponding author
Summary: Zaire Ebola virus (ZEBOV) survivors experience visual and CNS sequelae that suggests the ZEBOV glycoprotein can mediate neurotropism. Replication-competent rVSVΔG-ZEBOV-GP vaccine candidate is generally well tolerated; however, its potential neurotropism requires careful study. Here, we show that a single inoculation of rVSVΔG-ZEBOV-GP virus in neonatal C57BL/6 mice results in transient viremia, neurological symptoms, high viral titers in eyes and brains, and death. rVSVΔG-ZEBOV-GP infects the inner layers of the retina, causing severe retinitis. In the cerebellum, rVSVΔG-ZEBOV-GP infects neurons in the granular and Purkinje layers, resulting in progressive foci of apoptosis and neurodegeneration. The susceptibility to infection is not due to impaired type I IFN responses, although MDA5−/−, IFNβ−/−, and IFNAR1−/− mice have accelerated mortality. However, boosting interferon levels by co-administering poly(I:C) reduces viral titers in CNS and improves survival. Although these data should not be directly extrapolated to humans, they challenge the hypothesis that VSV-based vaccines are non-neurotropic. : Survivors of Ebola infections can experience neurologic and ocular symptoms, raising some concern that replication-competent vaccines expressing Ebola components could infect neurons in susceptible subjects. McWilliams et al. show that the rVSVΔG-EBOV-GP pseudovirus infects neurons in the eyes and brains of neonatal mice, causing tissue damage and lethality. Keywords: Ebola virus, ebolavirus, filovirus, Ebola glycoprotein, VSV, pseudotyped virus, VSV vaccine, innate immunity, neurotropism, neurovirulence, Ebola vaccine
