Pseudovirus rVSVΔG-ZEBOV-GP Infects Neurons in Retina and CNS, Causing Apoptosis and Neurodegeneration in Neonatal Mice
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 sho...
| Main Authors: | , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Elsevier
2019-02-01
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| Series: | Cell Reports |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2211124719300981 |
| _version_ | 1811285853588160512 |
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| author | 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 |
| author_facet | 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 |
| author_sort | Ian L. McWilliams |
| collection | DOAJ |
| description | 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 |
| first_indexed | 2024-04-13T02:50:17Z |
| format | Article |
| id | doaj.art-37200160765642d08b620f9f508e0380 |
| institution | Directory Open Access Journal |
| issn | 2211-1247 |
| language | English |
| last_indexed | 2024-04-13T02:50:17Z |
| publishDate | 2019-02-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Cell Reports |
| spelling | doaj.art-37200160765642d08b620f9f508e03802022-12-22T03:05:51ZengElsevierCell Reports2211-12472019-02-0126717181726.e4Pseudovirus rVSVΔG-ZEBOV-GP Infects Neurons in Retina and CNS, Causing Apoptosis and Neurodegeneration in Neonatal MiceIan L. McWilliams0Jennifer L. Kielczewski1Derek D.C. Ireland2Jacob S. Sykes3Aaron P. Lewkowicz4Krishnamurthy Konduru5Biying C. Xu6Chi-Chao Chan7Rachel R. Caspi8Mohanraj Manangeeswaran9Daniela Verthelyi10Division of Biotechnology Review and Research-III, Office of Biotechnology Products, Center for Drug Evaluation and Research, Food and Drug Administration, Silver Spring, MD 20993, USALaboratory of Immunology, National Eye Institute, NIH, Bethesda, MD 20892, USADivision of Biotechnology Review and Research-III, Office of Biotechnology Products, Center for Drug Evaluation and Research, Food and Drug Administration, Silver Spring, MD 20993, USADivision of Biotechnology Review and Research-III, Office of Biotechnology Products, Center for Drug Evaluation and Research, Food and Drug Administration, Silver Spring, MD 20993, USADivision of Biotechnology Review and Research-III, Office of Biotechnology Products, Center for Drug Evaluation and Research, Food and Drug Administration, Silver Spring, MD 20993, USALaboratory 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, USALaboratory of Immunology, National Eye Institute, NIH, Bethesda, MD 20892, USALaboratory of Immunology, National Eye Institute, NIH, Bethesda, MD 20892, USALaboratory of Immunology, National Eye Institute, NIH, Bethesda, MD 20892, USADivision 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 authorDivision 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 authorSummary: 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 vaccinehttp://www.sciencedirect.com/science/article/pii/S2211124719300981 |
| spellingShingle | 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 Pseudovirus rVSVΔG-ZEBOV-GP Infects Neurons in Retina and CNS, Causing Apoptosis and Neurodegeneration in Neonatal Mice Cell Reports |
| title | Pseudovirus rVSVΔG-ZEBOV-GP Infects Neurons in Retina and CNS, Causing Apoptosis and Neurodegeneration in Neonatal Mice |
| title_full | Pseudovirus rVSVΔG-ZEBOV-GP Infects Neurons in Retina and CNS, Causing Apoptosis and Neurodegeneration in Neonatal Mice |
| title_fullStr | Pseudovirus rVSVΔG-ZEBOV-GP Infects Neurons in Retina and CNS, Causing Apoptosis and Neurodegeneration in Neonatal Mice |
| title_full_unstemmed | Pseudovirus rVSVΔG-ZEBOV-GP Infects Neurons in Retina and CNS, Causing Apoptosis and Neurodegeneration in Neonatal Mice |
| title_short | Pseudovirus rVSVΔG-ZEBOV-GP Infects Neurons in Retina and CNS, Causing Apoptosis and Neurodegeneration in Neonatal Mice |
| title_sort | pseudovirus rvsvδg zebov gp infects neurons in retina and cns causing apoptosis and neurodegeneration in neonatal mice |
| url | http://www.sciencedirect.com/science/article/pii/S2211124719300981 |
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