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.
Laboratory of Immunology, National Eye Institute, NIH, Bethesda, MD 20892, USA.
Cell Rep. 2019 Feb 12;26(7):1718-1726.e4. doi: 10.1016/j.celrep.2019.01.069.
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.
扎伊尔埃博拉病毒（ZEBOV）幸存者会出现视觉和中枢神经系统后遗症，这表明 ZEBOV 糖蛋白可能介导嗜神经性。复制型 rVSVΔG-ZEBOV-GP 疫苗候选物通常具有良好的耐受性；然而，其潜在的嗜神经性需要仔细研究。在这里，我们表明，在新生 C57BL/6 小鼠中单次接种 rVSVΔG-ZEBOV-GP 病毒会导致短暂的病毒血症、神经症状、眼睛和大脑中的高病毒滴度以及死亡。rVSVΔG-ZEBOV-GP 感染视网膜内层，导致严重的视网膜炎。在小脑，rVSVΔG-ZEBOV-GP 感染颗粒层和浦肯野细胞层的神经元，导致进行性凋亡和神经退行性变焦点。感染的易感性不是由于 I 型 IFN 反应受损所致，尽管 MDA5、IFNβ 和 IFNAR1 小鼠的死亡率加快。然而，通过联合施用 poly(I:C) 来提高干扰素水平可降低中枢神经系统中的病毒滴度并提高存活率。尽管这些数据不应直接外推至人类，但它们挑战了基于 VSV 的疫苗无嗜神经性的假设。
