Virus Clearance from the Central Nervous System

描述（由申请人提供）：病毒性脑炎是一个令人信服的生物恐怖疾病目标。大多数病原体，如尼帕病毒（NV）、西尼罗河病毒（WNV）、日本脑炎（JE）和狂犬病毒，本质上是可获得的，可通过气溶胶传播感染，这是一种适合武器化的手段，并至少对一些感染者造成致命后果。这些RNA病毒感染的临床过程通常是非特异性的，因此诊断常常延迟到病毒到达中枢神经系统之后，现有的治疗方法不再有效。最致命的病毒性脑炎是狂犬病，直到最近才有记录的该病幸存者很少。虽然狂犬病病毒是C类生物恐怖制剂，因为在暴露之前或暴露后的头几天有保护疫苗，但目前的试剂无法从中枢神经系统清除病毒。我们最近构建了一种减毒狂犬病活疫苗病毒，命名为TriGAS，它具有独特的安全性和清除小鼠中枢神经系统中现有野生型狂犬病病毒的能力。这个项目的主要目的是翻译，以确定是否TriGAS给药，与或不被动给予狂犬病毒中和抗体，可能触发狂犬病毒从人中枢神经系统的非细胞溶解性清除。TriGAS疗法将在小鼠身上进行优化，在狗身上进行验证，并在体外与TriGAS感染的人脑组织的保护性免疫生物标志物进行临床前相关性研究。将研究死于中枢神经系统狂犬病感染或从中枢神经系统狂犬病感染中康复的患者的脑脊液和血清样本，以确定对保护性免疫反应发展至关重要的方面在人类和动物模型之间是否存在差异。如果是这样，TriGAS将被改造以减轻差异，例如通过表达趋化因子或细胞因子。TriGAS将被设计用于表达其他能够引起脑炎的病毒的糖蛋白，有可能作为清除中枢神经系统多种病毒的疫苗载体。因此，该项目的第二个目标是确定表达NV、WNV和乙脑糖蛋白的TriGAS是否具有与母病毒相似的安全性和有效性证据，目标是开发一种能够安全地清除中枢神经系统组织中几种脑炎病毒的单一疫苗。

DESCRIPTION (provided by applicant): Viral encephalitis is a compelling bioterror disease target. Most of the causative agents, such as Nipah (NV), West Nile (WNV), Japanese encephalitis (JE) and Rabies viruses are accessible in nature, can infect via aerosol delivery, a means suitable for weaponization, and cause a lethal outcome in at least some infected individuals. The clinical course of these RNA virus infections is usually non-specific such that diagnosis is often delayed until after virus reaches the CNS and existing therapies are no longer effective. The most lethal viral encephalitis is rabies, with few documented survivors of the disease until recently. While rabies virus is a Category C bioterror agent due to the availability of vaccines that are protective either prior to, or in the first days following exposure, the current reagents fail to clear the virus from the CNS. We have recently constructed a live-attenuated rabies vaccine virus, designated TriGAS, that has a unique safety profile and the capacity to clear an existing wild-type rabies virus from the CNS in mice. The primary objective of this project is translational, to determine if TriGAS administration, with or without passively administered rabies virus neutralizing antibodies, is likely to trigger non- cytolytic clearance of rabies virus from the human CNS. TriGAS therapy will be optimized in mice, validated in dogs, and preclinically correlated with biomarkers of protective immunity in TriGAS-infected human brain tissues in vitro. Cerebrospinal fluid and serum samples from patients who either died of or recovered from CNS rabies infection will be studied to determine whether aspects critical to the development of a protective immune response differ between humans and the animal models. If so, TriGAS will be engineered to mitigate the difference, for example by expressing a chemokine or cytokine. TriGAS will be engineered to express glycoproteins from other viruses capable of causing encephalitis, potentially to serve as a vaccine vector for the clearance of multiple viruses from the CNS. The secondary objective of the project is therefore to determine if TriGAS expressing NV, WNV, and JE glycoproteins have similar safety profiles and evidence of efficacy as the parent virus, the goal being to develop a single vaccine that can safely clear several types of encephalitis viruses from CNS tissues.