Virus Clearance from the Central Nervous System

描述(申请人提供)：病毒性脑炎是一个引人注目的生物恐怖疾病目标。大多数病原体，如尼帕(NV)、西尼罗河病毒(WNV)、日本脑炎(JE)和狂犬病病毒，在性质上是可以接触到的，可以通过气雾剂传播感染，这是一种适合武器化的手段，并至少在一些感染者中造成致命后果。这些RNA病毒感染的临床病程通常是非特异性的，因此诊断往往被推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这种疾病的幸存者。虽然狂犬病病毒是C类生物恐怖因子，因为在暴露前或暴露后的头几天可以获得具有保护性的疫苗，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名为TriGAS的狂犬病减毒活疫苗病毒，它具有独特的安全性，并能够从小鼠的中枢神经系统中清除现有的野生型狂犬病病毒。该项目的主要目标是翻译，以确定在被动注射狂犬病病毒中和抗体的情况下，TRGAS给药是否可能引发狂犬病病毒从人类中枢神经系统中的非细胞溶解清除。TriGAS疗法将在小鼠身上得到优化，在狗身上得到验证，并在体外与TriGAS感染的人脑组织中保护性免疫的生物标记物进行临床前相关。将对死于CNS狂犬病感染或从CNS狂犬病感染中康复的患者的脑脊液和血清样本进行研究，以确定在人类和动物模型中对保护性免疫反应发展至关重要的方面是否不同。如果是这样的话，TriGAS将被设计成缓解这种差异，例如通过表达趋化因子或细胞因子。TriGAS将被改造成表达其他能够引起脑炎的病毒的糖蛋白，可能成为从中枢神经系统清除多种病毒的疫苗载体。因此，该项目的次要目标是确定表达NV、WNV和JE糖蛋白的TriGAS是否与母病毒具有类似的安全性和有效性证据，目标是开发一种单一的疫苗，可以安全地清除中枢神经系统组织中的几种类型的脑炎病毒。

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.