Control of alphavirous replacation in the nervous system

描述（由申请方提供）：节肢动物传播（虫媒）病毒，最重要的是甲病毒和黄病毒，引起发热、脑炎和关节炎的广泛流行，并通过扩展到新的地理区域对人类构成越来越大的威胁。由于虫媒病毒感染神经元引起的脑脊髓炎是全球发病和死亡的一个特别重要的原因，因为神经元损伤可导致慢性疾病和长期残疾，以及急性致命性疾病。这些感染没有治疗方法，大多数人也没有疫苗。引起脑炎的甲病毒（委内瑞拉、西部和东部马脑炎病毒）感染神经元，在美洲流行。从感染中恢复需要从神经元中清除病毒，这对免疫系统提出了独特的挑战。需要非细胞溶解过程以避免不可逆的神经损伤，并且该过程必须有效避免慢性或进行性神经疾病。 我们在小鼠中对原型甲病毒辛德毕斯病毒（SINV）的研究表明，神经元是主要的靶细胞，病毒和宿主因素都决定了结果。在断奶小鼠中引起急性非致命性脑脊髓炎的菌株（例如AR 339、TE）提供了一个研究神经元病毒感染后恢复的复杂过程的系统。我们已经表明，感染性病毒可以清除抗体（Ab）的SINV E2糖蛋白和干扰素（IFN）-g的联合作用，通过过程中，不损害受感染的神经元。然而，这些必需细胞的保存导致病毒RNA在中枢神经系统（CNS）中的持续存在，并且需要长期抑制病毒复制。对免疫正常的4-6周龄C57 BL/6小鼠在6个月内从CNS清除病毒的详细研究揭示了清除过程的3个阶段：1）清除感染性病毒，但持续高水平的病毒RNA; 2）病毒RNA的量逐渐减少，而不产生感染性病毒; 3）维持病毒RNA在低水平，防止病毒再活化。我们假设，免疫反应的不同组成部分是必不可少的每个阶段。我们将通过以下具体目标来确定从SINV脑脊髓炎分期恢复的机制：（1）确定从CNS清除感染性病毒的免疫应答的组分;（2）确定在感染性病毒被清除后减少CNS中病毒RNA的免疫应答的组分;和（3）确定驻留抗体分泌细胞在抑制病毒再活化中的作用和维持。 公共卫生相关性：神经系统的病毒感染可导致急性神经系统疾病和在明显恢复多年后发展为慢性进行性疾病。这项研究将确定免疫介导的非细胞溶解性清除神经元中的感染性病毒和病毒RNA以及预防病毒再活化和晚期神经系统疾病所需的机制。

DESCRIPTION (provided by applicant): Arthropod-borne (arbo) viruses, most importantly alphaviruses and flaviviruses, cause widespread epidemics of fever, encephalitis and arthritis and pose increasing threats to human populations through expansion into new geographic areas. Encephalomyelitis due to arbovirus infection of neurons is a particularly important global cause of morbidity and mortality because neuronal damage can lead to chronic disease and long-term disability, as well as acute fatal disease. There are no treatments for these infections and vaccines are not available for most. Alphaviruses that cause encephalitis (Venezuelan, western and eastern equine encephalitis viruses) infect neurons and are endemic in the Americas. Recovery from infection requires virus clearance from neurons and this poses unique challenges for the immune system. A noncytolytic process is needed to avoid irreversible neurologic damage and the process must be effective to avoid chronic or progressive neurologic disease. Our studies of the prototype alphavirus, Sindbis virus (SINV), in mice have shown that neurons are the primary target cells and that both virus and host factors determine outcome. Strains that cause acute nonfatal encephalomyelitis in weanling mice (e.g. AR339, TE) provide a system for studying the complicated process of recovery from neuronal virus infection. We have shown that infectious virus can be cleared by the combined effects of antibody (Ab) to the SINV E2 glycoprotein and interferon (IFN)-g, through processes that do not damage the infected neurons. However, preservation of these essential cells results in persistence of viral RNA in the central nervous system (CNS) and the need for long-term suppression of virus replication. Detailed study of virus clearance from the CNS of immunologically normal 4-6 week-old C57BL/6 mice over 6 months has revealed 3 phases of the clearance process: 1) clearance of infectious virus, but continued high levels of viral RNA; 2) gradual decrease in the amounts of viral RNA without production of infectious virus; and 3) maintenance of viral RNA at low levels with prevention of virus reactivation. We hypothesize that different components of the immune response are essential for each of these stages. We will define the mechanisms of staged recovery from SINV encephalomyelitis through the following specific aims: (1) Determine the components of the immune response that clear infectious virus from the CNS; (2) Determine the components of the immune response that decrease viral RNA in the CNS after infectious virus is cleared; and (3) Determine the role and maintenance of resident antibody-secreting cells in inhibition of virus reactivation. PUBLIC HEALTH RELEVANCE: Virus infections of the nervous system can lead to both acute neurologic disease and to the development of chronic progressive disease many years after apparent recovery. This research will determine the mechanisms required for immune-mediated non-cytolytic clearance of infectious virus and viral RNA from neurons and for prevention of virus reactivation and late neurologic disease.