Control of alphavirous replacation in the nervous system

描述（由申请人提供）：节肢动物传播的（arbo）病毒，最重要的是甲病毒和黄病毒，引起发烧、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。由虫媒病毒感染神经元引起的脑脊髓炎是全球发病率和死亡率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，并在美洲流行。从感染中恢复需要清除神经元中的病毒，这对免疫系统提出了独特的挑战。为了避免不可逆的神经损伤，需要非细胞溶解过程，并且该过程必须有效地避免慢性或进行性神经疾病。我们在小鼠中对原型甲病毒Sindbis病毒（SINV）的研究表明，神经元是主要靶细胞，病毒和宿主因素共同决定结果。在断奶小鼠中引起急性非致命性脑脊髓炎的菌株（如AR339， TE）为研究神经病毒感染后的复杂恢复过程提供了一个系统。我们已经证明，传染性病毒可以通过抗体（Ab）对SINV E2糖蛋白和干扰素(IFN)-g的联合作用，通过不损害被感染神经元的过程被清除。然而，保存这些必需细胞会导致病毒RNA在中枢神经系统（CNS）中持续存在，需要长期抑制病毒复制。对免疫正常的4-6周龄C57BL/6小鼠6个月以上中枢神经系统病毒清除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，但病毒RNA持续高水平；2)在不产生感染性病毒的情况下，病毒RNA量逐渐减少；3)将病毒RNA维持在低水平，防止病毒再激活。我们假设免疫反应的不同组成部分对每个阶段都是必不可少的。我们将通过以下具体目标来定义SINV型脑脊髓炎分阶段恢复的机制：(1)确定从中枢神经系统清除感染性病毒的免疫反应成分；(2)确定感染性病毒被清除后降低中枢神经系统病毒RNA的免疫应答成分；(3)确定常驻抗体分泌细胞在抑制病毒再激活中的作用和维持。

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.