Effect of aging on neuroinvasion during West Nile virus (WNV) infection.

衰老与先天免疫和获得性免疫失调有关，这会削弱个人控制新遇到的病原体感染的能力。衰老还影响中枢神经系统(CNS)内的神经保护机制，包括限制中性病毒进入和复制的血脑屏障(BBB)的功能。西尼罗河病毒是美国节肢动物传播病毒感染的主要原因。虽然大多数西尼罗河病毒感染是无症状的，但有症状的人要么表现为流感样发烧疾病，要么发展为严重的神经侵袭性疾病，包括脑膜炎、脑炎或松弛麻痹。严重的西尼罗河病毒感染，特别是致命性感染，在老年人中占主导地位。目前尚不清楚这是否由于衰老对病毒入侵和/或周围组织或中枢神经系统内的病毒学控制的影响。为了研究成年小鼠免疫调节的许多不同方面，戴蒙德和克莱恩实验室建立了一种感染WNV强毒株的小鼠模型。然而，抗病毒免疫、神经炎症和中枢神经系统内衰老之间的相互作用尚未被研究。在这项建议中，我们将研究年龄对先天性和获得性免疫机制的影响，这些机制控制病毒特别是在中枢神经系统内的进入和清除。在UH2阶段，我们将建立繁殖队列，并确定使用21个月龄的动物进行西尼罗河病毒感染研究的可行性。在UH3阶段，我们将探索衰老过程中皮肤免疫、血脑屏障完整性和中枢神经系统炎症的变化如何影响与西尼罗河病毒感染相关的神经侵袭和疾病进展。

Aging is associated with dysregulation of innate and adaptive immunity, which impairs an individual's ability to control infection by newly encountered pathogens. Aging also impacts neuroprotective mechanisms within the central nervous system (CNS), including the function of the blood-brain barrier (BBB), which limits the entry and replication of neutrotropic viruses. West Nile virus (WNV) is the leading cause of arthropod-transmitted viral infections in the United States. While most WNV infections are asymptomatic, individuals with symptomatic disease present either with a flu-like febrile illness that can progress to severe neuroinvasive diseases including meningitis, encephalitis, or flaccid paralysis. Severe WNV infection, especially fatal forms, predominate in the elderly. It is unclear whether this is due to effects of aging on viral invasion and/or virologic control within peripheral tissues or the CNS. To study many different aspects of immune regulation in adult mice, the Diamond and Klein laboratories have established a murine model of infection with a virulent WNV strain. However, interactions between antiviral immunity, neuroinflammation, and aging within the CNS have not been investigated. In this proposal, we will examine the impact of age on innate and adaptive immune mechanisms that control viral entry and clearance specifically within the CNS. The UH2 phase we will establish breeding cohorts and determine the feasibility of using 21 month-old aged animals in WNV infection studies. In the UH3 phase, we will explore how changes in skin immunity, BBB integrity, and CNS inflammation during aging influence neuroinvasion and disease progression associated with WNV infection.