Role of Gamma/Delta T Cells in West Nile Virus Pathogenesis

描述(申请人提供)：西尼罗河病毒(WNV)引起的神经疾病已成为北美日益严重的公共卫生问题。虽然对西尼罗河病毒的免疫应答一直是深入研究的主题，但免疫介导的病理在西尼罗河病毒诱导的神经疾病中的作用尚不完全清楚。我们的长期目标是了解西尼罗河病毒的致病机制。在这份提案中，我们将重点关注一个具体的角色？？西尼罗河病毒所致脑炎的T细胞亚群--即V？4+T细胞。我们之前已经展示过了？？T细胞是非经典的T细胞群，对早期控制西尼罗河病毒的传播具有重要意义。在进一步调查？？在西尼罗河病毒感染的T细胞亚群中，我们发现V？1+T细胞的抗体耗竭增强了宿主的易感性，而V？+T细胞的耗尽降低了宿主的易感性。在西尼罗河病毒感染的早期，脾V？1+T细胞急剧膨胀，并产生大量的干扰素-β，这一数据使我们认为它在保护性免疫中起作用。相比之下，V？4+T细胞对感染的反应温和扩张。此外，我们的数据显示，老年小鼠比年轻小鼠更容易感染西尼罗河病毒。老年小鼠对V？1+T细胞的反应较慢且降低，而在感染早期维持较高数量的V？4+T细胞。基于这些事实，我们推测V？4+T细胞参与了西尼罗河病毒的致病调控。在特异的Aim1中，我们将进一步研究V？？4+T细胞在西尼罗河病毒感染过程中的致病作用。在特定的目标2中，我们将试图了解V？？4+T细胞在西尼罗河病毒感染过程中调节宿主免疫的机制。西尼罗河病毒现在已经在北美引发了最大规模的病毒性脑炎暴发，并已成为一个公共卫生问题。这项研究的结果将有助于加深我们对病毒致病机制的理解；它们也将导致开发新的策略来预防和治疗西尼罗河病毒引起的脑炎。 公共卫生意义：西尼罗河病毒(WNV)是一种媒介传播的病原体，自1999年以来已导致北美每年爆发病毒性脑炎。虽然对西尼罗河病毒的免疫应答一直是深入研究的主题，但对免疫介导的病理学作用，特别是T细胞在西尼罗河病毒相关性脑损伤中的作用，人们知之甚少。在这份提案中，我们将重点研究一个具体的？？西尼罗河病毒所致脑炎的T细胞亚群，即V？4+T细胞。

DESCRIPTION (provided by applicant): West Nile virus (WNV)-induced neurological disease has become an increasing public health concern in North America. Although immune responses to WNV have been the subject of intense investigation, the role of immune-mediated pathology in WNV-induced neurological diseases is incompletely understood. Our long- term goal is to understand the mechanism of WNV pathogenesis. In this proposal, we will focus on the role of one specific ?? T cell subtype- namely V?4+ T cells in WNV-induced encephalitis. We have previously shown that ?? T cells, the non-classical T cell population, are important for early control of WNV dissemination. In further investigation of the role of ?? T cell subsets in WNV infection, we have found that antibody depletion of V?1+ T cells enhances host susceptibility; while depletion of V??? + T cells reduces host susceptibility. Splenic V?1+ T cells expand dramatically at the early stage of WNV infection and produce significant amounts of IFN-?, data which lead us to suggest a role in protective immunity. In contrast, V?4+ T cells expand modestly in response to infection. Moreover, our data show that the aged mice are more susceptible to WNV infection than are young mice. Aged mice exhibit a slower and reduced response by V?1+ T cells, while maintaining a higher number of V??4+ T cells at the early stage of infection. Based on these facts, we hypothesize that V??4+ T cells are involved in the regulation of WNV pathogenesis. In Specific Aim1, we will further investigate the pathogenic effect of V??4+ T cells during WNV infection. In Specific Aim 2, we will attempt to understand the mechanisms by which V??4+ T cells regulate host immunity during WNV infection. WNV has now induced the largest outbreaks of viral encephalitis in North America and has become a public health concern. Results from this study will help to enhance our understanding of viral pathogenesis; they will also lead to the development of new strategies to prevent and treat WNV-induced encephalitis. PUBLIC HEALTH RELEVANCE: West Nile virus (WNV), a vector-borne pathogen, has resulted in annual outbreaks of viral encephalitis in North America since 1999. Although immune responses to WNV have been the subject of intense investigation, little is known about the role of immune-mediated pathology, especially the role of T cells in WNV-related brain damage. In this proposal, we will focus on the study of one specific ?? T cell subtype, namely V??4+ T cells in WNV-induced encephalitis.