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

描述（由申请人提供）：西尼罗河病毒（WNV）引起的神经系统疾病已成为北美日益严重的公共卫生问题。尽管对西尼罗河病毒的免疫应答一直是深入研究的主题，但免疫介导的病理学在西尼罗河病毒诱导的神经系统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发病机制.在本提案中，我们将重点关注一个特定的角色？？T细胞亚型-即V？WNV诱导的脑炎中的4+ T细胞。我们之前已经证明了？？T细胞，非经典的T细胞群，是重要的早期控制西尼罗河病毒传播。在进一步调查的作用？？在WNV感染的T细胞亚群中，我们发现V？1+ T细胞增强宿主易感性，而V？+ T细胞降低宿主易感性。脾V？1+ T细胞在西尼罗河病毒感染的早期阶段急剧扩增，并产生大量的IFN-？，这些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细胞在感染后适度扩增。此外，我们的数据表明，老年小鼠比年轻小鼠更容易感染西尼罗河病毒。老年小鼠表现出更慢，减少响应V？1+ T细胞，同时保持较高数量的V？？感染早期4+ T细胞。基于这些事实，我们假设V？4+ T细胞参与了WNV发病机制的调节。在具体目标1中，我们将进一步研究V？？4+ T细胞。在具体目标2中，我们将试图了解V？？4+ T细胞在WNV感染期间调节宿主免疫。西尼罗河病毒现已引起北美最大规模的病毒性脑炎爆发，并已成为一个公共卫生问题。这项研究的结果将有助于提高我们对病毒发病机制的理解，也将有助于开发预防和治疗WNV引起的脑炎的新策略。 公共卫生相关性：西尼罗河病毒（WNV）是一种病媒传播的病原体，自1999年以来每年在北美爆发病毒性脑炎。虽然对WNV的免疫反应一直是深入研究的主题，但对免疫介导的病理学的作用，特别是T细胞在WNV相关脑损伤中的作用知之甚少。在本建议中，我们将重点研究一个具体的？？T细胞亚型，即V？WNV诱导的脑炎中的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.