Induction of Apoptosis in T cells by Herpes Simplex Virus Type 2

说明(由申请人提供)：项目摘要：需要更好的治疗方法，以实现2010年健康人目标25-4和25-10，即减少新生儿生殖器疱疹感染及其后果。了解单纯疱疹病毒2型(HSV-2)如何逃避宿主的免疫系统是开发改进的生殖器和新生儿疱疹治疗方法的关键一步。候选人的长期目标是发展独立的研究生涯，成为一名专注于疱疹病毒感染免疫学的传染病临床科学家。这项应用的目的是确定HSV-2是如何诱导T细胞凋亡的。由于T细胞被招募来控制复发部位的HSV，我们预测在病毒感染重新激活过程中，诱导T细胞凋亡是一种完整的免疫逃避机制。这一应用重点是HSV-2，因为它是生殖器和新生儿疱疹的主要病原体。核心假设是HSV-2的关键病毒蛋白通过增加促凋亡基因的表达而诱导T细胞凋亡。在候选人先前工作的指导下，这一假说将通过追求两个具体目标来检验：1)鉴定诱导T细胞凋亡所需的HSV-2基因产物；2)确定受HSV-2调控的T细胞凋亡途径的细胞成分。这项拟议的研究意义重大，因为它提供了破坏病毒使用的免疫逃避机制所需的知识基础，同时提供了建立候选人作为内科科学家的独立性的手段。应聘者到目前为止的培训和研究经验，加上已经确定了一位可靠的导师，有助于确保这项申请的科学和培训目标将得到实现。与公共卫生相关：这是单纯疱疹病毒免疫学的一个重要领域，旨在确定对重新激活生殖器和新生儿感染非常重要的病毒免疫逃避机制。这项工作在开发新的治疗方法以减少生殖器和新生儿感染中病毒重新激活对公共健康的影响方面具有潜在的适用性。

DESCRIPTION (provided by applicant): Project Summary: Better therapeutic approaches are needed to attain the Healthy People 2010 objectives 25-4 and 25-10 of reducing genital herpes infection and its consequences in neonates. Understanding how herpes simplex virus type 2 (HSV-2) evades the host's immune system is a critical step toward the development of improved therapies for genital and neonatal herpes. The long-term goal of the Candidate is to develop an independent research career as an infectious disease clinician scientist focused on the immunology of herpesvirus infections. The objective of this application is to determine how HSV-2 induces apoptosis in T cells. Since T cells are recruited to control HSV at the site of recurrence, we predict that induction of T cell apoptosis is an integral immune evasion mechanism during reactivation of viral infection. This application focuses on HSV-2 because it is the major etiologic agent of genital and neonatal herpes. The central hypothesis is that key viral proteins of HSV-2 induce apoptosis in T cells by increasing expression of pro-apoptotic genes. Guided by the Candidate's previous work, this hypothesis will be tested by pursuing two specific aims: 1) Identification of HSV-2 gene products that are required to induce apoptosis in T cells; and 2) Determination of the cellular components of apoptosis pathways in T cells that are modulated by HSV-2. The proposed research is significant because it provides the knowledge base needed to disrupt an immune evasion mechanism used by the virus, while providing the means to establish the Candidate's independence as a physician-scientist. The Candidate's training and research experience to date, coupled with having identified a well-established mentor, helps to assure that the scientific and training goals of this application will be met. Relevance to Public Health: This is an important area of herpes simplex virus immunology that seeks to identify the viral immune evasion mechanisms important for reactivation of genital and neonatal infections. This work has potential applicability in developing novel therapies to reduce public health consequences from virus reactivation in genital and neonatal infections.