Protection of Genital Mucosa and Ganglia Against HSV-2

保护生殖器粘膜和神经节免受 HSV-2 侵害

• 批准号: 6871837
• 负责人: Gregg N. Milligan
• 金额: $ 13.21万
• 依托单位: UNIVERSITY OF TEXAS MED BR GALVESTON
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-02-01 至 2010-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6871837
• 关键词: Herpesviridae vaccine; attenuated microorganism; autonomic ganglion; biotechnology; cancer prevention; disease /disorder prevention /control; enzyme linked immunosorbent assay; genital herpes; helper T lymphocyte; herpes simplex virus 2; laboratory mouse; microorganism culture; microorganism immunology; mucosa; mucosal immunity; neoplasm /cancer vaccine; nervous system infection; sensory neuropathy; spinal cord; suppressor T lymphocyte; thymidine kinase; vaccine development; vagina

DESCRIPTION (provided by applicant): Approximately 1 in 5 Americans are infected with herpes simplex virus type 2 (HSV-2) and the approximate direct cost of genital HSV disease exceeds $200 million annually. In addition to the devastating effects of HSV infections in newborns, genital lesions caused by HSV represent a major risk factor for acquisition of HIV. The increased frequency of recurrent disease and the inability to resolve oral and anogenital HSV lesions remains a serious complication for many immunocompromised patients. There is no licensed vaccine for the prevention of HSV disease. Vaccines recently tested in clinical trial elicited high titers of specific antibody but did not protect all populations against HSV-2 infection. The proposed studies will focus on the protective responses by specific T cell subsets and examine the mechanisms by which they act in the genital epithelium, sensory ganglia, and spinal cord to resolve HSV infections. In Aim 1, we will transfer HSV-immune CD4+ and CD8+ T cell populations to bone marrow chimeric mice to examine the role of epithelial cells, innate immune cells, and IFN-gamma in clearance of HSV from the genital tract. We will determine if the cellular targets for IFN-gamma are hemopoietic or somatic cells and examine the molecular mechanisms of IFN-gamma -mediated protection of this site. HSV-1 is also emerging as an important genital pathogen. In Aim 2, we will identify the T cell subsets responsible for protection against genital HSV-1 infections. We will utilize ELISPOT and Tetramer staining to quantify recall T cell responses and assess their ability to protect the sensory ganglia following heterotypic genital HSV challenge. In Aim 3, we will analyze the protective role of CD4+ T cells in neuronal tissue. We will use cell depletion and adoptive transfer experiments to test the dependence of the HSV-specific recall antibody response and neuronal CD8+ T cell response on CD4+ T cells. Additionally, we will utilize adoptive transfer of immune CD4+ T cells to immunodeficient mice to determine if CD4+ T cells contribute to HSV clearance from neuronal tissue. The results of these studies should be important for the rational development of HSV vaccines as well as understanding the cellular interactions and specific molecular mechanisms required for resolution of HSV lesions.

描述（由申请人提供）：大约五分之一的美国人感染 2 型单纯疱疹病毒 (HSV-2)，每年生殖器 HSV 疾病造成的直接损失大约超过 2 亿美元。除了 HSV 感染对新生儿造成的破坏性影响外，HSV 引起的生殖器病变也是感染 HIV 的主要危险因素。对于许多免疫功能低下的患者来说，疾病复发频率的增加以及口腔和肛门生殖器 HSV 病变无法解决仍然是严重的并发症。目前尚无获得许可的疫苗可用于预防 HSV 疾病。最近在临床试验中测试的疫苗引发了高滴度的特异性抗体，但并不能保护所有人群免受 HSV-2 感染。拟议的研究将重点关注特定 T 细胞亚群的保护性反应，并检查它们在生殖器上皮、感觉神经节和脊髓中发挥作用以解决 HSV 感染的机制。 在目标 1 中，我们将 HSV 免疫 CD4+ 和 CD8+ T 细胞群转移至骨髓嵌合小鼠，以检查上皮细胞、先天免疫细胞和 IFN-γ 在从生殖道清除 HSV 中的作用。我们将确定 IFN-γ 的细胞靶标是造血细胞还是体细胞，并检查 IFN-γ 介导的该位点保护的分子机制。 HSV-1 也正在成为一种重要的生殖器病原体。在目标 2 中，我们将确定负责预防生殖器 HSV-1 感染的 T 细胞亚群。我们将利用 ELISPOT 和四聚体染色来量化回忆 T 细胞反应，并评估它们在异型生殖器 HSV 攻击后保护感觉神经节的能力。在目标 3 中，我们将分析 CD4+ T 细胞在神经组织中的保护作用。我们将使用细胞耗竭和过继转移实验来测试 HSV 特异性回忆抗体反应和神经元 CD8+ T 细胞反应对 CD4+ T 细胞的依赖性。此外，我们将利用免疫 CD4+ T 细胞过继转移至免疫缺陷小鼠体内，以确定 CD4+ T 细胞是否有助于神经组织中 HSV 的清除。这些研究的结果对于 HSV 疫苗的合理开发以及了解解决 HSV 病变所需的细胞相互作用和特定分子机制具有重要意义。