NEUROENDOCRINE EFFECTS ON HERPES SIMPLEX VIRUS IMMUNITY

从人类和动物研究中都有大量的证据 表明免疫系统在功能上与 中枢神经系统和内分泌系统。最近的实验证据 提示神经内分泌-免疫轴在 免疫系统接收并响应来自 神经和内分泌系统以及将信号传递给 这些系统可以各自做出响应。因此，免疫反应是 来指导神经内分泌调节。此外，多项研究显示， 人类和动物都已经证明，紧张的事件会对 在调节体液免疫和细胞免疫方面发挥重要作用。 然而，很少有研究集中于阐明 应激诱导的免疫反应的调节是 对于解决特定的病毒感染是必要的。 这项提案的总体目标是使用已建立的小鼠模型 单纯疱疹病毒(HSV)感染系统的调查 应激相关神经内分泌相互作用的机制 免疫系统以及这些相互作用可能如何促进 单纯疱疹病毒感染的发病机制。这项研究的重点必然是 仅限于应激相关的皮质酮和肾上腺素的释放 从肾上腺和去甲肾上腺素直接释放到 通过直接交感神经支配的淋巴组织。第一 这些研究的一个方面检查了这些制剂对 单纯疱疹病毒特异性记忆细胞毒性T淋巴细胞(CTLm)对小鼠免疫功能的影响 溶血表型和淋巴因子基因表达改变在脑出血中的作用 来调节这些影响。一种补充的方法来调查这些 单纯疱疹病毒对CTL增殖和功能的神经内分泌作用 特异性CTL细胞系。该提案的第二个方面扩展了这些 体外研究，以确定体内模型系统的影响 束缚压力和相应的皮质酮释放， 肾上腺素和去甲肾上腺素对单纯疱疹病毒特异性CTL杀伤作用的影响 预防体内原发和潜伏的单纯疱疹病毒感染。最后，一个In 将采用体外方法来研究这些神经内分泌对 HSV特异性所必需的HSV抗原处理和递呈 CTL激活。 防止HSV潜伏状态重新激活的能力和限制 单纯疱疹病毒感染复发的严重程度取决于 受感染宿主的免疫系统的能力。然而， 这种免疫调节最终导致单纯疱疹病毒的潜在基础 其发病机制尚不十分清楚。总体而言，本报告中提出的研究 应用程序将提供对以下各项的作用和机制的见解 应激相关激素和神经肽调节抗病毒免疫 答复，并应对总体理解作出重大贡献 应激、免疫功能和病毒致病机制之间的关系。

There is substantial evidence from both human and animal studies indicating that the immune system is functionally integrated with both the central nervous system and endocrine system. Recent experimental evidence suggests that the neuroendocrine-immune axis operates bi-directionally in that the immune system receives and responds to signals originating from the nervous and endocrine systems as well as delivering signals to which these systems can each respond. As a result, immune responses are subject to direct neuroendocrine regulation. In addition, a number of studies in both humans and animals have demonstrated that stressful events play a significant role in modulation of both humoral and cellular immunity. However, few studies have focused on elucidating the basic mechanisms that underlie stress-induced modulation of the immune response that is necessary for resolution of a specific virus infection. The overall aim of this proposal is to use an established murine model system of herpes simplex virus (HSV) infection to investigate the mechanisms underlying stress-associated neuroendocrine interactions with the immune system and how these interactions may contribute to the pathogenesis of HSV infection. The focus of this study is necessarily limited to the stress-associated release of corticosterone and epinephrine from the adrenal gland and norepinephrine which is released directly into lymphoid tissues via direct sympathetic neural innervation. The first aspect of these studies examines the effect of these agents on the activation of HSV-specific memory cytotoxic T lymphocytes (CTLm) to the lytic phenotype and the role that an altered lymphokine gene expression in mediating these effects. A complementary approach to investigate these neuroendocrine effects on CTL proliferation and function utilizes an HSV- specific CTL cell line. The second aspect of this proposal extends these in vitro studies to an in vivo model system to determine the effect of restraint stress and the corresponding release of corticosterone, epinephrine and norepinephrine on the ability of HSV-specific CTL to protect against primary and latent HSV infection in vivo. Last, an in vitro approach will be undertaken to study these neuroendocrine effects on HSV antigen processing and presentation that is necessary for HSV-specific CTL activation. The ability to prevent HSV reactivation from the latent state and to limit the severity of recurrent episodes of HSV infection is dependent upon the competence of the immune system of the infected host. However, the underlying basis for such immune modulation culminating in HSV pathogenesis is not understood well. Overall, the studies proposed in this application will provide insight into the role of and mechanisms by which stress-related hormones and neuropeptides modulate anti-viral immune responses and should contribute significantly to the overall understanding of the relationship among stress, immune function, and viral pathogenesis.