NEUROENDOCRINE EFFECTS ON HERPES SIMPLEX VIRUS IMMUNITY

描述（申请人摘要）：大量证据表明免疫系统在功能上与神经和内分泌系统整合。这种整合在调节对各种感染因子的先天性和适应性免疫应答中起关键作用。该计划的长期目标是确定神经内分泌和免疫机制，心理压力通过这些机制影响对单纯疱疹病毒（HSV）感染的基于T细胞的免疫反应。本提案的主要目的是确定下丘脑-垂体-肾上腺（HPA）轴和交感神经系统（SNS）与心理应激相关的产品如何调节记忆细胞毒性T淋巴细胞（CTLm）的产生和激活，以及这种调节在多大程度上是由这些产品对抗原加工和呈递的影响介导的。提出的研究的基本原理是基于这样一个事实，即CTLm不仅在介导对复发性HSV感染的保护作用中，而且在介导对其他病毒感染的保护作用中发挥关键作用。此外，病毒编码的CTL识别表位被抗原呈递细胞（APC）加工和呈递的效率对于这些CTLm的产生和活化都是至关重要的。为了实现这一目标，我们提出了三个具体的目标：（1）确定应激和应激相关的HPA轴和SNS激活对HSV特异性记忆CTL产生的影响：（2）评价应激和应激相关的HPA轴和SNS激活对体内HSV特异性记忆CTL激活和功能的影响;（3）确定皮质酮和β 2肾上腺素能受体激动剂对抗原加工和呈递的分子组分的作用。在该项目完成时，我们期望已经确定应激对CTLm应答的大小的影响取决于递送CTL表位的载体的性质以及表位本身的免疫原性。我们还预计，压力将降低HSV特异性CTLm在外周部位和中枢神经系统中的体内保护能力。我们预计，一种或多种参与抗原加工和呈递的分子组分将受到皮质酮和/或β-2肾上腺素能受体激动剂的影响。总体而言，这些研究将确定应激和相关HPA轴和SNS衍生产物对HSV特异性CTLm活化和功能的影响，并将提供对应激影响基于免疫的病毒感染保护的分子机制的深入了解。

DESCRIPTION (applicant's abstract): There is a large body of evidence that the immune system is functionally integrated with both the nervous and endocrine systems. This integration plays a key role in regulating both the innate and adaptive immune responses to a variety of infectious agents. The long-range goal of this program is to define the neuroendocrine and immune mechanisms by which psychological stress affects T cell-based immune responses to herpes simplex virus (HSV) infections. The main objective of this proposal is to determine how products of the hypothalamic- pituitary-adrenal (HPA) axis and the sympathetic nervous system (SNS) associated with psychological stress modulate the generation and activation of memory cytotoxic T lymphocytes (CTLm) and to what extent this modulation is mediated by the effects of these products on antigen processing and presentation. The rationale for the proposed research is based on the fact that CTLm play key roles in mediating protection against not only recurrent HSV infection but also other viral infections. Moreover, the efficiency with which virus-encoded CTL recognition epitopes are processed and presented by antigen presenting cells (APC) is central to both the generation and activation of these CTLm. To achieve this objective, three specific aims are proposed: (1) To determine the impact of stress and stress-associated activation of the HPA axis and SNS on the generation of HSV-specific memory CTL; (2) To evaluate the effects of stress and stress-associated activation of the HPA axis and SNS on the activation and function of HSV-specific memory CTL in vivo; and (3) To determine the role of corticosterone and beta-2 adrenergic receptor agonists on molecular components of antigen processing and presentation. At the completion of this project we expect to have determined that the effects of the stress on the magnitude of the CTLm response depend on both the nature of the vector delivering the CTL epitope as well as the immunogenicity of the epitope itself. We also expect that stress will diminish the protective ability of HSV-specific CTLm in vivo at both peripheral sites and in the central nervous system. We anticipate that one or more of the molecular components involved in antigen processing and presentation will be affected by corticosterone and/or beta-2 adrenergic receptor agonists. Overall, these studies will define the impact of stress and associated HPA axis- and SNS-derived products on HSV-specific CTLm activation and function and will provide insight into the molecular mechanisms by which stress effects immune-based protection to viral infection.