Stress Hormone-Mediated Reactivation of Latent Epstein-Barr Virus

描述(申请人提供)：爱泼斯坦-巴尔病毒(EBV)感染了全球90%以上的人口，并与几种B细胞和上皮性恶性肿瘤的发病有关，包括伯基特淋巴瘤、鼻咽癌和霍奇金病，以及其他非癌症疾病，如多发性硬化症和慢性疲劳综合征。生理和心理应激可以诱导潜伏的EB病毒重新激活，我们最近发现在应激过程中产生的糖皮质激素可以诱导即刻-早期裂解开关基因BZLF1的表达。然而，应激激素介导的潜伏EBV重新激活背后的分子机制尚不清楚。我的长期目标是确定生理和心理压力影响潜伏病毒的分子过程。我们的中心假设是，应激通过糖皮质激素诱导即刻早期基因BZLF1和/或BRLF1重新激活潜伏的EBV。提出的研究领域的基本原理是，了解应激如何影响潜伏感染细胞中的EBV将为理解与EBV相关的疾病相关的病理学提供有用的信息。我们计划通过追求以下具体目标来检验我们的中心假设。1.糖皮质激素对EB病毒即刻-早期裂解开关基因的诱导为了达到这一目的，我们将分析糖皮质激素对B细胞和上皮细胞来源的EBV基因组阳性细胞株BZLF1和BRLF1的mRNA和蛋白的诱导作用。2.确定ZP和RP启动子对糖皮质激素反应的区域。为了达到这一目的，将确定ZP和RP启动子的糖皮质激素诱导和响应区的鉴定。此外，还将确定这些启动子上的GR-DNA相互作用。预计这项研究的贡献将是确定应激通过糖皮质激素诱导EBV即刻早期基因，从而诱导潜伏病毒重新激活的分子机制。这一贡献意义重大，因为它将确定防止应激介导的EBV重新激活的药理学靶点，这将防止感染的传播，并为EBV相关疾病提供新的治疗靶点。 公共卫生相关性：拟议的研究与公共健康相关，因为它将确定身体和心理应激导致潜伏的EBV重新激活的机制。目前，应激对EBV相关癌症的影响尚不清楚，尽管有证据表明，在其他EBV相关疾病中，如慢性疲劳综合征，应激具有有害影响。这与美国国立卫生研究院的使命有关，因为这项研究将提供开发EBV相关疾病新疗法所需的基本信息。

DESCRIPTION (provided by applicant): Epstein-Barr virus (EBV) infects more than 90% of the world's population and is implicated in the pathogenesis of several B-cell and epithelial malignancies, including Burkitt's lymphoma, nasopharyngeal carcinoma and Hodgkin's disease, as well as other non-cancer diseases, such as multiple sclerosis and chronic fatigue syndrome. Physical and psychological stress is known to induce reactivation of latent EBV and we have recently shown that glucocorticoids, which are produced during stress, induce expression of the immediate-early lytic switch gene BZLF1. However, the molecular mechanism behind stress hormone-mediated reactivation of latent EBV is poorly understood. My long-term goal is to identify the molecular processes by which physiological and psychological stress affect latent viruses. Our central hypothesis is that stress induces reactivation of latent EBV through glucocorticoid induction of the immediate-early genes, BZLF1 and/or BRLF1. The rationale that underlies the proposed research area is that understanding how stress affects EBV in latently infected cells will provide useful information for understanding the pathology associated with EBV-related diseases. We plan to test our central hypothesis by pursuing the following specific aims. 1. Induction of the EBV immediate-early lytic switch genes by glucocorticoids. To attain this aim glucocorticoid induction of BZLF1 and BRLF1 mRNA and protein in both B-cell and epithelial cell derived EBV genome positive cell lines will be analyzed. 2. Identification of the region of the Zp and Rp promoter that responds to glucocorticoids. To attain this aim glucocorticoid induction of the Zp and Rp promoters and identification of the responsive regions will be determined. In addition, GR-DNA interactions on these promoters will be determined. The contribution of the proposed research is expected to be in the identification of the molecular mechanism by which stress, through glucocorticoids, induces EBV immediate-early genes, thereby inducing reactivation of latent virus. This contribution is significant because it would identify pharmacological targets to prevent stress-mediated EBV reactivation which would prevent spread of infection and also provide new therapeutic targets for EBV-related diseases. PUBLIC HEALTH RELEVANCE: The proposed research is relevant to public health because it will identify the mechanism by which physical and psychological stress induces reactivation of latent EBV. Currently the effect of stress on EBV-related carcinomas are unknown although there is evidence of the detrimental effect of stress in other EBV-related diseases such as chronic fatigue syndrome. This is relevant to the mission of the NIH as this research will provide the basic information needed for the development of new therapies for EBV-related diseases.