Role of TLR9 in infection and host response to HHV-6A

TLR9 在 HHV-6A 感染和宿主反应中的作用

基本信息

批准号：
8823158
负责人：
CYNTHIA A LEIFER
金额：
$ 21.39万
依托单位：
CORNELL UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-12-01 至 2016-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8823158
关键词：
Address Age Animal Model B-Lymphocytes Brain CD46 Antigen Cells Chromosomes Chronic Fatigue Syndrome DNA Data Demyelinations Development Emerging Communicable Diseases Encephalitis Epilepsy Family Genomic DNA HHV-6A HHV-6B Herpesviridae Herpesviridae Infections Human Human Herpesvirus 6 Immune Immune response Immunologic Receptors In Vitro Infection Infiltration Inherited Injury Investigation Kinetics Knowledge Life Link Modeling Multiple Sclerosis Mus Neurologic Neurological outcome Pathology Play Population Production RNA Reagent Relative (related person)Resistance Role Serum T-Lymphocyte TLR9 gene Testing Transgenic Mice Up-Regulation Vertical Disease Transmission Viral Load result Virus Virus Diseases brain cell cellular targeting chemokine cytokine ds-DNA human disease in vivo insight macrophage mouse toll-like receptor 9 nervous system disorder neuroinflammation neuropathology neuroprotection nonhuman primate novel therapeutics novel virus prevent public health relevance receptor reconstitution response sensor tool transmission process viral DNA

项目摘要

DESCRIPTION (provided by applicant): Herpes viruses are a leading cause of human diseases, and nearly 100% of the human population harbors at least one latent herpes virus. Encephalitis, multiple sclerosis, chronic fatigue syndrome and epilepsy have all been correlated with the presence of human herpes virus 6 (HHV-6). The HHV-6 family consists of two closely related double stranded DNA beta herpes viruses, HHV-6A and HHV-6B. Our understanding of infection by HHV-6 in the brain has been limited by lack of a genetically tractable small animal model. We have now established that transgenic mice expressing human CD46, a receptor for HHV-6A, are susceptible to HHV-6A infection, and we detect viral DNA up to nine months post infection. Our preliminary studies implicate Toll-like receptor 9 in the host response to infection Therefore, we hypothesize that HHV-6A will infect specific brain cells and elicit TLR9-dependent cytokines and chemokines. To address this hypothesis we will identify the cellular targets, kinetics of infection in the brain, define the early innate immune responses, and characterize any developing neuropathology. We will also investigate the role of TLR9 in eliciting these responses. The results from the proposed studies will increase our understanding of HHV-6A infection and the resulting immune response in the brain, and provide important information on the broader applicability of this model to the study of HHV-6A neuropathology. Information gained from our studies will help guide development of appropriate therapies to limit or prevent HHV-6-associated neuropathologies.

描述（由适用提供）：疱疹病毒是人类疾病的主要原因，几乎100％的人口藏有至少一种潜在疱疹病毒。脑炎，多发性硬化症，慢性疲劳综合征和癫痫都与人类疱疹病毒6（HHV-6）的存在有关。 HHV-6家族由两个密切相关的双链DNAβ疱疹病毒HHV-6A和HHV-6B组成。我们对HHV-6在大脑中感染的理解受到了缺乏一般可拖动的小动物模型的限制。我们现在已经确定，表达人CD46的转基因小鼠（一种HHV-6A受体）易受HHV-6A感染的影响，并且在感染后9个月内检测到病毒DNA。我们的初步研究暗示了Toll样受体9在宿主对感染的反应中，我们假设HHV-6A会感染特定的脑细胞并引起TLR9依赖性细胞因子和趋化因子。为了解决这一假设，我们将确定细胞靶标，大脑感染的动力学，定义先天免疫调查，并表征任何发展中的神经病理学。我们还将研究TLR9在引起这些反应中的作用。拟议研究的结果将增加我们对HHV-6A感染和大脑中的免疫反应的理解，并提供有关该模型对HHV-6A神经病理研究的更广泛适用性的重要信息。从我们的研究中获得的信息将有助于指导开发适当的疗法，以限制或预防与HHV-6相关的神经病理学。