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

• 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
• 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

 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（由申请人提供）：疱疹病毒是人类疾病的主要原因，几乎100%的人口都携带至少一种潜伏的疱疹病毒。脑炎、多发性硬化症、慢性疲劳综合症和癫痫都与人类疱疹病毒 6 (HHV-6) 的存在有关。 HHV-6 家族由两种密切相关的双链 DNA β 疱疹病毒 HHV-6A 和 HHV-6B 组成。由于缺乏遗传上易于处理的小动物模型，我们对大脑中 HHV-6 感染的了解受到限制。我们现在已经确定，表达人 CD46（HHV-6A 受体）的转基因小鼠易受 HHV-6A 感染，并且我们在感染后九个月内检测到病毒 DNA。我们的初步研究表明 Toll 样受体 9 与宿主对感染的反应有关，因此，我们假设 HHV-6A 会感染特定的脑细胞并引发 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、大脑感染动力学、定义早期先天免疫反应，并描述任何正在发展的神经病理学特征。我们还将研究 TLR9 在引发这些反应中的作用。拟议研究的结果将增加我们对 HHV-6A 感染以及由此产生的大脑免疫反应的理解，并为该模型在 HHV-6A 神经病理学研究中更广泛的适用性提供重要信息。从我们的研究中获得的信息将有助于指导适当疗法的开发，以限制或预防 HHV-6 相关的神经病理学。