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

 描述(申请人提供)：疱疹病毒是人类疾病的主要原因，几乎100%的人类人口至少携带一种潜伏的疱疹病毒。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型(HHV-6)的存在有关。HHV-6家族由两种关系密切的双链DNAβ疱疹病毒组成，即HHV-6A和HHV-6B。我们对HHV-6在大脑中感染的了解一直受到缺乏遗传上易驯服的小动物模型的限制。我们现在已经确定，表达人CD46(HHV-6A的受体)的转基因小鼠对HHV-6A感染敏感，我们在感染后九个月检测到病毒DNA。我们的初步研究表明，Toll样受体9参与了宿主对感染的反应，因此，我们假设HHV-6A将感染特定的脑细胞，并诱导依赖TLR9的细胞因子和趋化因子。为了解决这一假说，我们将确定脑部感染的细胞靶点、动力学，定义早期的先天免疫反应，并描述任何发展中的神经病理学。我们还将研究TLR9在引发这些反应中的作用。这些研究结果将加深我们对HHV-6A感染和由此产生的脑内免疫反应的理解，并为该模型在HHV-6A神经病理学研究中的更广泛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的治疗方法的开发，以限制或预防HHV-6相关的神经病理。

 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.