The Role of the Autonomic Nervous System in HSV Infection

自主神经系统在 HSV 感染中的作用

• 批准号: 8617218
• 负责人: Andrea S Bertke
• 金额: $ 10.8万
• 依托单位: VIRGINIA POLYTECHNIC INST AND ST UNIV
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-02-15 至 2016-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8617218
• 关键词: Ablation; Adult; Afferent Neurons; Animal Model; Autonomic Pathways; Autonomic ganglion; Autonomic nervous system; Binding Sites; Biological Assay; Cavia; Chemical Sympathectomy; Clinical; Constipation; DNA; DNA-Binding Proteins; Disease; Encephalitis; Foundations; Funding; Future; Genital system; Genome; Goals; Herpes Labialis; Herpesvirus 1; Human; Human Herpesvirus 2; Impotence; In Vitro; Infection; Keratitis; Lesion; Meningitis; Modeling; Molecular; Mus; Neuraxis; Neurologic; Neurons; Outcome; Pathogenesis; Pathway interactions; Pattern; Peripheral; Process; Recurrence; Recurrent disease; Role; Sensory; Simplexvirus; Site; Source; Specificity; Spinal; Spinal Ganglia; Symptoms; System; Training; Trigeminal System; Urinary Retention; Viral; Viral Genome; Viral Proteins; Virus; Virus Diseases; Virus Latency; disease phenotype; improved; in vitro Model; in vivo; in vivo Model; latency associated transcript; latent infection; preference; prevent; public health relevance; skin lesion; transcription factor; viral DNA

DESCRIPTION (provided by applicant): The long-term goal is to compare the different mechanisms by which HSV1 and HSV2 establish latent infection and reactivate to cause recurrent disease, particularly the involvement of the autonomic nervous system (ANS) pathways in these processes. HSV1 and HSV2 have different patterns of latent infection and different patterns of recurrent disease. While autonomic neurons have been recognized as a site for HSV infection for many years, their contribution to recurrent viral disease has not been closely examined, and differences in autonomic infection may contribute to the clinical and molecular patterns that differentiate HSV1 and HSV2. The central hypothesis is that HSV1 and HSV2 are capable of differentially establishing latency in, and reactivating from, specific types of autonomic neurons to cause some portion of recurrent HSV disease, regulated in part by the latency-associated transcript (LAT). The objectives of this proposal are 1) to compare the preferential pathways by which HSV1 and HSV2 reach the central nervous system (sensory or autonomic pathways), by using biologically relevant primary neuronal culture Campenot chamber infection systems in vitro and a guinea pig infection model (both genital and ocular) in vivo; 2) to examine the capabilities of HSV1 and HSV2 to reactivate from autonomic neurons, using a Campenot chamber infection and reactivation model in vitro, by reactivating autonomic neurons from latently infected mice ex vivo, and by using a chemical sympathectomy model in vivo to determine if pathway ablation alters infection and reactivation patterns; and 3) to demonstrate that the latency-associated transcript (LAT) region of the HSV genome regulates autonomic neuron specificity for HSV1 and HSV2 productive infection, by using chimeric viruses in which the LAT region has been swapped between HSV1 and HSV2 in in vitro and in vivo infection models to determine if switching LAT regions also switches patterns of infection and reactivation, as well as using protein-DNA binding assays to determine the host or viral proteins that differentially interact with the LAT regions of HSV1 and HSV2. Results from these studies will contribute to the overall understanding of HSV pathogenesis and suggest auxiliary treatments to prevent reactivation specifically from autonomic neurons to improve clinical outcomes of HSV-related recurrent disease. Completion of these studies will also provide the basic foundation for future R01 funding.

描述（由申请人提供）：长期目标是比较HSV1和HSV2建立潜伏感染和重新激活引起复发性疾病的不同机制，特别是自主神经系统（ANS）通路在这些过程中的参与。HSV1和HSV2具有不同的潜伏感染模式和不同的复发疾病模式。虽然自主神经元多年来一直被认为是HSV感染的一个位点，但它们对复发性病毒性疾病的贡献尚未得到仔细研究，自主神经元感染的差异可能有助于区分HSV1和HSV2的临床和分子模式。核心假设是，HSV1和HSV2能够在特定类型的自主神经元中不同地建立潜伏期并重新激活，从而导致部分复发性HSV疾病，部分由潜伏期相关转录物（LAT）调节。本研究的目的是：1)比较HSV1和HSV2到达中枢神经系统的优先途径（感觉或自主神经途径），采用生物学相关的原代神经元培养体外Campenot室感染系统和豚鼠体内感染模型（包括生殖器和眼部）；2)通过体外Campenot室感染和再激活模型，在体外激活潜伏感染小鼠的自主神经元，以及在体内使用化学交感神经切除术模型来检测HSV1和HSV2从自主神经元重新激活的能力，以确定通路消融是否改变感染和再激活模式；3)在体外和体内感染模型中，利用嵌合病毒在HSV1和HSV2之间交换LAT区域，验证HSV基因组的潜伏期相关转录物（LAT）区域调节HSV1和HSV2生产感染的自主神经元特异性，以确定切换LAT区域是否也会切换感染和再激活模式。以及使用蛋白质- dna结合试验来确定宿主或病毒蛋白与HSV1和HSV2的LAT区相互作用的差异。这些研究的结果将有助于全面了解HSV的发病机制，并建议辅助治疗以防止自主神经元特异性再激活，以改善HSV相关复发性疾病的临床结果。这些研究的完成也将为未来的R01基金提供基础。