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: 8224181
• 负责人: Andrea S Bertke
• 金额: $ 16.2万
• 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 2015-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8224181
• 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建立潜在感染并重新激活以引起复发性疾病的不同机制，尤其是在这些过程中自主神经系统（ANS）途径的参与。 HSV1和HSV2具有不同的潜在感染模式和复发性疾病的不同模式。尽管自主神经元已被认为是HSV感染的部位多年，但它们对复发病毒疾病的贡献尚未受到仔细检查，并且自主神经感染的差异可能有助于与HSV1和HSV2区分开的临床和分子模式。中心假设是HSV1和HSV2能够从特定类型的自主神经元中差异化并重新激活潜伏期，从而引起一定部分复发性HSV疾病，部分受到延迟相关的转录本（LAT）的调节。该提案的目标是1）比较HSV1和HSV2到达中枢神经系统（感觉或自主教途径）的优先途径，通过使用生物学上相关的原发性神经元培养Campenot Campenot Campenot室内感染系统和豚鼠症状感染模型（颗粒和眼球）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蛋白-DNA结合测定法确定与HSV1和HSV2差异相互作用的宿主或病毒蛋白。这些研究的结果将有助于对HSV发病机理的总体理解，并提出辅助处理，以防止自主神经元特别反应，以改善与HSV相关的复发性疾病的临床结果。这些研究的完成还将为未来R01资金提供基础。