VZV in the enteric nervous system: pathogenesis and consequences

肠神经系统中的水痘带状疱疹病毒：发病机制和后果

• 批准号: 8704927
• 负责人: MICHAEL D GERSHON
• 金额: $ 34.8万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-08-01 至 2016-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8704927
• 关键词: Afferent Neurons; Animal Model; Animals; Axon; Axonal Transport; Behavior Control; Blood; Brain; Breathing; Cavia; Cells; Chickenpox; Chickenpox Vaccine; Chronic; Coculture Techniques; Complex; Cranial Nerves; Cutaneous; Differential Diagnosis; Disease; Dorsal; Enteral; Enteric Nervous System; Enterocytes; Epithelium; Exanthema; Exocytosis; Fibroblasts; Frequencies; Functional disorder; Ganglia; Gastrointestinal Motility; Gastroparesis; Growth; Herpes zoster disease; Herpesvirus Type 3; Human; Immunity; Immunocompromised Host; Immunologic Deficiency Syndromes; In Situ; In Vitro; Individual; Infection; Infection prevention; Inflammation; Inflammatory Bowel Diseases; Injection of therapeutic agent; Intestinal Pseudo-Obstruction; Intestines; Investigation; Irritable Bowel Syndrome; Label; Life; Link; Lymphocyte; Lytic; Lytic Phase; Mus; Nerve; Nerve Block; Nerve Fibers; Neurons; Open Reading Frames; Operative Surgical Procedures; Paint; Pathogenesis; Peripheral Blood Mononuclear Cell; Phase; Proteins; Reverse Transcriptase Polymerase Chain Reaction; Route; Sensory Nerve Endings; Severities; Simplexvirus; Skin; Spinal Cord; Sympathectomy; Synapses; T-Lymphocyte; Testing; Tracer; Travel; Vesicle; Viral; Viral Proteins; Viremia; Virion; Virus; Virus Diseases; Virus Latency; Viscera; afferent nerve; base; design; experience; immunocytochemistry; in vitro Model; in vivo; intradermal injection; keratinocyte; killings; late endosome; latent infection; man; mutant; particle; preference; protein expression; research study; secondary infection; spinal nerve posterior root; true blue; viral DNA; visceral afferent nerve

DESCRIPTION (provided by applicant): The enteric nervous system (ENS) can control the behavior of the bowel without input from brain or spinal cord. A functioning ENS is essential for life and, when abnormal, causes discomfort and may contribute to the pathophysiology or severity of disorders of gastrointestinal motility, secretion, and inflammation. We have recently discovered that varicella zoster virus (VZV) establishes latency within human enteric neurons in most individuals who have experienced natural varicella or received varicella vaccine. VZV, moreover, has been linked to the occurrence of lethal pseudoobstruction in immunocompromised individuals. Neither the route by which VZV gains access to the ENS, nor the frequency or consequences of its reactivation in enteric neurons ("enteric zoster") has previously been explored. The current proposal is designed to test the hypotheses that transport in visceral afferent nerves conducts VZV to the ENS, that cell- free virions establish latency in enteric neurons, and that the non-structural VZV ORF61 protein must be expressed in neurons to enable VZV to manifest lytic infection or to reactivate from latency. Although VZV displays a marked preference for human cells, we have developed animal models that permit VZV infection of the ENS to be studied in vitro and in vivo. Depending on conditions, VZV recapitulates latent, lytic, and reactivating infection in enteric neurons isolated from guinea pigs or mice and, when introduced to the bowel, VZV establishes latency in the guinea pig ENS in situ. The proposal has 3 specific aims: (1) Can VZV travel from the skin to the ENS in sensory nerve fibers? Preliminary studies have identified neurons in dorsal route ganglia that project both to skin and gut. We will determine whether latent infection is established in the ENS when VZV is introduced to the skin and whether VZV-infected nerve terminals release infectious cell-free VZV that crosses synaptic gaps to transfer latent infection to target neurons. (2) Can a viremia establish latent VZV infection of enteric neurons? We will determine whether VZV-infected T lymphocytes release infectious cell-free VZV and whether they can establish latency directly in enteric neurons or indirectly via infections of the mucosal epithelium or skin. Preliminary studies have shown that VZV DNA is present in guinea pig enteric neurons following the iv injection of VZV-infected peripheral blood mononuclear cells. (3) Is VZV ORF61 protein expression necessary for the manifestation of lytic infection in enteric neurons? We will study the ability of a VZV mutant that lacks ORF61 to establish lytic infection of enteric neurons or reactivate from latency. The significance of understanding VZV infection of the ENS is enhanced by the possibility that unsuspected reactivation of VZV in enteric neurons might contribute to the pathogenesis of GI disorders such as irritable bowel syndrome, inflammatory bowel disease, idiopathic gastroparesis, and chronic intestinal pseudoobstruction.

描述（由申请人提供）：肠神经系统（ENS）可以在没有来自大脑或脊髓的输入的情况下控制肠道的行为。功能正常的ENS对生命至关重要，当异常时，会引起不适，并可能导致胃肠道运动、分泌和炎症疾病的病理生理学或严重程度。我们最近发现，水痘带状疱疹病毒（VZV）建立潜伏期内的人肠神经元在大多数人谁经历了自然水痘或接受水痘疫苗。此外，VZV与免疫功能低下个体中致命性假性梗阻的发生有关。VZV进入ENS的途径，以及其在肠神经元中再激活的频率或后果（“肠带状疱疹”）以前都没有被探索过。目前的提议旨在测试以下假设：内脏传入神经中的转运将VZV传导至ENS，无细胞病毒粒子在肠神经元中建立潜伏期，以及非结构性VZV ORF 61蛋白必须在神经元中表达以使VZV能够表现出裂解性感染或从潜伏期重新激活。虽然VZV显示出对人类细胞的明显偏好，但我们已经开发出允许VZV感染ENS的动物模型，以在体外和体内进行研究。根据条件，VZV重演从豚鼠或小鼠分离的肠神经元中的潜伏性、溶解性和再活化感染，并且当引入肠时，VZV在豚鼠ENS中原位建立潜伏期。该提案有3个具体目标：（1）VZV能否从皮肤到感觉神经纤维中的ENS旅行？初步研究已经确定了背路神经节中的神经元，它们可以投射到皮肤和肠道。我们将确定当VZV被引入皮肤时是否在ENS中建立潜伏感染，以及VZV感染的神经末梢是否释放感染性无细胞VZV，其穿过突触间隙将潜伏感染转移到靶神经元。(2)病毒血症是否能引起肠神经元的潜伏性VZV感染？我们将确定VZV感染的T淋巴细胞是否释放感染性无细胞VZV，以及它们是否可以直接在肠神经元中建立潜伏期或间接通过粘膜上皮或皮肤的感染。初步研究表明，VZV DNA存在于豚鼠肠神经元静脉注射VZV感染的外周血单核细胞。(3)VZV ORF61蛋白表达是否是肠神经元溶解性感染的表现所必需的？我们将研究缺乏ORF61的VZV突变体建立肠神经元裂解性感染或从潜伏期重新激活的能力。肠神经元中VZV的意外再激活可能导致胃肠道疾病（如肠易激综合征、炎症性肠病、特发性胃轻瘫和慢性假性肠梗阻）的发病机制，这一可能性增强了理解ENS VZV感染的意义。