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

基本信息

批准号：
9175467
负责人：
MICHAEL D GERSHON
金额：
$ 37.15万
依托单位：
COLUMBIA UNIVERSITY HEALTH SCIENCES
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-08-01 至 2021-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9175467
关键词：
Abdominal Pain Adult Affect Animal Model Animals Attenuated Autonomic ganglion Axon Biopsy CD4 Positive T Lymphocytes Cavia Cell fusion Cell membrane Cells Chickenpox Chickenpox Vaccine Child Childhood Corticotropin-Releasing Hormone Country Cranial Nerves Cutaneous Cytoplasmic Vesicles Cytosol Data Detection Diagnosis Disease Dyes Endoscopic Biopsy Endoscopy Enteral Enteric Nervous System Epidermis Event Exanthema Ganglia Gene Expression Genes Herpes zoster disease Herpesvirus 1 Herpesvirus Type 3 Histologic Home environment Human Hyperalgesia Immigrant Immunocompromised Host Immunologic Deficiency Syndromes Immunosuppression In Vitro Individual Infection Injectable Interferons Intestines Label Latent Virus Latent virus infection phase Lead Lesion Life Life Cycle Stages Lipids Lymphocyte Lytic Lytic Phase Methods Modeling Molecular Morbidity - disease rate Nervous system structure Neurons Oropharyngeal Pain Pathogenesis Pathologic Pathway interactions Patients Population Postherpetic neuralgia Primary Infection Proteins Public Health Receptor Protein-Tyrosine Kinases Research Saliva Salivary Signal Transduction Skin Stress Suggestion Surrogate Markers Syndrome T-Lymphocyte Tacrolimus Techniques Testing Tissues Tonsil Transcript Vaccination Vaccines Viral Genome Viremia Virus Diseases Visceral Zoster Vaccine allodynia anterograde transport dodecyldimethylamine oxide exosome experience immunosuppressed in vivo intravenous injection latent infection mortality nanoparticle novel pathogen reactivation from latency response secondary infection spinal nerve posterior root tool transmission process viral DNA virtual

项目摘要

Summary Varicella zoster virus (VZV) famously establishes latency in dorsal root (DRG) and cranial nerve (CNG) ganglia after its disseminated primary infection (varicella; chickenpox). VZV can reactivate from latency to cause a localized secondary infection (zoster; shingles). VZV latency, however, is not restricted to DRG/CNG; latent VZV is present in the enteric nervous system (ENS) in virtually everyone who has experienced varicella or received the live attenuated varicella vaccine. VZV reactivates in the ENS (enteric zoster) as it does in DRG/CNG but because enteric neurons lack cutaneous projections, enteric zoster occurs without rash and may be an unsuspected cause of GI disease. A major hindrance to research on VZV has been the absence of a suitable animal model. To overcome this difficulty, we demonstrated that VZV infects, establishes latency, and reactivates in isolated guinea pig enteric neurons; moreover, VZV infects guinea pigs in vivo, establishes latent infection in their DRG/CNG and ENS, and can be reactivated to produce a secondary infection resembling disseminated zoster. VZV can be transported to the ENS from infected epidermis in axons of DRG neurons that project both to the skin and gut but intravenous injection of VZV- infected T lymphocytes establishes latency in almost every ENS and DRG neuron of the animal. It had been thought that latent infection of enteric neurons could be established by cell-free VZV (VZVCF) but not by cell associated VZV (VZVCA). VZV-infected lymphocytes, however, do not secrete VZVCF but they are able transmit infection to neurons in vitro and in vivo that is exclusively latent. Aim 1 tests hypotheses that: (i) evanescent cell fusion is responsible for transmission of VZV from lymphocytes to neurons; (ii) exosomes derived from VZV-infected lymphocytes introduce stimulator of interferon genes (STING) to neurons; (iii) STING induces a type1 interferon response in neurons that inhibits VZV proliferation and facilitates establishment of latency. Aim 2 tests hypotheses that: (i) VZV-infected lymphocytes can induce a varicella- like primary infection in guinea pigs if immunosuppression and stress precedes infection; (ii) restriction of VZV latency allows localized reactivations to be confined to gut or skin; (iii) continuous activation of a receptor tyrosine kinase transduction pathway, similar to that in HSV1 reactivation in sympathetic neurons, regulates latent VZV genomes in enteric neurons. Aim 3 directly tests the hypothesis that salivary VZV DNA in patients with unexplained abdominal pain severe enough to warrant endoscopy and biopsy is a marker of enteric zoster. To validate this idea with a tissue diagnosis, we will analyze VZV DNA in saliva and GI mucosal expression of gE transcripts and protein which would indicate productive VZV infection (enteric zoster) in the bowel. This research makes the first use a novel animal model in which VZV reactivates in vivo and the first application of a non-invasive technique to identify patients that might have enteric zoster.

概括水痘带状疱疹病毒（VZV）著名地建立了背根（DRG）和颅神经（CNG）的潜伏期神经节在其传播原发性感染后（水痘；水痘）。 VZV可以从潜伏期重新激活引起局部继发感染（带状疱疹；带状疱疹）。但是，VZV延迟不限于 DRG/CNG;潜在的vzv存在于肠神经系统（ENS）中，几乎每个人经历过的水疗或接收了活的衰减水痘疫苗。 VZV在ENS中重新激活（肠带Zoster）就像在DRG/CNG中一样没有皮疹，可能是胃肠道疾病的无引起的原因。 VZV研究的主要障碍是没有合适的动物模型。为了克服这一困难，我们证明了VZV感染，建立潜伏期，并在孤立的豚鼠肠神经元中重新激活；此外，VZV感染了几内亚猪体内，在其DRG/CNG和ENS中建立潜在感染，可以重新激活以产生A 继发感染类似于传播带状吊带。 VZV可以从感染中传输到ENS 表皮在DRG神经元的轴突中，这些神经元的轴突均投射到皮肤和肠道，但静脉注射VZV- 受感染的T淋巴细胞几乎在动物的每个ENS和DRG神经元中确定潜伏期。曾经认为可以通过无细胞的VZV（VZVCF）建立肠神经元的潜在感染，但不能通过细胞建立相关的VZV（VZVCA）。但是，VZV感染的淋巴细胞不分泌VZVCF，但它们能够在体外和体内将感染传递到神经元，这仅是潜在的。 AIM 1测试假设：（i） Evanescent细胞融合负责将VZV从淋巴细胞传播到神经元。（ii）外泌体源自VZV感染的淋巴细胞将干扰素基因（STING）的刺激剂引入神经元。（iii） STING诱导型神经元中的1型干扰素反应抑制VZV增殖并促进建立潜伏期。 AIM 2测试假设：（i）VZV感染的淋巴细胞可以诱导水痘例如，如果免疫抑制和压力在感染之前，豚鼠的原发性感染也是如此；（ii）限制 VZV潜伏期允许将局部重新激活局限于肠道或皮肤。（iii）连续激活受体酪氨酸激酶转导途径，类似于交感神经元中HSV1重新激活的途径，调节肠神经元中的潜在VZV基因组。 AIM 3直接检验了唾液VZV DNA的假设在无法解释的腹痛的患者中，严重严重以保证内窥镜检查，活检是进入肠网绳。为了通过组织诊断来验证这一想法，我们将分析唾液和GI中的VZV DNA GE转录物和蛋白质的粘膜表达，这将表明生产性VZV感染（肠带状疱疹）在肠道中。这项研究使第一次使用新型动物模型，其中VZV在体内重新激活以及第一次应用非侵入性技术来识别可能具有肠goster的患者。