VZV in the enteric nervous system: pathogenesis and consequences

总结 水痘带状疱疹病毒（VZV）在背根（DRG）和脑神经（CNG）中建立潜伏期 神经节后，其传播的主要感染（水痘;水痘）。VZV可以从延迟重新激活， 引起局部的继发感染（带状疱疹）。然而，VZV延迟不限于 DRG/CNG;潜伏性VZV存在于肠神经系统（ENS）中，几乎每个人都有 经历水痘或接受水痘减毒活疫苗。VZV在ENS（肠道）中重新激活 带状疱疹），如在DRG/CNG中一样，但由于肠神经元缺乏皮肤投射， 没有皮疹，可能是胃肠道疾病的意外原因。VZV研究的一个主要障碍是 缺乏合适的动物模型。为了克服这个困难，我们证明了VZV感染， 建立潜伏期，并在分离的豚鼠肠神经元中重新激活;此外，VZV感染豚鼠 猪体内，在其DRG/CNG和ENS中建立潜伏感染，并且可以重新激活以产生 类似播散性带状疱疹的继发感染。VZV可以从感染者转移到ENS DRG神经元轴突中的表皮投射到皮肤和肠道，但静脉注射VZV- 感染的T淋巴细胞在动物的几乎每个ENS和DRG神经元中建立潜伏期。已经 认为无细胞VZV（VZVCF）可以建立肠神经元的潜伏感染，而细胞VZVCF不能建立肠神经元的潜伏感染 相关VZV（VZVCA）。然而，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，这是完全潜伏的。目标1检验以下假设：（i） 渐逝细胞融合负责VZV从淋巴细胞向神经元的传递;（ii）外泌体 来源于VZV感染的淋巴细胞，将干扰素基因刺激物（STING）引入神经元;（iii） STING诱导神经元中的1型干扰素应答，其抑制VZV增殖并促进VZV增殖。 建立潜伏期。目的2检验以下假设：（i）VZV感染的淋巴细胞可诱导水痘- 如豚鼠的原发性感染，如果免疫抑制和应激先于感染;（ii）限制 VZV潜伏期允许局限于肠道或皮肤的局部再激活;（iii）持续激活的VZV潜伏期， 受体酪氨酸激酶转导途径，类似于HSV 1在交感神经元中的再激活， 调节肠神经元中潜伏的VZV基因组。目的3直接验证唾液VZV DNA 在不明原因腹痛严重到足以保证内镜检查和活检的患者中， 肠带状疱疹为了用组织诊断来验证这一想法，我们将分析唾液和胃肠道中的VZV DNA， 粘膜表达gE转录物和蛋白质，这将表明生产性VZV感染（肠 带状疱疹）。这项研究首次使用了一种新的动物模型，其中VZV在体内重新激活 以及首次应用非侵入性技术来识别可能患有肠道带状疱疹的患者。

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.