Systemic Neurotropic virus infection effects on GI Dysmotility

全身嗜神经病毒感染对胃肠道运动障碍的影响

• 批准号: 10611909
• 负责人: Michael S Diamond
• 金额: $ 66.5万
• 依托单位: CLEVELAND CLINIC LERNER COM-CWRU
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-07-01 至 2025-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10611909
• 关键词: Acute; Address; Adoptive Cell Transfers; Adoptive Transfer; Affect; Agonist; Anatomy; Animal Model; Animals; Antibiotics; Antibodies; Antigens; Area; CD8-Positive T-Lymphocytes; Cells; Chronic; Chronic Phase; Clinical; Complex; Data; Defect; Development; Diamond; Disease; Disease remission; Enteral; Enteric Nervous System; Enteroendocrine Cell; Experimental Models; Exposure to; Flavivirus; Flow Cytometry; Functional disorder; Gastrointestinal Motility; Gastrointestinal Transit; Gastrointestinal tract structure; Germ-Free; Goals; Health; Hormones; Human; Immune; Immune response; Immunity; Impairment; Individual; Inflammatory; Injury; Intervention; Intestinal Pseudo-Obstruction; Intestines; Knockout Mice; Measurement; Mechanics; Mediating; Medical; Modeling; Mus; Myenteric Plexus; Nature; Nervous System Trauma; Neuroglia; Neuronal Injury; Neurons; Neurosecretory Systems; Obstruction; Ovalbumin; Parenteral Nutrition; Pathogenicity; Patients; Phase; Phenotype; Publishing; RNA Viruses; Receptor Signaling; Relapse; Role; Serotonergic System; Serotonin; Serotonin Receptors 5-HT4; Signal Transduction; Small Intestines; Stimulus; Stretching; Structure; Submucous Plexus; T cell infiltration; T cell response; T-Lymphocyte; T-Lymphocyte Subsets; Testing; Therapeutic Intervention; Transgenic Organisms; Transplantation; Tropism; Viral; Virus Diseases; West Nile viral infection; West Nile virus; Work; acute infection; cell motility; cell type; effector T cell; enteric virus infection; experimental study; functional restoration; gastrointestinal; gut microbiota; improved; lymphocyte trafficking; microbial; microbiota; motility disorder; mouse model; neuron loss; neurotropic; neurotropic virus; novel strategies; novel therapeutic intervention; prevent; receptor; reconstitution; response; serotonin receptor; system architecture; therapeutic evaluation

ABSTRACT Dysfunction and/or degeneration of the enteric nervous system (ENS) can cause gastrointestinal tract dysmotility. One particularly severe and clinically challenging dysmotility disorder in humans is chronic intestinal pseudo-obstruction (CIPO). The most effective current therapies for CIPO are parenteral nutrition and small bowel transplantation. New animal models to develop and test therapeutic options for CIPO are a substantial unmet need in this area. To this end, we found that mice infected with RNA viruses of the Flavivirus genus including West Nile (WNV) demonstrate features of CIPO that may help reveal new modes of treatment. WNV infects enteric neurons in the submucosal and myenteric plexus of the GI tract of mice, resulting in T cell infiltration, injury and cell death of neurons, and decreased bowel motility. The diminished bowel motility occurs in the absence of any gross anatomic or mechanical obstructive defects. In the chronic phase, mice clear virus infection but still have sustained GI dysmotility that resolves slowly over a few months. Remarkably, a relapse of GI dysmotility can be triggered in the convalescent phase after WNV-infected animals are exposed to unrelated inflammatory stimuli. To explain the relapsing/remitting nature of this disease course, we propose a model whereby structural and function defects in the ENS in response to WNV infection and the resultant immune response affect an enteric neuroendocrine-immune (NEI) circuit that, along with the microbiota, becomes chronically dysregulated. In this proposal, we will test novel approaches to correct that dysregulated NEI circuit by modulating: (i) CD8+ T cell responses that induce acute injury of enteric neurons following WNV infection; (ii) the microbiota, which becomes dysregulated following WNV infection and can transfer the dysmotility phenotype to uninfected mice and (iii) neuroendocrine hormones, specifically the 5-HT serotonergic system, which appears diminished in the WNV model. Our goal is to use this mouse model to dissect the underlying regulatory mechanisms of the NEI circuit, elucidate the interplay between the various components of the NEI circuit and the microbiota, and understand how it malfunctions in response to viral infection. Our group will define mechanistically how perturbation of the enteric NEI circuit following WNV infection results in acute, chronic and relapsing GI dysmotility. This information may facilitate the development of agents that prevent damage to or restore the function of the enteric NEI circuit and the microbiota following systemic neurotropic virus infection, which could form the basis of therapies for CIPO and related bowel motility disorders.

摘要 肠神经系统（ENS）的功能障碍和/或变性可引起胃肠道疾病， 运动障碍人类中一种特别严重且具有临床挑战性的运动障碍是慢性的 假性肠梗阻（锡波）。目前对锡波最有效的疗法是肠外营养， 小肠移植开发和测试锡波治疗方案的新动物模型是一种新的方法。 这一领域大量未满足的需求。为此，我们发现，感染了RNA病毒的黄病毒 包括西尼罗河病毒（WNV）在内的许多其他属的研究表明，锡波的特征可能有助于揭示新的治疗模式。 WNV感染小鼠胃肠道粘膜下和肌间神经丛中的肠神经元，导致T细胞增殖。 神经元的浸润、损伤和细胞死亡，以及肠蠕动降低。肠蠕动减弱 在没有任何大体解剖或机械阻塞性缺陷的情况下。在慢性阶段，小鼠清除病毒 感染，但仍有持续的胃肠道动力障碍，在几个月内缓慢解决。值得注意的是， 在WNV感染的动物暴露于以下物质后的恢复期， 无关的炎症刺激。为了解释这种疾病过程的复发/缓解性质，我们提出了一个 模型，其中结构和功能缺陷的ENS在响应西尼罗河病毒感染和由此产生的 免疫应答影响肠神经内分泌免疫（NEI）回路，其沿着微生物群， 变得长期失调在这项提案中，我们将测试新的方法来纠正这种失调， NEI回路通过调节：（i）诱导WNV后肠神经元急性损伤的CD 8 + T细胞应答 感染;（ii）微生物群，其在西尼罗河病毒感染后变得失调，并且可以将微生物群转移到西尼罗河病毒。 （iii）神经内分泌激素，特别是5-HT肾上腺素能受体， 系统，这似乎在WNV模型减少。我们的目标是用这个小鼠模型来解剖 NEI电路的潜在调节机制，阐明了各种组件之间的相互作用 NEI电路和微生物群，并了解它如何在应对病毒感染时发生故障。我们 研究组将从机制上定义西尼罗河病毒感染后肠道NEI回路的扰动如何导致 急性、慢性和复发性胃肠道动力障碍。这些信息可以促进开发 防止对肠道NEI回路和微生物群的损害或恢复其功能， 嗜神经病毒感染，这可能成为锡波和相关肠动力治疗的基础 紊乱

项目成果

Ablation of cDC2 development by triple mutations within the Zeb2 enhancer.

• DOI: 10.1038/s41586-022-04866-z
• 发表时间: 2022-07
• 期刊: Nature
• 影响因子: 64.8

Helminth-virus interactions: determinants of coinfection outcomes.

• DOI: 10.1080/19490976.2021.1961202
• 发表时间: 2021-01
• 期刊: Gut microbes
• 影响因子: 12.2
• 作者: Desai P;Diamond MS;Thackray LB
• 通讯作者: Thackray LB