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: 10190929
• 负责人: Michael S Diamond
• 金额: $ 69.01万
• 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 2024-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10190929
• 关键词: Acute; Address; Adoptive Cell Transfers; Adoptive Transfer; Affect; Agonist; Anatomy; Animal Model; Animals; Antibiotics; Antibodies; Antigens; Antiviral Agents; Area; CD8-Positive T-Lymphocytes; Cecum; Cells; Chronic; Chronic Phase; Clinical; Complex; Data; Defect; Development; Diamond; Disease; 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; Infection; 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 response; T-Lymphocyte; T-Lymphocyte Subsets; Testing; Therapeutic Intervention; Transgenic Organisms; Transplantation; Tropism; Tumor-infiltrating immune cells; Virus Diseases; West Nile virus; Work; acute infection; base; 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.

抽象的 肠神经系统 (ENS) 功能障碍和/或退化可导致胃肠道 运动障碍。人类的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（CIPO）。目前 CIPO 最有效的治疗方法是肠外营养和 小肠移植。开发和测试 CIPO 治疗方案的新动物模型是 该领域存在大量未满足的需求。为此，我们发现小鼠感染了黄病毒RNA病毒 包括西尼罗河 (WNV) 在内的多种属证明了 CIPO 的特征，这可能有助于揭示新的治疗模式。 WNV 感染小鼠胃肠道粘膜下层和肌间神经丛的肠神经元，产生 T 细胞 神经元浸润、损伤和细胞死亡，以及肠蠕动下降。肠蠕动减弱 在没有任何严重的解剖或机械阻塞缺陷的情况下。在慢性期，小鼠清除病毒 感染，但仍然存在持续的胃肠道运动障碍，并会在几个月内缓慢消退。值得注意的是，复发 感染西尼罗河病毒的动物接触到后恢复期可能会引发胃肠道运动障碍 无关的炎症刺激。为了解释这种疾病病程的复发/缓解性质，我们提出了 ENS 结构和功能缺陷响应 WNV 感染的模型以及由此产生的结果 免疫反应影响肠道神经内分泌免疫（NEI）回路，该回路与微生物群一起， 变得长期失调。在本提案中，我们将测试纠正失调的新方法 NEI 回路通过调节：(i) CD8+ T 细胞反应诱导 WNV 后肠道神经元的急性损伤 感染; (ii) 微生物群，在西尼罗河病毒感染后变得失调，并且可以转移 未感染小鼠的运动障碍表型和 (iii) 神经内分泌激素，特别是 5-HT 血清素能 系统，该系统在 WNV 模型中似乎有所减弱。我们的目标是使用这个小鼠模型来剖析 NEI 回路的潜在调节机制，阐明各个组件之间的相互作用 了解 NEI 回路和微生物群，并了解它如何因病毒感染而发生故障。我们的 该小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运动障碍。这些信息可能会促进代理的开发 预防系统性损伤或恢复肠道 NEI 回路和微生物群的功能 嗜神经病毒感染，这可能构成 CIPO 和相关肠蠕动治疗的基础 失调。