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

基本信息

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
项目类别：
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

项目摘要

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）的功能障碍和/或变性会引起胃肠道运动障碍。人类特别严重且在临床上具有挑战性的运动障碍障碍是慢性肠道伪孔（CIPO）。 CIPO最有效的当前疗法是肠胃外营养和小肠移植。开发和测试CIPO治疗选择的新动物模型是该领域的大量未满足需求。为此，我们发现感染了黄病毒的RNA病毒的小鼠包括西尼罗河（WNV）在内的属展示了密码的特征，可能有助于揭示新的治疗方式。 WNV感染小鼠胃肠道的粘膜粘膜和肌丛中的肠神经元，导致T细胞神经元的浸润，损伤和细胞死亡，并降低了肠运动。肠运动发生降低在没有任何总体解剖或机械阻塞性缺陷的情况下。在慢性期，小鼠清除病毒感染，但仍具有持续的胃肠道不一致，几个月内可以缓慢解决。值得注意的是，复发 WNV感染动物暴露于无关的炎症刺激。为了解释这种疾病病程的复发/恢复性质，我们提出了一个响应WNV感染的ENS中的结构和功能缺陷的模型和最终的功能缺陷免疫反应会影响肠神经内分泌 - 免疫（NEI）电路，该电路与微生物群一起长期失调。在此提案中，我们将测试新方法以纠正失调通过调节：（i）CD8+ T细胞反应，诱导肠神经元的急性损伤WNV 感染; （ii）微生物群在WNV感染后会失调，可以转移对未感染小鼠和（iii）神经内分泌激素的运动型表型，特别是5-HT血清素能系统，在WNV模型中似乎减少了。我们的目标是使用此鼠标模型剖析 NEI回路的基本调节机制，阐明了各个组件之间的相互作用 NEI回路和微生物群的，并了解其对病毒感染的响应方式。我们的组将从机械上定义WNV感染后肠NEI电路的扰动如何导致急性，慢性和复发性胃肠道失调。这些信息可能促进代理商的发展防止损坏或恢复全身后肠Nei电路和微生物群的功能神经性病毒感染，这可能构成CIPO和相关肠运动疗法的基础疾病。