Neuro-immune interactions at the intestinal surface

肠道表面的神经免疫相互作用

基本信息

批准号：
10598074
负责人：
Daniel S Mucida
金额：
$ 51.95万
依托单位：
ROCKEFELLER UNIVERSITY
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 2024-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10598074
关键词：
Acceleration Afferent Neurons Bacterial Gastroenteritis Bacterial Infections Body Surface Cell Death Cell Separation Cells Central Nervous System Diseases Clinical Cues Data Disease Enteral Environment Exposure to Functional Gastrointestinal Disorders Gastrointestinal Motility Gastrointestinal tract structure Gene Expression Genetic Human Image Immune Immune system Impairment Infection Inflammasome Inflammation Inflammatory Bowel Diseases Injury Interneurons Interstitial Cell of Cajal Intestines Invaded Irritable Bowel Syndrome Macrophage Maintenance Modeling Molecular Motor Neurons Mus Myeloid Cells Myenteric Plexus Nervous System Neuroglia Neuroimmune Neurons Pathogenicity Pathology Pathway interactions Peristalsis Persons Physiological Processes Population Prevention Process Receptor Signaling Recording of previous events Recovery Reporting Resistance Role Salmonella infections Spinal Cord Surface Tissues beta-2 Adrenergic Receptors dietary enteric infection enteric pathogen gain of function gastrointestinal genetic approach gut inflammation gut microbiota helminth infection loss of function microbial microbiome microbiota microorganism antigen motility disorder nerve damage nervous system disorder neuroinflammation neuron loss pathogen prevent programs response secondary infection transcriptomics

项目摘要

Project Summary The gastrointestinal (GI) tract comprises the largest environmental interface of the body; its immune system is posed with the unique challenge of maintaining tolerance to dietary and microbial antigens while remaining poised to protect against pathogen invasion. Coordinated resistance and tolerance mechanisms serve to prevent pathogenic dissemination, limit excessive GI damage, and initiate recovery responses induced by pathogenic burden or injury. The GI tract hosts as many neurons (enteric-associated neurons, EANs) as the spinal cord and more immune cells than all other compartments together. EANs include sensory neurons, interneurons, and motor neurons with cell bodies within (intrinsic) or outside the intestine (extrinsic), which control a variety of functions within the GI tract. EANs are often targeted by enteric pathogens, resulting in functional gastrointestinal disorders post pathogen clearance. The clinical presentations of post-infectious enteric neuronal damage include unresolved low-grade intestinal inflammation, gastrointestinal motility impairment, and nerve damage. Nevertheless, the underlying mechanisms involved in infection–induced neuronal damage are incompletely understood. Our recent data indicates that murine enteric infection results in a rapid and persistent loss of iEANs, which is associated with prolonged gastrointestinal changes including intestinal dysmotility. However, infection history and microbiota composition can prevent iEAN loss or accelerate iEAN recovery, respectively; findings that may lead to a better understanding of human post-infectious IBS and additional disorders associated with EAN damage during inflammation. Imaging analyses suggested a subtype–specific neuronal loss upon Salmonella infection, and transcriptomics and genetic approaches indicated an iEAN cell death mechanism that is dependent on components of the inflammasome pathway. Depletion of intestinal muscularis macrophages (MMs), located in close proximity to enteric neurons, as well as targeting of β2-AR on myeloid cells, resulted in enhanced infection-induced neuronal loss, suggesting a functional role for a MM tissue protective program induced upon infection. Our observations suggest a functional role for neuron–macrophage interactions in limiting infection-induced neuronal damage or accelerating neuronal recovery, supporting the significance and impact of this proposal. We will characterize mechanisms underlying neuronal cell death post enteric infection with different pathogens (Aim 1). We will also to define how microbiota manipulations can rescue neuronal death post infection, possibly defining a role for specific bacterial species in this process (Aim 2). Finally, we will investigate the cellular and molecular immune mechanisms regulating neuronal loss during heterologous secondary infections (Aim3). By utilizing imaging, cell sorting–independent transcriptomics, single-cell approaches and genetic gain– and loss–of-function approaches, this proposal aims to characterize cellular and molecular components of neuro-immune crosstalk following enteric infections.

项目概要胃肠道 (GI) 是人体最大的环境界面，其免疫系统是面临着保持对饮食和微生物抗原的耐受性的独特挑战，同时保持准备好防止病原体入侵。协调的抵抗和耐受机制有助于预防。病原体传播，限制过度的胃肠道损伤，并启动由病原体引起的恢复反应胃肠道拥有与脊髓一样多的神经元（肠相关神经元，EAN）。比所有其他区室加起来还要多的免疫细胞包括感觉神经元、中间神经元和运动神经元的细胞体位于肠内（内在）或肠外（外在），控制着多种胃肠道内的功能通常是肠道病原体的目标，从而导致胃肠道功能受损。病原体清除后的疾病感染后肠神经元损伤的临床表现包括未解决的低度肠道炎症、胃肠动力障碍和神经损伤。然而，感染引起的神经元损伤的潜在机制尚不完全清楚。我们最近的数据表明，小鼠肠道感染会导致 iEAN 快速而持续地丧失，这与长期胃肠道变化有关，包括肠道蠕动障碍。病史和微生物群组成可以分别防止 iEAN 丢失或加速 iEAN 恢复；这可能有助于更好地了解人类感染后 IBS 以及与 IBS 相关的其他疾病炎症期间的 EAN 损伤表明亚型特异性神经元丢失。沙门氏菌感染、转录组学和遗传学方法表明 iEAN 细胞死亡机制依赖于肠道肌层巨噬细胞的炎症小体途径的成分。 (MM) 位于肠神经元附近，并且靶向骨髓细胞上的 β2-AR，导致感染引起的神经元损失增加，表明多发性骨髓瘤组织保护程序的功能作用我们的观察表明，神经元-巨噬细胞相互作用在感染中发挥着功能作用。限制感染引起的神经元损伤或加速神经元恢复，支持这一意义和我们将描述肠道感染后神经细胞死亡的机制。我们还将定义微生物群操作如何拯救神经死亡。感染后，可能会定义特定细菌种类在此过程中的作用（目标 2）。研究异源性过程中调节神经元丢失的细胞和分子免疫机制继发感染（Aim3）。通过利用成像、细胞分选独立的转录组学、单细胞。方法和遗传功能获得和丧失方法，该提案旨在表征细胞和肠道感染后神经免疫串扰的分子成分。