Campylobacter jejuni Mediated Autoimmune Neuropathy in Hu-microbiota Mouse Model

Hu 微生物群小鼠模型中空肠弯曲菌介导的自身免疫性神经病

基本信息

批准号：
8026704
负责人：
LINDA S. MANSFIELD
金额：
$ 28.3万
依托单位：
MICHIGAN STATE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-08-15 至 2015-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8026704
关键词：
Acute Affect Animal Model Antibodies Area Ataxia Autoantibodies Autoimmune Diseases Autoimmune Process Autoimmune Responses Autoimmunity Bacteria Bacterial Gastroenteritis Binding Bystander Effect Campylobacter infection Campylobacter jejuni Cells Characteristics Communities Complement Developed Countries Development Diplopia Disease Ensure Enteral Epitopes Eye Functional disorder Future GD1a ganglioside Gangliosides Gap Junctions Genes Genetic Polymorphism Genotype Germ-Free Goals Guanine Nucleotide Dissociation Inhibitors Guillain-Barré Syndrome Human Immune response Immunoglobulin G Inbred Strains Mice Incidence Individual Infection Interleukin-10 Interleukin-12 Interleukin-17 Interleukin-6 Lead Left Lesion Life Limb structure Mammals Mediating Membrane Methodology Microbe Miller Fisher Syndrome Modeling Molecular Mimicry Motor Motor Neurons Mus Muscle Nausea Nerve Neurologic Neuropathy Non obese Oligosaccharides Ophthalmoplegia Oral Outcome Paralysed Pathogenesis Pathway interactions Patients Peripheral Nerves Pharmaceutical Preparations Phase Phenotype Predisposition Prevention Productivity Proteins Reactive Arthritis Reflex action Research Resources Role Sampling Screening procedure Secondary to Signal Transduction Single-Blind Method Site T-Lymphocyte Tremor Validation Variant Water Work afferent nerve autoreactive T cell bean cytokine data modeling disability enteric pathogen foodborne foodborne pathogen gastrointestinal improved innovation interleukin-23 microbial microbial community microbiome microorganism mouse model nervous system disorder neuromuscular oral infection prebiotics response therapy development toll-like receptor 4

项目摘要

The incidence of foodborne disease due to Campylobacter jejuni remains very high woridwide. Serious disease sequelae can follow gastrointesfinal (Gl) infections with C. jejuni. The acute neuropathies Guillain Barre Syndrome (GBS) and Miller Fisher Syndrome (MFS) are autoimmune conditions associated with recent Campy/o/jacter infection. GBS is the worid's leading cause of acute neuromuscular paralysis. 5% of GBS patients die; 15-20% are left with life-long disability. Our long-term goal is to understand the mechanisms that initiate autoimmunity secondary to C.ye/un/infection. Our short-term goal in this proposal is to further develop murine models of GBS and MFS to allow understanding of how infection with particular C. jejuni strains leads to inifiafion of autoimmunity. Eariy work by our group showed that autoantibodies and neurological disease develop spontaneously in Non-Obese Diabefic (NOD) WT, NOD IL-10-/- and NOD B7- 2-1- mice after oral infection with C. jejuni strains from GBS patients. Some infected mice of all genotypes had autoreactive IgGI anfibodies directed against gangliosides GDI a and GM1 and displayed a neurological phenotype characteristic of motor neuron dysfunction with flaccid limbs. C57BL/6 IL-IO''- mice infected with a C. jejuni MFS strain developed neurological disease with tremors and asymmetric hind limb weakness. Mice colonized with human fecal samples validated in Area 1 have the potenfial to improve these murine models. Our overall hvpothesis is that murine model(s) with a "humanized" microbiome develop spontaneous autoimmune sequelae secondary to C. jejuni infecfion with strains with class A LOS. Our Specific Aims are to: (1) Characterize definitively the neurological signs and disease lesions associated with GBS and MFS in murine models; (2) Determine whether autoimmune sequelae vary with C. jejuni LOS profiles and LOS genes; (3) Characterize the role of complement in C. ye/t/n/-induced MFS lesions; (4) Determine whether innate responses and adaptive responses mediate GBS and MFS in murine models; (5) Determine whether autoantibody or autoreactive T cells transfer the response to naive mice; and (6) Determine effects of (Hu) microbiota on murine host innate, adaptive and autoimmune responses in the presence and absence of three pathotypes of Campylobacter jejuni. These models can be used to dissect mechanisms of autoimmunity and to serve as treatment and prevention surrogates for GBS and MFS patients.

空肠弯曲杆菌引起的食源性疾病的发生率仍然很高。严重的疾病后遗症可以跟随胃肠局（GL）感染J. jejuni。急性神经病Guillain Barre综合征（GBS）和Miller Fisher综合征（MFS）是与最近的CAMPY/O/JACTER感染相关的自身免疫性疾病。 GBS是急性神经肌肉麻痹的主要原因。 5％的GBS患者死亡； 15-20％的残疾剩下。我们的长期目标是了解启动c.ye/un/infection继发自身免疫的机制。我们在该提案中的短期目标是进一步开发GB和MFS的鼠模型，以了解如何感染特定的空肠菌菌株，导致自身免疫性的侵害。我们小组的耳朵工作表明，自身抗体和神经系统疾病在非肥胖腹膜腹膜内（nod）WT，nod IL-10 - / - 和点头B7-- 口服梭菌菌株后，2-1-小鼠来自GBS患者。一些所有基因型的感染小鼠具有针对神经节剂GDI A和GM1的自动反应性IgGI肌动物，并显示出具有松软四肢的运动神经元功能障碍的神经表型的特征。 C57BL/6 IL-io'' - 感染了J. jejuni MFS菌株的小鼠患有震颤和不对称后肢无力的神经系统疾病。用1.区域验证的人类粪便样品定殖的小鼠具有改善这些鼠模型的能力。我们的总体HVPothesis是，具有“人性化”微生物组的鼠模型会发展为自发性自身免疫后遗症，其继发于J. jejunic。c.c。c.c。c. c.c。c.c。c.c。slavea class a class a class a class los。我们的具体目的是：（1）明确表征与GB和MFS相关的神经系统症状和疾病。鼠模型；（2）确定自身免疫后遗症是否随圆柱体LOS谱和LOS基因而变化；（3）表征补体在C. ye/t/n/n/诱导的MFS病变中的作用；（4）确定先天反应和自适应反应是否介导了鼠模型中的GB和MF；（5）确定自身抗体或自动反应性T细胞是否转移对天真小鼠的反应；（6）在存在和不存在三种病原体空肠病原体的情况下，（HU）微生物群对鼠宿主先天，适应性和自身免疫反应的影响。这些模型可用于剖析自身免疫的机制，并作为GBS和MFS患者的治疗和预防替代物。