Campylobacter jejuni Mediated Autoimmune Neuropathy in Hu-microbiota Mouse Model

由空肠弯曲菌引起的食源性疾病在全球范围内的发病率仍然很高。严重的疾病后遗症可能发生在空肠弯曲菌感染胃肠道(Gl)之后。急性神经病格林-巴利综合征(GBS)和米勒-费舍尔综合征(MFS)是一种自身免疫性疾病，与最近的Campy/o/Jacter感染有关。GBS是世界上导致急性神经肌肉麻痹的主要原因。5%的GBS患者死亡；15%-20%的人终身残疾。我们的长期目标是了解启动继发于C.ye/un/感染的自身免疫的机制。我们在这项建议中的短期目标是进一步发展GBS和MFS的小鼠模型，以了解感染特定的空肠弯曲菌株是如何导致自身免疫失败的。我们小组的早期工作表明，自身抗体和神经系统疾病在非肥胖糖尿病(NOD)WT、NOD IL-10-/-和NOD B7- 2-1-GBS患者空肠弯曲菌口服感染小鼠。部分感染小鼠具有针对神经节苷脂GDIa和GM1的自身反应性抗体，表现为运动神经元功能障碍伴肢体松弛的神经学表型特征。C57BL/6 IL-IO‘-感染空肠弯曲菌MFS株的小鼠出现伴有震颤和不对称性后肢无力的神经系统疾病。用人类粪便样本在第一区验证的小鼠有潜力改进这些小鼠模型。我们的总体设想是，具有人源化微生物群的小鼠模型(S)在A类LOS菌株感染空肠弯曲菌后继发自发性自身免疫后遗症。我们的具体目标是：(1)明确与GBS和MFS相关的神经系统体征和疾病损害 (2)确定自身免疫后遗症是否随空肠弯曲菌LOS谱和LOS基因的变化而变化；(3)确定补体在C.ye/t/n/诱导的MFS损害中的作用；(4)确定先天反应和适应性反应是否介导GBS和MFS在小鼠模型中；(5)确定自身抗体或自身反应性T细胞是否将反应传递给幼稚小鼠；以及(6)确定在存在和不存在三种空肠弯曲菌病原体的情况下，(Hu)微生物区系对小鼠宿主先天、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，并可作为GBS和MFS患者的治疗和预防替代品。

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.