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Camplyobacter Jejuni Mediated Autoimmune Neuropathy in HU-Microbiota Mouse Model

Investigators
Mansfield, Linda
Institutions
Michigan State University
Start date
2013
End date
2014
Objective
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;
(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.

Funding Source
Nat'l. Inst. of Allergy and Infectious Diseases
Project source
View this project
Project number
1U19AI090872-01
Categories
Natural Toxins
Bacterial Pathogens