The incidence of foodborne disease due to Campylobacter jejuni remains very high worldwide. Serious disease sequelae can follow gastrointestinal (Gl) infections with C. jejuni. The acute neuropathies Guillain Barre Syndrome (GBS) and Miller Fisher Syndrome (MFS) are autoimmune conditions associated with recent Campylobacter infection. GBS is the world?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 initiation of autoimmunity. Early work by our group showed that autoantibodies and neurological disease develop spontaneously in Non-Obese Diabetic (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 antibodies 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 potential to improve these murine models. Our overall hypothesis is that murine model(s) with a "humanized" microbiome develop spontaneous autoimmune sequelae secondary to C. jejuni infection 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.
Autoimmune regulatory disorders are rapidly increasing in incidence especially in developed countries. A number of autoimmune diseases have been documented to be triggered by infection with enteric pathogens.
|Sambanthamoorthy, Karthik; Luo, Chunyuan; Pattabiraman, Nagarajan et al. (2014) Identification of small molecules inhibiting diguanylate cyclases to control bacterial biofilm development. Biofouling 30:17-28|
|Jensen, Hanne; Roos, Stefan; Jonsson, Hans et al. (2014) Role of Lactobacillus reuteri cell and mucus-binding protein A (CmbA) in adhesion to intestinal epithelial cells and mucus in vitro. Microbiology 160:671-81|
|Tseng, Marion; Fratamico, Pina M; Manning, Shannon D et al. (2014) Shiga toxin-producing Escherichia coli in swine: the public health perspective. Anim Health Res Rev 15:63-75|
|Koestler, Benjamin J; Waters, Christopher M (2014) Bile acids and bicarbonate inversely regulate intracellular cyclic di-GMP in Vibrio cholerae. Infect Immun 82:3002-14|
|Britton, Robert A; Young, Vincent B (2014) Role of the intestinal microbiota in resistance to colonization by Clostridium difficile. Gastroenterology 146:1547-53|
|Koestler, Benjamin J; Seregin, Sergey S; Rastall, David P W et al. (2014) Stimulation of innate immunity by in vivo cyclic di-GMP synthesis using adenovirus. Clin Vaccine Immunol 21:1550-9|
|Robinson, Catherine D; Auchtung, Jennifer M; Collins, James et al. (2014) Epidemic Clostridium difficile strains demonstrate increased competitive fitness compared to nonepidemic isolates. Infect Immun 82:2815-25|
|Britton, Robert A; Irwin, Regina; Quach, Darin et al. (2014) Probiotic L. reuteri treatment prevents bone loss in a menopausal ovariectomized mouse model. J Cell Physiol 229:1822-30|
|Malik, A; Sharma, D; St Charles, J et al. (2014) Contrasting immune responses mediate Campylobacter jejuni-induced colitis and autoimmunity. Mucosal Immunol 7:802-17|
|Hunter, Jessica L; Severin, Geoffrey B; Koestler, Benjamin J et al. (2014) The Vibrio cholerae diguanylate cyclase VCA0965 has an AGDEF active site and synthesizes cyclic di-GMP. BMC Microbiol 14:22|
Showing the most recent 10 out of 15 publications