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.
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. The food-borne pathogen C. jejuni is a leading cause of bacterial gastroenteritis infecting 2.5 million yeariy in the US. The acute neuropathies GBS and MFS, and RA have all been associated with recent Campylobacter infection. These animal models can be used to understand the causes and to develop the cures.
|St Charles, J L; Bell, J A; Gadsden, B J et al. (2017) Guillain Barré Syndrome is induced in Non-Obese Diabetic (NOD) mice following Campylobacter jejuni infection and is exacerbated by antibiotics. J Autoimmun 77:11-38|
|Brooks, Phillip T; Brakel, Kelsey A; Bell, Julia A et al. (2017) Transplanted human fecal microbiota enhanced Guillain Barré syndrome autoantibody responses after Campylobacter jejuni infection in C57BL/6 mice. Microbiome 5:92|
|Spinler, Jennifer K; Auchtung, Jennifer; Brown, Aaron et al. (2017) Next-Generation Probiotics Targeting Clostridium difficile through Precursor-Directed Antimicrobial Biosynthesis. Infect Immun 85:|
|Mukherjee, Sanjana; Mosci, Rebekah E; Anderson, Chase M et al. (2017) Antimicrobial Drug-Resistant Shiga Toxin-Producing Escherichia coli Infections, Michigan, USA. Emerg Infect Dis 23:1609-1611|
|Cha, W; Henderson, T; Collins, J et al. (2016) Factors associated with increasing campylobacteriosis incidence in Michigan, 2004-2013. Epidemiol Infect 144:3316-3325|
|Cha, Wonhee; Mosci, Rebekah; Wengert, Samantha L et al. (2016) Antimicrobial Susceptibility Profiles of Human Campylobacter jejuni Isolates and Association with Phylogenetic Lineages. Front Microbiol 7:589|
|Boughner, Lisa A; Singh, Pallavi (2016) Microbial Ecology: Where are we now? Postdoc J 4:3-17|
|Sloup, Rudolph E; Cieza, Roberto J; Needle, David B et al. (2016) Polysorbates prevent biofilm formation and pathogenesis of Escherichia coli O104:H4. Biofouling 32:1131-1140|
|Auchtung, Jennifer M; Robinson, Catherine D; Farrell, Kylie et al. (2016) MiniBioReactor Arrays (MBRAs) as a Tool for Studying C. difficile Physiology in the Presence of a Complex Community. Methods Mol Biol 1476:235-58|
|Venegas-Vargas, Cristina; Henderson, Scott; Khare, Akanksha et al. (2016) Factors Associated with Shiga Toxin-Producing Escherichia coli Shedding by Dairy and Beef Cattle. Appl Environ Microbiol 82:5049-56|
Showing the most recent 10 out of 63 publications