Linda S. Mansfield
Professor, Large Animal Clinical Sciences, Microbiology and Molecular Genetics
1129 FARM LN ROOM 181
EAST LANSING MI 48824 US
Comparative Enteric Diseases Laboratory (CEDL)
CEDL explores and elucidates the relationship of the enteric microbiome to acute diarrheal illness. We focus on the inter-relationships among factors mediating diarrheal disease, 1) enteric bacterial pathogens, 2) the human enteric microbiome, and 3) host responses controlling susceptibility, resistance, or autoimmunity. Our specific objective is to understand the mechanisms that initiate autoimmunity secondary to Campylobacter jejuni infection. The incidence of foodborne disease due to C. jejuni remains very high worldwide (36, 50). Serious disease sequelae can follow gastrointestinal (GI) infections with C. jejuni. The acute neuropathies Guillain Barré Syndrome (GBS) and Miller Fisher Syndrome (MFS), and Reactive Arthritis (RA) are autoimmune conditions associated with recent Campylobacter infection (79). GBS is the world’s leading cause of acute neuromuscular paralysis (114) with incidence of 1.3 cases per 1000 in the US annually (107). Disease begins 2-3 wks after C. jejuni infection; weakness of limbs develops rapidly followed by symmetrical ascending paralysis. 5% of GBS patients die; 15-20% does not recover completely and life-long disability may result.
It is clear that C. jejuni carriage or colonization is sometimes sufficient to trigger GBS. Humoral autoimmune mechanisms are implicated in GBS/MFS pathogenesis (2). Molecular mimicry between GBS-associated C. jejuni lipo-oligosaccharides (LOS) and peripheral nerve gangliosides are a known mechanism for anti-ganglioside antibody induction (2, 53, 112). It is thought that these aberrant responses result in demyelination of motor and sensory nerves although the exact pathogenesis and sites of lesions are currently unknown. Little progress has been made in understanding the pathogenesis of GBS and MFS and even less in developing therapies largely because of the lack of good, tractable animal models. CEDL has developed murine models of GBS/MFS to allow understanding of how infection with particular C. jejuni strains leads to initiation of autoimmunity. Our overall hypothesis is that murine model(s) with a “humanized” microbiome will develop spontaneous autoimmune sequelae secondary to C. jejuni infection with strains with class A LOS surface structures. Our specific hypotheses are: 1) In genetically susceptible inbred mouse strains challenged with C. jejuni strains from GBS/MFS patients, aberrant innate and adaptive responses are initiated that result in nerve damage mediated by autoantibodies and T cells reactive to the axolemma of nerves and neuromuscular junctions, 2) Anti-ganglioside autoantibody binding will be found in axolemma and neuro-muscular junction lesions of mice with GBS/MFS and complement participates in this nerve destruction, 3) Certain C. jejuni strains induce heightened innate signaling through Toll-like receptor (TLR)-4 that initiates cytokine expression (IL-6, IL-12, TNFα, IFNg, IL-17, IL-23) enhancing induction of mixed cell and antibody-mediated autoimmunity, and 4) Humicrobiota mice with decreased microbial community diversity will have increased GI proinflammatory responses and greater susceptibility to particular C. jejuni pathotypes. We expect that these models can be used to dissect mechanisms of autoimmunity and to serve as treatment and prevention surrogates for GBS/MFS patients. Thus, we expect to find a number of molecules including LPS and LOS on the surface of this bacterium that trigger long term autoimmune disease.
The gut microbiome has been demonstrated to affect many disease processes. CEDL also collaborates with Dr. Harkema (Glacier Center) and Dr. Ewart (asthma pathogenesis) to determine the role of the microbiome in airway diseases. Here, high throughput genomic methods are applied to determine microbial community members associated with airway damage and allergic disease in humans and mouse models.
University of Delaware, B.S., 1975, Biology
University of Delaware, M.S., 1980, Virology
University of Pennsylvania, V.M.D., 1986, Veterinary Medicine
University of Pennsylvania, Ph.D., 1990, Parasite Immunology
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