Experimental and epidemiological approaches to Campylobacter jejuni-associated Guillain Barre Syndrome

Guillain Barre Syndrome (GBS), an immune-mediated acute polyneuropathy of the peripheral nerves, is the leading cause of acute autoimmune neuromuscular paralysis in the Western world. Approximately two-thirds of patients report a prior respiratory or gastrointestinal infection; Campylobacter jejuni is the most commonly reported antecedent infection. C. jejuni is the leading cause of foodborne bacterial gastrointestinal infection; transmission is by ingestion of contaminated water, milk, and poultry. The proposed mechanism of GBS is similarity of the lipo-oligosaccharide (LOS) on the outer surface of some C. jejuni strains to gangliosides, glycolipid structures found in the nervous system. This molecular mimicry results in an immune response directed at both the LOS and gangliosides. Current data surrounding molecular mimicry are conflicting, therefore suggesting that other surface structures of C. jejuni are involved in GBS pathogenesis. Epidemiological studies on isolates collected from patients that presented with either enteritis or neuropathy to define potential genetic relationships of GBS to the highly variable C. jejuni flagellar and major outer membrane proteins have given inconclusive and contradictory results. Therefore additional work is needed to improve molecular typing of C. jejuni isolates.;The work reported here took two complementary directions: development of a murine model of GBS using C. jejuni strains of an LOS type known to be associated with GBS in humans and an epidemiological study of C. jejuni isolates from the U.S. with a focus in Michigan, in which the LOS biosynthetic locus, the flagellar protein, and the major outer membrane protein were all characterized in addition to standard multilocus sequence typing.;To understand the role of the genetic factors of C. jejuni and potential host factors in the pathogenesis of GBS more in vivo studies are needed. However, current animal models to study GBS employ immunization of rabbits with purified LOS or mice with bovine myelin to initiate an immune response similar to that in GBS patients. These are not natural models of GBS following C. jejuni infection. In a more natural model in chickens, birds given GBS-associated strains of C. jejuni develop both clinical signs and immunological responses similar to those seen in GBS patients. However, chickens are anatomically and physiologically different from humans. The goal of the first half of my studies was development of a murine model secondary to C. jejuni infection; we found a strain of mouse that has the potential to be such a model, but more work must be done.;The goal of the second half of my studies was to examine possible epidemiological relationships between other variable surface components of C. jejuni and LOS types associated with GBS. In epidemiological studies using molecular typing of both variable and conserved genes, we found that both human C. jejuni isolates from a limited collection from the U.S. with focus in Michigan and from calves on a Michigan dairy farm that had a C. jejuni outbreak had LOS biosynthetic loci characteristic of GBS-associated strains.