Phase Variation ofCampylobacter jejuni81-176 Lipooligosaccharide Affects Ganglioside Mimicry and Invasiveness In Vitro

Abstract

The outer cores of the lipooligosaccharides (LOS) of many strains of Campylobacter jejuni mimic human gangliosides in structure. A population of cells of C. jejuni strain 81-176 produced a mixture of LOS cores which consisted primarily of structures mimicking GM 2 and GM 3 gangliosides, with minor amounts of structures mimicking GD 1b and GD 2 . Genetic analyses of genes involved in the biosynthesis of the outer core of C. jejuni 81-176 revealed the presence of a homopolymeric tract of G residues within a gene encoding CgtA, an N-acetylgalactosaminyltransferase. Variation in the number of G residues within cgtA affected the length of the open reading frame, and these changes in cgtA corresponded to a change in LOS structure from GM 2 to GM 3 ganglioside mimicry. Site-specific mutation of cgtA in 81-176 resulted in a major LOS core structure that lacked GalNAc and resembled GM 3 ganglioside. Compared to wild-type 81-176, the cgtA mutant showed a significant increase in invasion of INT407 cells. In comparison, a site-specific mutation of the neuC1 gene resulted in the loss of sialic acid in the LOS core and reduced resistance to normal human serum but had no affect on invasion of INT407 cells.Campylobacter jejuni is one of the most common causes of bacterial diarrhea worldwide (10, 25) and has been shown to be frequently associated with the development of Guillain-Barré syndrome (GBS), a postinfectious polyneuropathy (23). The association of C. jejuni and the development of GBS is thought to result from the molecular mimicry between outer core structures of bacterial lipooligosaccharides (LOS) and human gangliosides (18,19). Thus, for example, the cores of different isolates of C. jejuni have been shown to mimic GM 1 , GM 2 , GD 3 , GD 1a , GT 1a , and GQ 1b (1-3, 18-24, 29, 30, 42, 43). However, similar ganglioside mimicry can be found in strains associated with both uncomplicated enteritis and GBS (18). While considerable research efforts have focused on the role of LOS in the development of GBS, little attention has been placed on the function of these sialylated LOS structures in the pathogenesis of gastrointestinal disease. A locus involved in LOS biosynthesis in C. jejuni MSC57360, the type strain of the HS:1 serogroup, has been described previously (12). It has also been shown that the loss of sialic acid (NeuNAc) from the LOS core results in the increased immunogenicity of the core and an increased sensitivity to normal human serum (12). However, strain MSC57360 is noninvasive in vitro (P. Guerry and C. P. Ewing, unpublished data), and little is known about its virulence potential. In this report, we have characterized the LOS core of C. jejuni 81-176 (serogroups HS:23 and HS:36), which is one of the best-characterized strains of C. jejuni (5-7, 14, 15, 26, 28, 41) and one which has been shown to induce diarrhea in human volunteers in two separate studies (7; D. Tribble et al., unpublished data). These results indicate that the LOS core of C. jejuni 81-176 is composed of structures that mimic several gan...

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“…Further, a recent study by Keo et al established that capsule expression was essential for Campylobacter resistance to human serum [114], though, in contrast to earlier reports [41,115], they did not find any essential contribution of sialylated LOS to serum resistance [114]. Therefore, the actual involvement of LOS in serum resistance is still under discussion.…”

Ganglioside Molecular Mimicry and Its Pathological Roles in Guillain-Barré Syndrome and Related Diseases

“…C. jejuni, including the Miller-Fisher syndrome-associated serotypes HS:2 and HS:23, had GT1a-like and GQ1b-like oligosaccharides (59). A population of cells of C. jejuni strain 81-176 produced a mixture of LPS cores that consisted primarily of structures mimicking GM2 and GM3 gangliosides, with significantly fewer structures mimicking GD1b and GD2 (29). Anti-GQ1b IgG antibody was detected in most Miller-Fisher patients infected with C. jejuni or Haemophilus influenzae.…”

“…In this regard, Linton et al (49) have reported that the wlaN gene product, which encodes a ␤-1,3-galactosyltransferase, is responsible for converting the GM2-like LOS structure to a GM1-like structure. The LPS of C. jejuni strain 81-176 expresses mainly a mixture of LPS cores containing GM2 and GM3 gangliosides (29). Genetic analyses of genes involved in the biosynthesis of the outer core of this strain revealed the presence of a homopolymeric tract of G residues within a gene encoding CgtA.…”

Complete 6-Deoxy-d-altro-heptose Biosynthesis Pathway from Campylobacter jejuni

“…Several virulence factors contribute to the pathogenicity of C. jejuni, including the flagella that confer motility and are important for colonization (10,11), the glycosylation of proteins that allows antigen protection/masking (12,13), and surface glycolipids such as the lipooligosaccharide (14), and the capsule (15) that provide resistance to a wide array of innate immune defenses (16). The capsule is required for diarrheal disease and colonization in animal models of infection, as well as adherence, invasion, and serum resistance in human infections (17).…”