The Genetic Bases for the Variation in the Lipo-oligosaccharide of the Mucosal Pathogen, Campylobacter jejuni

We have compared the lipo-oligosaccharide (LOS) biosynthesis loci from 11 Campylobacter jejunistrains expressing a total of 8 different ganglioside mimics in their LOS outer cores. Based on the organization of the genes, the 11 corresponding loci could be classified into three classes, with one of them being clearly an intermediate evolutionary step between the other two. Comparative genomics and expression of specific glycosyltransferases combined with in vitro activity assays allowed us to identify at least five distinct mechanisms that allowC. jejuni to vary the structure of the LOS outer core as follows: 1) different gene complements; 2) phase variation because of homopolymeric tracts; 3) gene inactivation by the deletion or insertion of a single base (without phase variation); 4) single mutation leading to the inactivation of a glycosyltransferase; and 5) single or multiple mutations leading to “allelic” glycosyltransferases with different acceptor specificities. The differences in the LOS outer core structures expressed by the 11 C. jejuni strains examined can be explained by one or more of the five mechanisms described in this work. We have compared the lipo-oligosaccharide (LOS) biosynthesis loci from 11 Campylobacter jejunistrains expressing a total of 8 different ganglioside mimics in their LOS outer cores. Based on the organization of the genes, the 11 corresponding loci could be classified into three classes, with one of them being clearly an intermediate evolutionary step between the other two. Comparative genomics and expression of specific glycosyltransferases combined with in vitro activity assays allowed us to identify at least five distinct mechanisms that allowC. jejuni to vary the structure of the LOS outer core as follows: 1) different gene complements; 2) phase variation because of homopolymeric tracts; 3) gene inactivation by the deletion or insertion of a single base (without phase variation); 4) single mutation leading to the inactivation of a glycosyltransferase; and 5) single or multiple mutations leading to “allelic” glycosyltransferases with different acceptor specificities. The differences in the LOS outer core structures expressed by the 11 C. jejuni strains examined can be explained by one or more of the five mechanisms described in this work. lipo-oligosaccharides cytidine monophosphate-N-acetylneuraminic acid 6-(5-fluorescein-carboxamido)-hexanoic acid succimidyl ester open reading frame heptose nucleotide. The abbreviated designations of glycolipids are according to IUPAC-IUC nomenclature Many pathogenic bacteria have variable cell-surface glycoconjugates such as capsules in Streptococcus spp. andNeisseria meningitidis (1Roberts I.S. Annu. Rev. Microbiol. 1996; 50: 285-315Crossref PubMed Scopus (515) Google Scholar), lipopolysaccharides in Gram-negative bacteria (2Preston A. Mandrell R.E. Gibson B.W. Apicella M.A. Crit. Rev. Microbiol. 1996; 22: 139-180Crossref PubMed Scopus (235) Google Scholar), and glycosylated surface-layer proteins (3Castric P. Cassels F.J. Carlson R.W. J. Biol. Chem. 2001; 276: 26479-26485Abstract Full Text Full Text PDF PubMed Scopus (160) Google Scholar). In mucosal pathogens, the variability of cell-surface polysaccharides has been shown to play a major role in virulence (4Moxon E.R. Kroll J.S. Curr. Top. Microbiol. Immunol. 1990; 150: 65-85PubMed Google Scholar). This variation is caused by the diversity of monosaccharide components and the linkages between them, derivatization with noncarbohydrate moieties, and in some cases, by the length and sequence of the repeating units. The variation of these glycan structures can sometimes be correlated with a specific gene complement, but it is probable that other genetic mechanisms are also employed to create variable cell-surface glycoconjugates. The DNA sequencing of the relevant genetic loci from multiple strains of a pathogen can provide insights into the genetic origins of important strain variable traits such as cell-surface glycoconjugates. The mucosal pathogen Campylobacter jejuni has been recognized as an important cause of acute gastroenteritis in humans (5Allos B.M. Clin. Infect. Dis. 2001; 32: 1201-1206Crossref PubMed Scopus (863) Google Scholar) and has been shown to have variable cell-surface carbohydrates that are associated with virulence (6Bacon D.J. Szymanski C.M. Burr D.H. Silver R.P. Alm R.A. Guerry P. Mol. Microbiol. 2001; 40: 769-777Crossref PubMed Scopus (226) Google Scholar, 7Guerry P. Szymanski C.M. Prendergast M.M. Hickey T.E. Ewing C.P. Pattarini D.L. Moran A.P. Infect. Immun. 2002; (in press)Google Scholar). Epidemiological studies have shown that Campylobacter infections are more common thanSalmonella infections in developed countries, and they are also an important cause of diarrheal diseases in developing countries.C. jejuni is also considered the most frequent antecedent infection to the development of Guillain-Barré syndrome, a form of neuropathy that is the most common cause of generalized paralysis since the eradication of poliomyelitis in developed countries (8Jacobs B.C. Rothbarth P.H. van der Meché F.G.A. Herbrink P. Schmitz P.I.M. de Klerk M.A. van Doorn P.A. Neurology. 1998; 51: 1110-1115Crossref PubMed Scopus (618) Google Scholar). The core oligosaccharides of low molecular weight lipo-oligosaccharides of C. jejuni strains have been shown to molecular of the of oligosaccharides to of and have been in C. jejuni strains of structures by the of LOS is considered to be a virulence of mucosal pathogens, this to the A.P. Prendergast M.M. Immunol. Microbiol. 1996; PubMed Google Scholar). The molecular between C. jejuni LOS outer core structures and has also been to as a mechanisms in the development of Guillain-Barré Scopus Google of the C. jejuni strains in this the of the the LOS outer core biosynthesis M.A. 1998; Scopus Google Moran A.P. J. PubMed Scopus Google PubMed Scopus Google PubMed Scopus Google PubMed Scopus Google Moran A.P. J. PubMed Scopus Google Moran A.P. J. PubMed Scopus Google A. B.W. Mol. Microbiol. PubMed Scopus Google and and Moran A.P. J. PubMed Scopus Google Moran A.P. J. PubMed Scopus Google the of the A. B.W. Mol. Microbiol. PubMed Scopus Google Scholar) and and in a Moran A.P. J. PubMed Scopus Google Scholar, Moran A.P. J. PubMed Scopus Google Scholar, PubMed Scopus Google Scholar, C.M. Moran A.P. J. PubMed Scopus Google Scholar) and M.A. 1998; Scopus Google Scholar) the LOS outer core structures of C. jejuni strains of the The of C. jejuni is on and it that the is to LOS J. Clin. Microbiol. PubMed Scopus Google Scholar, A.P. J. Microbiol. PubMed Scopus Google Scholar). and genetic studies that polysaccharides (6Bacon D.J. Szymanski C.M. Burr D.H. Silver R.P. Alm R.A. Guerry P. Mol. Microbiol. 2001; 40: 769-777Crossref PubMed Scopus (226) Google Scholar, B.W. Mol. Microbiol. PubMed Scopus Google Scholar). the loci and LOS biosynthesis are in the C. jejuni J. B.W. C. M.A. van PubMed Scopus Google Scholar) and gene are to be frequent in C. jejuni J. Clin. Microbiol. 2001; PubMed Scopus Google Scholar, A. J. 2001; PubMed Scopus Google Scholar), it is that strains the could different LOS outer cores. to the LOS outer core structures 1) with the specific strain with the the are also The of the in LOS and the of their are of a of the mechanisms by these The of the sequence of C. jejuni J. B.W. C. M.A. van PubMed Scopus Google Scholar) has the of loci in the biosynthesis of cell-surface carbohydrates LOS A. B.W. Mol. Microbiol. PubMed Scopus Google Scholar, A. B.W. Mol. Microbiol. PubMed Scopus Google Scholar). The sequence also to the corresponding LOS biosynthesis in other C. jejunistrains J. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar, P. Ewing C.P. Hickey T.E. Prendergast M.M. Moran A.P. Infect. Immun. PubMed Scopus Google Scholar), allowed the of in the of and acid or to the LOS outer cell-surface structures such as the LOS are recognized as by the it is that these structures to the of the The C. jejuni strains in this shown to a total of 8 different LOS outer and The LOS biosynthesis loci of C. jejuni and C. jejuni to have common as to strain J. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar), provide a differences in LOS outer cores. mechanisms other differences in gene are in a of LOS outer cores. In the strain C. jejuni the gene in the of the of the LOS outer core shown to be a This in the expression of a LOS outer core compared with strain PubMed Scopus Google Scholar, J. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar). J. B.W. C. M.A. van PubMed Scopus Google Scholar) that homopolymeric of variable length are in in the biosynthesis of C. jejuni a form of of these A. B.W. Mol. Microbiol. PubMed Scopus Google Scholar) in a gene a that with an or a in the expression of a or a ganglioside in C. jejuni We that the gene as a in C. jejuni and as a in C. jejuni that in the expression of a or J. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar). In this the mechanisms by C. jejuni to outer core In to other of expression of to variable homopolymeric assays to that acid are the expression of glycosyltransferases with different a that the of C. LOS outer cores. 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