Sialylation Lessens the Infectivity of Neisseria gonorrhoeae MS11mkC

Schneider, Herman; Schmidt, Katherine A.; Skillman, Donald R.; Verg, Lillian Van De; Warren, Richard L.; Wylie, Hugh J.; Sadoff, Jerald C.; Deal, Carolyn D.; Cross, Alan S.

doi:10.1093/infdis/173.6.1422

Cited by 48 publications

(43 citation statements)

References 28 publications

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“…Sialylation of the LNnT epitope, in vitro, impairs the ability of gonococci to invade primary urethral epithelial cells (96) and epithelial cell lines (249,251) and to be phagocytosed by neutrophils (131,201). These data are supported by one study in which, in vivo, sialylation of gonococci also impaired the ability of these organisms to cause disease in human volunteers (212 with sialic acid removal by neuraminidase or, presumably, by the replication of gonococci within the lumen of the urethra in the absence of host-derived CMP-N-acetylneuraminic acid. Neuraminidase (158,232) and the ASGP-R (98) are present on human sperm.…”

Section: Gonococcal Infection Of the Male Urethramentioning

confidence: 65%

The Molecular Mechanisms Used byNeisseria gonorrhoeaeTo Initiate Infection Differ between Men and Women

2004

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The molecular mechanisms used by the gonococcus to initiate infection exhibit gender specificity. The clinical presentations of disease are also strikingly different upon comparison of gonococcal urethritis to gonococcal cervicitis. An intimate association occurs between the gonococcus and the urethral epithelium and is mediated by the asialoglycoprotein receptor. Gonococcal interaction with the urethral epithelia cell triggers cytokine release, which promotes neutrophil influx and an inflammatory response. Similarly, gonococcal infection of the upper female genital tract also results in inflammation. Gonococci invade the nonciliated epithelia, and the ciliated cells are subjected to the cytotoxic effects of tumor necrosis factor alpha induced by gonococcal peptidoglycan and lipooligosaccharide. In contrast, gonococcal infection of the lower female genital tract is typically asymptomatic. This is in part the result of the ability of the gonococcus to subvert the alternative pathway of complement present in the lower female genital tract. Gonococcal engagement of complement receptor 3 on the cervical epithelia results in membrane ruffling and does not promote inflammation. A model of gonococcal pathogenesis is presented in the context of the male and female human urogenital tracts

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Section: Gonococcal Infection Of the Male Urethramentioning

confidence: 65%

The Molecular Mechanisms Used byNeisseria gonorrhoeaeTo Initiate Infection Differ between Men and Women

2004

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“…N. gonorrhoeae MS11 (PorB.1B, Sm r ) is a serum-resistant strain from a patient with uncomplicated endocervical infection. Strain MS11 has been tested extensively in male volunteers (47,48,55). N. gonorrhoeae was cultured on GC agar (Difco) with Kellogg's supplements (27) at 37°C under 7% CO 2 or in supplemented GC broth (GCB) with 5 mM NaHCO 3 in an air incubator with rotation as described previously (25).…”

Section: Methodsmentioning

confidence: 99%

α-2,3-Sialyltransferase EnhancesNeisseria gonorrhoeaeSurvival during Experimental Murine Genital Tract Infection

Jerse

2006

Infect Immun

115

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The addition of host-derived sialic acid to Neisseria gonorrhoeae lipooligosaccharide is hypothesized to be an important mechanism by which gonococci evade host innate defenses. This hypothesis is based primarily on in vitro assays of complement-mediated and phagocytic killing. Here we report that a nonpolar ␣-2,3-sialyltransferase (lst) mutant of N. gonorrhoeae was significantly attenuated in its capacity to colonize the lower genital tract of 17-␤ estradiol-treated female BALB/c mice during competitive infection with the wild-type strain. Genetic complementation of the lst mutation restored recovery of the mutant to wild-type levels. Studies with B10.D2-HC o H2 d H 2 -T18c/OSN (C5-deficient) mice showed that attenuation of the lst mutant was not due to increased sensitivity to complement-mediated bacteriolysis, a result that is consistent with recently reported host restrictions in the complement cascade. However, Lst-deficient gonococci were killed more rapidly than sialylated wild-type gonococci following intraperitoneal injection into normal mice, which is consistent with sialylation conferring protection against killing by polymorphonuclear leukocytes (PMNs). As reported for human PMNs, sialylated gonococci were more resistant to killing by murine PMNs, and sialylation led to reduced association with and induction of a weaker respiratory burst in PMNs from estradiol-treated mice. In summary, these studies suggest sialylation confers a survival advantage to N. gonorrhoeae in mice by increasing resistance to PMN killing. This report is the first direct demonstration that ␣-2,3-sialyltransferase contributes to N. gonorrhoeae pathogenesis in an in vivo model. This study also validates the use of experimental murine infection to study certain aspects of gonococcal pathogenesis.

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“…When N. gonorrhoeae MS11mkC was used to inoculate healthy male volunteers, 100% of the volunteers developed urethritis, compared to an infectivity rate of 40% for strains expressing a truncated LOS (23). Fresh isolates from the volunteers who had contracted urethritis produced LOS molecules with N-acetyllactosamine repeats, whereas the isolates in the original inoculum expressed paraglobsyl and gangliosyl LOS (23,24). However, the number of disaccharide repeats was limited to two or three (10).…”

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confidence: 99%

Structural Characterization of an Oligosaccharide Made by Neisseria sicca

et al. 2009

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Neisseria sicca 4320 expresses two carbohydrate-containing components with sodium dodecyl sulfatepolyacrylamide gel electrophoresis mobilities that resemble those of lipooligosaccharide and lipopolysaccharide. Using matrix-assisted laser desorption ionization-time of flight and electrospray ionization mass spectrometry, we characterized a disaccharide carbohydrate repeating unit expressed by this strain. Commensal Neisseria strains colonize the human respiratory tract. Frequent interspecific genetic exchange between commensal Neisseria strains and the pathogens Neisseria meningitidis and Neisseria gonorrhoeae occurs (13). It is thought the commensal organisms serve as reservoirs for antibiotic resistance genes (20). The similarity between the gene complements of the commensals and pathogens suggests that the virulence of the pathogenic Neisseria spp. may not result from the genes that they possess but rather from a "genetic personality" which is a result of combinations of these genes, sequence variations that alter the function of gene products, the presence of genes for which a virulence phenotype has not yet been identified, and/or differences in the regulation of genes (25).Lipooligosaccharide (LOS) is an important neisserial virulence determinant consisting of an oligosaccharide (OS) component attached to lipid A via 3-deoxy-2-keto-D-manno-octulosonic acid (Kdo). The structures of a sufficient number of neisserial LOS molecules have been determined to form a coherent yet incomplete picture of the structural diversity of their LOS (Fig. 1). The different LOS structures have a conserved core with two Kdo molecules, two heptose (Hep) molecules, and one N-acetylhexosamine (HexNAc) molecule and vary in the composition and size of the OS attached to one Hep (HepI; ␣-chain variation) and in the attachment of an OS or phosphoethanolamine to the other Hep (HepII; ␤-chain variation) or by addition of a galactose to the Nacetylglucosamine (GlcNAc) found on HepII (␥-chain extension) (3, 6, 7, 9-11). This structural motif is different from that of lipopolysaccharide (LPS) of other types of bacteria, which contains an O antigen composed of a repeating sugar polymer, typically consisting of four to seven sugars (26). No one has reported the presence of an O antigen in pathogenic strains of Neisseria.A few studies have analyzed the structure of LOS produced by commensal Neisseria strains, and the data indicate that the LOS heterogeneity is greater than the heterogeneity in the gonococcus and meningococcus (21). Commensal Neisseria strains are capable of producing LOS molecules that are structurally different from the molecules in the known Neisseria repertoire in that they fail to bind monoclonal antibodies specific for LOS epitopes characteristic of the gonococcus and meningococcus (1). They also can lack some of the LOS biosynthesis genes found in N. meningitidis and N. gonorrhoeae (1,33). These findings suggest that alternative LOS structures are present in commensal Neisseria strains. Sandlin and Stein (21) identified ...

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Sialylation Lessens the Infectivity of Neisseria gonorrhoeae MS11mkC

Cited by 48 publications

References 28 publications

The Molecular Mechanisms Used byNeisseria gonorrhoeaeTo Initiate Infection Differ between Men and Women

The Molecular Mechanisms Used byNeisseria gonorrhoeaeTo Initiate Infection Differ between Men and Women

α-2,3-Sialyltransferase EnhancesNeisseria gonorrhoeaeSurvival during Experimental Murine Genital Tract Infection

Structural Characterization of an Oligosaccharide Made by Neisseria sicca

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