Phase variable changes in genes lgtA and lgtC within the lgtABCDE operon of Neisseria gonorrhoeae can modulate gonococcal susceptibility to normal human serum

Shafer, William M.; Datta, Anup; Kolli, V. S. Kumar; Rahman, Motiur; Balthazar, Jacqueline T.; Martin, Larry E.; Veal, Wendy L.; Stephens, David S.; Carlson, Russell W.

doi:10.1177/09680519020080010501

Cited by 43 publications

(47 citation statements)

References 48 publications

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“…This has led to the suggestion that LOS antigenic phase variation may allow the gonococcus to fluctuate between invasive and serum-resistant phenotypes and thus promote bacterial survival in vivo (249). This idea is supported by the work of Shafer and colleagues, who have recently provided evidence that phase variation, resulting in elongated LOS structures, also increases the serum sensitivity of gonococci bearing these structures (216). Additionally, although it has not been examined for the gonococcus, recent studies performed with Neisseria meningitidis have demonstrated that the oligosaccharide determinant of LOS may also influence the defensin-enhanced mucosal adherence observed with these bacteria (83).…”

Section: Outer Membrane Constituents Associated With Gonococcal Virulmentioning

confidence: 48%

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: Outer Membrane Constituents Associated With Gonococcal Virulmentioning

confidence: 48%

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

2004

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“…The ability of certain strains of gonococci (e.g., DGI isolates) to stably resist the bactericidal action of NHS has been linked, in part, to structural changes in the carbohydrate component of the core oligosaccharide of LOS (28,31,39,41,46). Phase-variable changes in the nucleotide repeat sequences within the lgtA and lgtC genes of the lgtABCDE operon (13) are important in determining resistance to killing by NHS expressed by strain FA19 (39).…”

Section: Resultsmentioning

confidence: 99%

“…Phase-variable changes in the nucleotide repeat sequences within the lgtA and lgtC genes of the lgtABCDE operon (13) are important in determining resistance to killing by NHS expressed by strain FA19 (39). In particular, strain FA19 with a phase-off lgtA produces a 3.6-kDa LOS species that contains an ␣-chain of Gal-Glc-HepI-Kdo (3-deoxy-D-manno-octulosonic acid) and is resistant to NHS, while FA19 with a phase-on lgtA produces an extended ␣-chain of Gal-GlcNac-Gal-Glc-HepIKdo and is susceptible to NHS.…”

Section: Resultsmentioning

confidence: 99%

“…Changes in LOS structure can have a profound impact on bacterial interactions with host cells and/or defensive systems (18,20,35,45,46). As an example, the NHS resistance expressed by certain gonococci can be lost by high-frequency, spontaneous mutations within the lgtABCDE operon (39), which encodes the glycosyl transferases responsible for extending the LOS ␣-chain (13).…”

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confidence: 99%

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Phosphoethanolamine Substitution of Lipid A and Resistance ofNeisseria gonorrhoeaeto Cationic Antimicrobial Peptides and Complement-Mediated Killing by Normal Human Serum

et al. 2009

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The capacity of Neisseria gonorrhoeae to cause disseminated gonococcal infection requires that such strains resist the bactericidal action of normal human serum. The bactericidal action of normal human serum against N. gonorrhoeae is mediated by the classical complement pathway through an antibody-dependent mechanism. The mechanism(s) by which certain strains of gonococci resist normal human serum is not fully understood, but alterations in lipooligosaccharide structure can affect such resistance. During an investigation of the biological significance of phosphoethanolamine extensions from lipooligosaccharide, we found that phosphoethanolamine substitutions from the heptose II group of the lipooligosaccharide ␤-chain did not impact levels of gonococcal (strain FA19) resistance to normal human serum or polymyxin B. However, loss of phosphoethanolamine substitution from the lipid A component of lipooligosaccharide, due to insertional inactivation of lptA, resulted in increased gonococcal susceptibility to polymyxin B, as reported previously for Neisseria meningitidis. In contrast to previous reports with N. meningitidis, loss of phosphoethanolamine attached to lipid A rendered strain FA19 susceptible to complement killing. Serum killing of the lptA mutant occurred through the classical complement pathway. Both serum and polymyxin B resistance as well as phosphoethanolamine decoration of lipid A were restored in the lptA-null mutant by complementation with wild-type lptA. Our results support a role for lipid A phosphoethanolamine substitutions in resistance of this strict human pathogen to innate host defenses.

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“…LOS analysis by silver staining of sodium dodecyl sulfate-polyacrylamide gel electrophoresis gels showed that FA1090 and each of its Opa mutants expressed more than one LOS species and that there was wide variation in LOS expression among the strains (data not shown). LOS structure also impacts complement binding and serum resistance (20,21,49,65,66), and therefore it was not possible to assess the effects of Opa expression on complement-dependent killing independent of other potential serum resistance-modifying variables on the strains we used. It is possible that Opa expression may have different effects on serum resistance in different strains, and LOS-Opa interactions may also play a role in modulating the effects of Opa (4,47).…”

Section: Discussionmentioning

confidence: 99%

Defining Targets for Complement Components C4b and C3b on the Pathogenic Neisseriae

Lewis

Ram

Prasad³

et al. 2008

Infect Immun

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Complement is a key arm of the innate immune defenses against the pathogenic neisseriae. We previously identified lipooligosaccharide on Neisseria meningitidis as an acceptor for complement C4b. Little is known about other neisserial targets for complement proteins C3 and C4, which covalently attach to bacterial surfaces and initiate opsonization and killing. In this study we demonstrate that Neisseria gonorrhoeae porin (Por) 1B selectively binds C4b via amide linkages and C3b via ester linkages. Using strains expressing hybrid Por1A/1B molecules, a region spanned by loops 4 and 5 of Por1B was identified as the preferred binding site for C4b. We also identified the opacity protein (Opa), a major adhesin of pathogenic neisseriae, as a target for C4b and C3b on both N. meningitidis and N. gonorrhoeae. Using N. gonorrhoeae variants that predominantly expressed individual Opa proteins, we found that all Opa proteins tested (A, B, C, D, E, F, and I) bound C4b and C3b via amide and ester linkages, respectively. Amide linkages with Por1B and Opa were confirmed using serum containing only the C4A isoform, which exclusively forms amide linkages with targets. While monomers and heterodimers of C4Ab were detected on bacterial targets, C4Bb appeared to preferentially participate in heterodimer (C5 convertase) formation. Our data provide another explanation for the enhanced serum sensitivity of Por1B-bearing gonococci. The binding of C3b and C4b to Opa provides a rationale for the recovery of predominantly "transparent" (Opa-negative) neisserial isolates from persons with invasive disease, where the bacteria encounter high levels of complement.

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Phase variable changes in genes lgtA and lgtC within the lgtABCDE operon of Neisseria gonorrhoeae can modulate gonococcal susceptibility to normal human serum

Cited by 43 publications

References 48 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

Phosphoethanolamine Substitution of Lipid A and Resistance ofNeisseria gonorrhoeaeto Cationic Antimicrobial Peptides and Complement-Mediated Killing by Normal Human Serum

Defining Targets for Complement Components C4b and C3b on the Pathogenic Neisseriae

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