Complement Processing and Immunoglobulin Binding to<i>Neisseria gonorrhoeae</i>Determined In Vitro Simulates In Vivo Effects

McQuillen, Daniel P.; Gulati, Sunita; Ram, Sanjay; Turner, Adrian K.; Jani, Darshana; Heeren, Timothy; Rice, Peter A.

doi:10.1086/314545

Cited by 55 publications

(56 citation statements)

References 62 publications

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“…This observation has been confirmed by other investigators (10,11). The sialylation of gonococci occurs in vivo in humans (12,13) and in the genital tract of experimentally infected mice (14). Mechanisms of serum resistance conferred by gonococcal LOS sialylation include the decreased binding of Ab (15) and enhanced factor H binding (7).…”

supporting

confidence: 79%

Factor H Binding and Function in Sialylated Pathogenic Neisseriae is Influenced by Gonococcal, but Not Meningococcal, Porin

Madico

Ngampasutadol

Gulati

et al. 2007

The Journal of Immunology

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Neisseria gonorrhoeae and Neisseria meningitidis both express the lacto-N-neotetraose (LNT) lipooligosaccharide (LOS) molecule that can be sialylated. Although gonococcal LNT LOS sialylation enhances binding of the alternative pathway complement inhibitor factor H and renders otherwise serum-sensitive bacteria resistant to complement-dependent killing, the role of LOS sialylation in meningococcal serum resistance is less clear. We show that only gonococcal, but not meningococcal, LNT LOS sialylation enhanced factor H binding. Replacing the porin (Por) B molecule of a meningococcal strain (LOS sialylated) that did not bind factor H with gonococcal Por1B augmented factor H binding. Capsule expression did not alter factor H binding to meningococci that express gonococcal Por. Conversely, replacing gonococcal Por1B with meningococcal PorB abrogated factor H binding despite LNT LOS sialylation. Gonococcal Por1B introduced in the background of an unsialylated meningococcus itself bound small amounts of factor H, suggesting a direct factor H-Por1B interaction. Factor H binding to unsialylated meningococci transfected with gonococcal Por1B was similar to the sialylated counterpart only in the presence of higher (20 μg/ml) concentrations of factor H and decreased in a dose-responsive manner by ∼80% at 1.25 μg/ml. Factor H binding to the sialylated strain remained unchanged over this factor H concentration range however, suggesting that LOS sialylation facilitated optimal factor H-Por1B interactions. The functional counterpart of factor H binding showed that sialylated meningococcal mutants that possessed gonococcal Por1B were resistant to complement-mediated killing by normal human serum. Our data highlight the different mechanisms used by these two related species to evade complement.

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supporting

confidence: 79%

Factor H Binding and Function in Sialylated Pathogenic Neisseriae is Influenced by Gonococcal, but Not Meningococcal, Porin

Madico

Ngampasutadol

Gulati

et al. 2007

The Journal of Immunology

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“…Ram et al (1998) suggested that an increased conversion of C3b to iC3b on the gonococcal surface might contribute to serum resistance in vivo. This idea is supported by in vitro studies of gonococcal infection of neutrophils, in which a predominance of iC3b (in comparison with C3b) is found on the surface of gonococci (Jarvis et al, 1999;McQuillen et al, 1999;Vogel and Frosch, 1999). Conversion of C3b to iC3b on the gonococcal surface would permit efficient internalization of infecting gonococci (via CR3) into the cervical epithelium and could lead to the asymptomatic condition observed with gonococcal infection in a substantial proportion of women.…”

Section: Discussionmentioning

confidence: 96%

“…Several lines of evidence suggest that C H alternative pathway inactivation occurs with N. gonorrhoeae infection (Densen et al, 1982;Densen, 1989;Wetzler et al, 1992;de la Paz et al, 1995;Ram et al, 1998;Jarvis et al, 1999;McQuillen et al, 1999;Vogel and Frosch, 1999). This prompted us to examine the role of CR3 in N. gonorrhoeae infection of the cervical epithelium.…”

Section: Analysis Of Cr3 Expression In Primary Human Cervical Epithelmentioning

confidence: 99%

The role of complement receptor 3 (CR3) inNeisseria gonorrhoeaeinfection of human cervical epithelia

Edwards¹,

Brown²,

Ault³

et al. 2001

Cellular Microbiology

115

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“…However, sialylation in the experiments described was performed using low concentrations (2 g/ml) of CMP-NANA, which results in Ͻ5% of the total LOS becoming sialylated (70). Classical pathway regulation by gonococcal LOS sialylation is not secondary to a decrease in NHSderived Ig binding to bacteria (71) or because of an increase in C4BP binding (72). Therefore, a unifying explanation of how sialylation of gonococci reduces C4 binding to organisms in chimpanzee (but not rhesus) serum is not evident presently.…”

Section: Discussionmentioning

confidence: 99%

Human Factor H Interacts Selectively with Neisseria gonorrhoeae and Results in Species-Specific Complement Evasion

Ngampasutadol

Ram

Gulati

et al. 2008

The Journal of Immunology

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113

143

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Complement forms a key arm of innate immune defenses against gonococcal infection. Sialylation of gonococcal lipo-oligosaccharide, or expression of porin 1A (Por1A) protein, enables Neisseria gonorrhoeae to bind the alternative pathway complement inhibitor, factor H (fH), and evade killing by human complement. Using recombinant fH fragment-murine Fc fusion proteins, we localized two N. gonorrhoeae Por1A-binding regions in fH: one in complement control protein domain 6, the other in complement control proteins 18–20. The latter is similar to that reported previously for sialylated Por1B gonococci. Upon incubation with human serum, Por1A and sialylated Por1B strains bound full-length human fH (HufH) and fH-related protein 1. In addition, Por1A strains bound fH-like protein 1 weakly. Only HufH, but not fH from other primates, bound directly to gonococci. Consistent with direct HufH binding, unsialylated Por1A gonococci resisted killing only by human complement, but not complement from other primates, rodents or lagomorphs; adding HufH to these heterologous sera restored serum resistance. Lipo-oligosaccharide sialylation of N. gonorrhoeae resulted in classical pathway regulation as evidenced by decreased C4 binding in human, chimpanzee, and rhesus serum but was accompanied by serum resistance only in human and chimpanzee serum. Direct-binding specificity of HufH only to gonococci that prevents serum killing is restricted to humans and may in part explain species-specific restriction of natural gonococcal infection. Our findings may help to improve animal models for gonorrhea while also having implications in the choice of complement sources to evaluate neisserial vaccine candidates.

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Complement Processing and Immunoglobulin Binding toNeisseria gonorrhoeaeDetermined In Vitro Simulates In Vivo Effects

Cited by 55 publications

References 62 publications

Factor H Binding and Function in Sialylated Pathogenic Neisseriae is Influenced by Gonococcal, but Not Meningococcal, Porin

Factor H Binding and Function in Sialylated Pathogenic Neisseriae is Influenced by Gonococcal, but Not Meningococcal, Porin

The role of complement receptor 3 (CR3) inNeisseria gonorrhoeaeinfection of human cervical epithelia

Human Factor H Interacts Selectively with Neisseria gonorrhoeae and Results in Species-Specific Complement Evasion

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