Binding of complement factor H to loop 5 of porin protein 1A: A molecular mechanism of serum resistance of non-sialylated Neisseria gonorrhoeae

Ram, Sanjay; McQuillen, Daniel P.; Gulati, Sunita; Elkins, Christopher A.; Pangburn, Michael K.; Rice, Peter A.

doi:10.1016/s0161-5890(98)90800-8

Cited by 85 publications

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“…In contrast to our study, the precise interacting sequence motif responsible for the binding of factor H could not be identified. For example, a sequence of the M5 protein of Streptococcus pyogenes composed of 42 amino acids located in the hypervariable A-region [26,27], or a 222 amino acid sequence harbored in the pneumococcal Hic protein (residues 39-261) [28], and loop 5 of the neisserial PorA1 protein [29] were shown to exerts factor H-binding capacities. Thus, the identification of a conserved peptide motif of nine amino acids shows that rather short peptides can mediate interaction of pathogenic organisms with host immune regulators.…”

Section: Discussionmentioning

confidence: 99%

Immune evasion of Borrelia burgdorferi: mapping of a complement‐inhibitor factor H‐binding site of BbCRASP‐3, a novel member of the Erp protein family

et al. 2003

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The causative agents of Lyme disease, Borrelia burgdorferi s.s., B. garinii, and B. afzelii, differ in their susceptibility to complement‐mediated lysis. This phenomenon apparently depends on the expression of proteins termed complement regulator‐acquiring surface proteins (CRASP) and their binding to the inhibitory plasma proteins factor H and FHL‐1. To characterize these bacterial proteins in more detail we have now isolated from a B. burgdorferi expression library a novel factor H‐binding protein. In accordance with our previous studies this protein was termed BbCRASP‐3 and represents a novel member of the polymorphic Erp (OspE/F‐related) protein family. On the basis of protease accessibility assays using intact spirochetes, BbCRASP‐3 isidentified as a surface‐exposed protein and binds the C‐terminal short consensus repeats of factor H. Applying deletion mutants of BbCRASP‐3, the factor H‐binding site was mapped to the nine‐amino‐acid motif LEVLKKNLK localized at the C‐terminal end of BbCRASP‐3. Factor H bound to BbCRASP‐3 maintains its cofactor activity in factor I‐mediated C3b inactivation. Binding of BbCRASP‐3 to factor H can be inhibited by heparin, a physiological ligand of the complement regulator factor H. Blocking of factor‐H‐binding by soluble BbCRASP‐3 leads to an increase of complement deposition on intermediate serum‐resistant strain ZS7. In conclusion, BbCRASP‐3 has been identified as a novel factor H‐binding protein on B. burgdorferi which by conferring complement resistance to the pathogen may contribute to its persistence in the mammalian host.

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Section: Discussionmentioning

confidence: 99%

Immune evasion of Borrelia burgdorferi: mapping of a complement‐inhibitor factor H‐binding site of BbCRASP‐3, a novel member of the Erp protein family

et al. 2003

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“…There are several ways in which N. gonorrhoeae may avoid attack from the complement system. For example, many strains bind complement factor H via LPS or one of the major outer membrane proteins, porin Por1A (11,12). Moreover, C4BP binds to porins of some strains of N. gonorrhoeae (13).…”

Section: Discussionmentioning

confidence: 99%

“…These isolates may persist locally without evoking clinically significant local inflammation, in contrast to serum-sensitive gonococci, which usually cause acute severe local inflammation and pelvic inflammatory disease (9,10). Recently, the serum resistance of certain strains of N. gonorrhoeae has been attributed to binding of complement regulatory protein factor H to LPS or to a major outer membrane protein, Por1A (11,12). Furthermore, porins bind another complement regulator, C4b-binding protein (C4BP) (13).…”

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confidence: 99%

A Novel Interaction Between Type IV Pili ofNeisseria gonorrhoeaeand the Human Complement Regulator C4b-Binding Protein

Blom

Rytkönen

Vásquez

et al. 2001

The Journal of Immunology

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C4b-binding protein (C4BP) is an important plasma inhibitor of the classical pathway of complement activation. Several bacterial pathogens bind C4BP, which may contribute to their virulence. In the present report we demonstrate that isolated type IV pili from Neisseria gonorrhoeae bind human C4BP in a dose-dependent and saturable manner. C4BP consists of seven identical α-chains and one β-chain linked together with disulfide bridges. We found that pili bind to the α-chain of C4BP, which is composed of eight homologous complement control protein (CCP) domains. From the results of an inhibition assay with C4b and a competition assay in which we tested mutants of C4BP lacking individual CCPs, we concluded that the binding area for pili is localized to CCP1 and CCP2 of the α-chain. The binding between pili and C4BP was abolished at 0.25 M NaCl, implying that it is based mostly on ionic interactions, similarly to what have been observed for C4b-C4BP binding. Furthermore, the N-terminal part of PilC, a structural component of pili, appeared to be responsible for binding of C4BP. Membrane cofactor protein, previously shown to be a receptor for pathogenic N. gonorrhoeae on the surface of epithelial cells, competed with C4BP for binding to pili only at high concentrations, suggesting that different parts of pili are involved in these two interactions. Accordingly, high concentrations of C4BP were required to inhibit binding of N. gonorrhoeae to Chang conjunctiva cells, and no inhibition of binding was observed with cervical epithelial cells.

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“…This increase in FH binding is dependent on expression of gonococcal porin (PorB); replacing gonococcal PorB with meningococcal PorB abrogates Neu5Ac-mediated enhancement of FH binding (25). Several strains of N. gonorrhoeae also bind FH independently of LOS sialylation (26).…”

Section: Introductionmentioning

confidence: 99%

A novel factor H-FC chimeric immunotherapeutic molecule against Neisseria gonorrhoeae

Shaughnessy¹,

Gulati²,

Monks³

et al. 2012

Immunobiology

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Neisseria gonorrhoeae (Ng), the causative agent of the sexually transmitted infection gonorrhea, has developed resistance to almost every conventional antibiotic. There is an urgent need to develop novel therapies against gonorrhea. Many pathogens, including Ng, bind the complement inhibitor factor H (FH) to evade complement-dependent killing. Sialylation of gonococcal lipooligosaccharide, as occurs in vivo, augments binding of human FH through its domains [18][19][20]. We explored the utility of fusing FH18-20 with IgG Fc (FH18-20/Fc) to create a novel anti-infective immunotherapeutic. FH18-20 also binds to select host glycosaminoglycans to limit unwanted complement activation on host cells. To identify mutation(s) in FH18-20 that eliminated complement activation on host cells, yet maintained binding to Ng, we created four mutations in domains 19 or 20 described in atypical hemolytic uremic syndrome that prevented binding of mutated fH to human erythrocytes. HHS Public Access

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Binding of complement factor H to loop 5 of porin protein 1A: A molecular mechanism of serum resistance of non-sialylated Neisseria gonorrhoeae

Cited by 85 publications

References 0 publications

Immune evasion of Borrelia burgdorferi: mapping of a complement‐inhibitor factor H‐binding site of BbCRASP‐3, a novel member of the Erp protein family

Immune evasion of Borrelia burgdorferi: mapping of a complement‐inhibitor factor H‐binding site of BbCRASP‐3, a novel member of the Erp protein family

A Novel Interaction Between Type IV Pili ofNeisseria gonorrhoeaeand the Human Complement Regulator C4b-Binding Protein

A novel factor H-FC chimeric immunotherapeutic molecule against Neisseria gonorrhoeae

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