1.
Blom, Anna, et al.
(författare)
Contribution of interactions between complement inhibitor C4b-binding protein and pathogens to their ability to establish infection with particular emphasis on Neisseria gonorrhoeae.
2008
Ingår i: Vaccine. - : Elsevier BV. - 1873-2518 .- 0264-410X. ; 26 Suppl 8, s. 49-55
Tidskriftsartikel (refereegranskat) abstract
Complement activation and resulting opsonisation with C3b form key arms of the innate immune defense against infections. However, a wide variety of pathogens subvert complement attack by binding host complement inhibitors, which results in diminished opsonophagocytosis and killing of bacteria by lysis. Human C4b-binding protein (C4BP) binds Neisseria gonorrhoeae and Streptococcus pyogenes, both uniquely human pathogens. This binding specificity is circumvented by other bacterial species, which bind C4BP from numerous mammalian hosts that they infect. Binding of C4BP to Neisseria is mediated by outer membrane porin proteins and appears to be one of the main factors mediating serum resistance. Targeting C4BP binding sites on bacterial surfaces with vaccine-induced antibodies may block binding of C4BP and enhance a common vaccine design strategy that depends on the generation of complement-dependent bactericidal and opsonophagocytic antibody activities.
2.
Frye, Amber M., et al.
(författare)
A soft tick Ornithodoros moubata salivary protein OmCI is a potent inhibitor to prevent avian complement activation
2020
Ingår i: Ticks and Tick-borne Diseases. - : Elsevier BV. - 1877-959X. ; 11:2
Tidskriftsartikel (refereegranskat) abstract
Complement is a key first line innate host defense system in the blood of vertebrates. Upon activation, this powerful defense mechanism can elicit inflammatory responses, lyse non-self-cells, or mark them for opsonophagocytic removal. Blood-feeding arthropods thus require the ability to block host complement activation in the bloodmeal to prevent undesired cell or tissue damage during feeding. The soft tick Ornithodoros moubata produces a complement inhibitory protein, OmCI. This protein binds to a mammalian complement protein C5 and blocks further activation of complement cascades, which results in the prevention of complement-mediated bacterial killing through membrane attack complex. Interestingly, the amino acids involved in OmCI binding are highly conserved among mammalian and avian C5, but the ability of this protein to inhibit the complement from birds remains unclear. Here we demonstrated that OmCI is capable of preventing quail complement-mediated erythrocyte lysis, inhibiting the capability of this animal's complement to eliminate a serum-sensitive Lyme disease bacterial strain. We also found that the ability of OmCI to inhibit quail complement-mediated killing of Lyme disease bacteria can be extended to different domestic and wild birds. Our results illustrate the utility of OmCI to block bird complement. These results provide the foundation for further use of this protein as a tool to study the molecular basis of avian complement and pathogen evasion to such a defense mechanism.
3.
Lewis, Lisa A., et al.
(författare)
Defining targets for complement components C4b and C3b on the pathogenic neisseriae
2008
Ingår i: Infection and Immunity. - 1098-5522. ; 76:1, s. 339-350
Tidskriftsartikel (refereegranskat) abstract
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 N. 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 predominately expressed individual Opa proteins, we found that all expressed 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 enhanced serum sensitivity of Por1B-bearing gonococci. The binding of C3b and C4b to Opa provide 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.
4.
Ngampasutadol, Jutamas, et al.
(författare)
Species-specificity of Neisseria gonorrhoeae infection: Do human complement regulators contribute?
2008
Ingår i: Vaccine. - : Elsevier BV. - 1873-2518 .- 0264-410X. ; 26, s. 62-66
Tidskriftsartikel (refereegranskat) abstract
Neisseria gonorrhoeae is the causative agent of gonorrhea, a disease restricted to humans. Complement forms a key arm of the innate immune system that combats gonococcal infections. N. gonorrhoeae uses its outer membrane porin (Por) molecules to bind complement clown-regulatory proteins, C4b-binding protein (C4BP) and factor H (M), to evade killing by human complement. In addition, sialylation of gonococcal lipooligosaccharide (LOS) also enables N. gonorrhoeae to bind fH. Strains of N. gonorrhoeae that resist killing by human serum complement are killed by serum from rodent, lagomorph and primate species, which cannot be readily infected experimentally with this organism and whose C4BP and/or fH molecules do not bind to N. gonorrhoeae. Serum resistance of gonococci is restored in these sera by human C4BP and/or fH Direct binding specificity of human and chimpanzee C4BP and human fH to gonococci may explain, in part, species-specific restriction of natural gonococcal infection and address why Por1B, but not Por1A containing gonococcal strains, have been successful in experimental chimpanzee 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. (C) 2008 Elsevier Ltd. All rights reserved.
5.
Ram, Sanjay, et al.
(författare)
Heptose I glycan substitutions on Neisseria gonorrhoeae lipooligosaccharide influence C4b-binding protein binding and serum resistance.
2007
Ingår i: Infection and Immunity. - 1098-5522. ; 75:8, s. 4071-4081
Tidskriftsartikel (refereegranskat) abstract
Lipooligosaccharide (LOS) heptose (Hep) glycan substitutions influence gonococcal serum resistance. Several gonococcal strains bind the classical complement pathway inhibitor, C4b-binding protein (C4BP), via their porin (Por) molecule to escape complement-dependent killing by normal human serum (NHS). We show that the proximal glucose (Glc) on HepI is required for C4BP binding to Por1B-bearing gonococcal strains MS11 and 1291 but not to FA19 (Por1A). The presence of only the proximal Glc on HepI (lgtE mutant) permitted maximal C4BP binding to MS11 but not to 1291. Replacing 1291 lgtE Por with MS11 Por increased C4BP binding to levels that paralleled MS11 lgtE, suggesting that replacement of the Por1B molecule dictated the effects of HepI glycans on C4BP binding. The remainder of the strain background did not affect C4BP binding; replacing the Por of strain F62 with MS11 Por (F62 PorMS11) and truncating HepI mirrored the findings in the MS11 background. C4BP binding correlated with resistance to killing by NHS in most instances. F62 PorMS11 and its lgtE mutant were sensitive to NHS despite binding C4BP, secondary to kinetically overwhelming classical pathway activation and possibly increased alternative pathway activation (measured by factor Bb binding) by the F62 background. FA19 lgtF (HepI unsubstituted) resisted killing by only 10% NHS, not 50% NHS, despite binding levels of C4BP similar to those of FA19 and FA19 lgtE (both resistant to 50% serum), suggesting a role for the proximal Glc in serum resistance independently of C4BP binding. This study provides mechanistic insights into how HepI LOS substitutions affect the serum resistance of N. gonorrhoeae.
