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Complement

Complement research in the Rice laboratory involves the identification of unique determinants present on bacterial surfaces that may serve as suitable vaccine candidates to protect against infection in humans. In some cases these determinants may also activate or regulate a series of inflammatory mediators called complement (C), which are made up of a group of proteins that are activated sequentially as part of the innate immune response: (1) to combat invading bacteria that infect humans by killing the bacteria and to also enhance their clearance by phagocytes; (2) to facilitate the development of the adaptive immune response to invading bacteria to protect against future infection caused by these organisms and (3) to amplify this immune response once it has developed. Under certain conditions C works to the disadvantage of the host because it is hijacked by microorganisms to down-regulate the activation and binding of C and to also enhance entry into phagocytes (professional and non-professional) where organisms can gain sanctuary; these areas of study are important to consider when vaccines sometimes don’t work. The laboratory examines C interactions with bacteria, particularly the Neisseria species, having been first to report interactions of Neiseria gonorrhoeae with complement (C) down-regulator molecules (factor H; an alternative pathway of C inhibitor) and C4 binding protein (C4BP; a classical pathway of C inhibitor) but also with the only known complement up-regulator, properdin. C down-regulator molecules are important in enabling Neisseria to escape immune surveillance.

Gonococcal vaccine development

As a prelude to identifying suitable vaccine candidates to protect against gonococcal infection, the laboratory first identified and characterized blocking (or subverting) antibody targets on Neisseria species that interfere with productive killing (in vitro ) by complement (C)-dependent bactericidal antibodies. These antibody responses were elicited in a human vaccination trial that used a complex outer membrane structure as an immunogen that had been derived from Neisseria gonorrhoeae. A potentially protective response (C dependent bactericidal antibodies) that was elicited in men by the vaccine was subverted by the accompanying blocking antibody response directed against small amounts of a reduction modifiable protein (Rmp) present in the vaccine, which caused the vaccine to fail when the men who received it were not protected upon subsequent urethral (experimental) challenge with virulent N. gonorrhoeae (experimental urethral gonorrhea in men is safe and an IRB approved method to study this disease). Removal of Rmp-antibody from vaccine serum that has lost baseline bactericidal activity as a result of immunization, restores killing. These experiments were subsequently repeated (and verified) in the mouse experimental model of gonococcal infection. Blocking antibodies are present in normal human serum and are also elicited by gonococcal infection itself. These antibodies may reverse a protective immune antibody response (--a response that may occur with other bacterial infections) and may explain the lack of protective immunity that occurs after gonococcal infection.

In efforts to identify suitable subunit vaccine candidates against gonorrhea devoid of blocking activity, the laboratory examined the chemistry (and immunochemistry) of gonococcal lipopolysaccharide (also known as lipooligosaccharide [LOS]), having reported the first known conserved gonococcal LOS derived oligosaccharide epitope (called 2C7) that is present on almost all wild-type strains of N. gonorrhoeae. This epitope, located in the core of LOS as lactose substitutions on each of the two core heptose molecules of LOS, elicits complement dependent antibody activity in humans both in natural human infection and as a consequence of experimental animal immunization. The Rice laboratory and its collaborators have performed extensive biochemical, structural and genetic analysis of this carbohydrate epitope and the surrounding structure(s) to define their role in complement (C) binding. The 2C7 epitope is: i) broadly expressed as a gonococcal antigenic target in human infection; ii) a critical requirement for gonococcal colonization in the experimental setting and iii) a virulence determinant that is maintained and expressed by gonococci.

To circumvent inherent limitations of carbohydrate antigens as immunogens when they are used as vaccines, the laboratory also “converted” the 2C7 epitope into peptide mimics, first into an anti-idiotope (protein) and then into a complex peptide mimic for testing as vaccine candidates; both have been shown to be the immunologic counterparts (surrogates) of the oligosaccharide epitope. To formulate a prototype vaccine candidate intended for use in humans that represented the 2C7 epitope in antigenicity and immunogenicity, the lab synthesized the candidate compound to >95% purity.  This vaccine candidate, called TMCP2, when administered to BALB/c mice in combination with glucopyranosyl lipid A-stable oil-in-water nanoemulsion (GLA-SE; a Toll-like receptor 4 and TH1 promoting adjuvant), elicited bactericidal IgG and reduced colonization levels of gonococci in experimentally infected mice while accelerating clearance by each of two different gonococcal strains.

These inventions (prototypes and finalized products) have been issued U.S. and foreign patents and are being configured with appropriate adjuvants for use in: (1) humans and (2) experimental models in mice adapted to stimulate the human complement down-regulator system by creating human FH/C4BP transgenic mice.  A gonococcal vaccine candidate has been developed that can be scaled up and produced economically to a high degree of purity. The candidate elicits bactericidal antibodies and is efficacious in a pre-clinical experimental infection model.

One or more keywords matched the following items that are connected to Rice, Peter
Item TypeName
Academic Article A novel sialic acid binding site on factor H mediates serum resistance of sialylated Neisseria gonorrhoeae.
Academic Article The contrasting mechanisms of serum resistance of Neisseria gonorrhoeae and group B Neisseria meningitidis.
Academic Article C4bp binding to porin mediates stable serum resistance of Neisseria gonorrhoeae.
Academic Article Binding of complement factor H to loop 5 of porin protein 1A: a molecular mechanism of serum resistance of nonsialylated Neisseria gonorrhoeae.
Academic Article Complement processing and immunoglobulin binding to Neisseria gonorrhoeae determined in vitro simulates in vivo effects.
Academic Article Binding of vitronectin by the Moraxella catarrhalis UspA2 protein interferes with late stages of the complement cascade.
Academic Article Early complement components enhance neutralization of Chlamydia trachomatis infectivity by human sera.
Academic Article Binding of C4b-binding protein to porin: a molecular mechanism of serum resistance of Neisseria gonorrhoeae.
Academic Article Factor H binding and function in sialylated pathogenic neisseriae is influenced by gonococcal, but not meningococcal, porin.
Academic Article Molecular characterization of the interaction between porins of Neisseria gonorrhoeae and C4b-binding protein.
Academic Article Molecular basis for serum resistance in Neisseria gonorrhoeae.
Academic Article Infections of people with complement deficiencies and patients who have undergone splenectomy.
Academic Article A meningococcal factor H binding protein mutant that eliminates factor H binding enhances protective antibody responses to vaccination.
Academic Article Regulation of the mannan-binding lectin pathway of complement on Neisseria gonorrhoeae by C1-inhibitor and alpha 2-macroglobulin.
Academic Article Linkage specificity and role of properdin in activation of the alternative complement pathway by fungal glycans.
Academic Article Enhanced bacteremia in human factor H transgenic rats infected by Neisseria meningitidis.
Academic Article Properdin is critical for antibody-dependent bactericidal activity against Neisseria gonorrhoeae that recruit C4b-binding protein.
Academic Article Phosphoethanolamine residues on the lipid A moiety of Neisseria gonorrhoeae lipooligosaccharide modulate binding of complement inhibitors and resistance to complement killing.
Academic Article Mechanism of action of blocking immunoglobulin G for Neisseria gonorrhoeae.
Academic Article Neisserial lipooligosaccharide is a target for complement component C4b. Inner core phosphoethanolamine residues define C4b linkage specificity.
Academic Article Killing of dsrA mutants of Haemophilus ducreyi by normal human serum occurs via the classical complement pathway and is initiated by immunoglobulin M binding.
Academic Article Enhanced factor H binding to sialylated Gonococci is restricted to the sialylated lacto-N-neotetraose lipooligosaccharide species: implications for serum resistance and evidence for a bifunctional lipooligosaccharide sialyltransferase in Gonococci.
Academic Article Human C4b-binding protein selectively interacts with Neisseria gonorrhoeae and results in species-specific infection.
Academic Article Heptose I glycan substitutions on Neisseria gonorrhoeae lipooligosaccharide influence C4b-binding protein binding and serum resistance.
Academic Article Defining targets for complement components C4b and C3b on the pathogenic neisseriae.
Academic Article Human factor H interacts selectively with Neisseria gonorrhoeae and results in species-specific complement evasion.
Academic Article Phosphoethanolamine substitution of lipid A and resistance of Neisseria gonorrhoeae to cationic antimicrobial peptides and complement-mediated killing by normal human serum.
Academic Article Species-specificity of Neisseria gonorrhoeae infection: do human complement regulators contribute?
Academic Article An evaluation of the role of properdin in alternative pathway activation on Neisseria meningitidis and Neisseria gonorrhoeae.
Academic Article Factor H facilitates adherence of Neisseria gonorrhoeae to complement receptor 3 on eukaryotic cells.
Academic Article Molecular characterization of the interaction between sialylated Neisseria gonorrhoeae and factor H.
Academic Article Relative contributions of dectin-1 and complement to immune responses to particulate ?-glucans.
Academic Article Mechanisms of stable serum resistance of Neisseria gonorrhoeae.
Academic Article Natural serum bactericidal activity against Neisseria gonorrhoeae isolates from disseminated, locally invasive, and uncomplicated disease.
Academic Article Complement-mediated bacterial killing assays.
Academic Article Serum resistance of Neisseria gonorrhoeae. Does it thwart the inflammatory response and facilitate the transmission of infection?
Concept Complement C1 Inactivator Proteins
Concept Complement C3b Inactivator Proteins
Concept Complement C4b-Binding Protein
Concept Complement Pathway, Classical
Concept Complement Factor H
Concept Complement Inactivator Proteins
Concept Complement System Proteins
Concept Receptors, Complement
Concept Complement Inactivating Agents
Concept Complement C4
Concept Complement C3 Convertase, Alternative Pathway
Concept Complement C9
Concept Complement Factor B
Concept Complement C3b
Concept Complement Activation
Concept Complement Pathway, Alternative
Concept Complement C1q
Concept Complement C4b
Concept Complement C3
Academic Article a-2,3-sialyltransferase expression level impacts the kinetics of lipooligosaccharide sialylation, complement resistance, and the ability of Neisseria gonorrhoeae to colonize the murine genital tract.
Academic Article Virulence of Group A Streptococci Is Enhanced by Human Complement Inhibitors.
Academic Article Utilizing CMP-Sialic Acid Analogs to Unravel Neisseria gonorrhoeae Lipooligosaccharide-Mediated Complement Resistance and Design Novel Therapeutics.
Academic Article A Novel Factor H-Fc Chimeric Immunotherapeutic Molecule against Neisseria gonorrhoeae.
Academic Article Utilizing complement evasion strategies to design complement-based antibacterial immunotherapeutics: Lessons from the pathogenic Neisseriae.
Academic Article Gonococcal lipooligosaccharide sialylation: virulence factor and target for novel immunotherapeutics.
Academic Article Human IgG Increases Virulence of Streptococcus pyogenes through Complement Evasion.
Academic Article Human Factor H Domains 6 and 7 Fused to IgG1 Fc Are Immunotherapeutic against Neisseria gonorrhoeae.
Academic Article Role of Gonococcal Neisserial Surface Protein A (NspA) in Serum Resistance and Comparison of Its Factor H Binding Properties with Those of Its Meningococcal Counterpart.
Academic Article Targeting Lipooligosaccharide (LOS) for a Gonococcal Vaccine.
Academic Article Complement-Dependent Serum Bactericidal Assays for Neisseria gonorrhoeae.
Academic Article Complement alone drives efficacy of a chimeric antigonococcal monoclonal antibody.
Academic Article Efficacy of Antigonococcal CMP-Nonulosonate Therapeutics Require Cathelicidins.
Academic Article Synthetic DNA Delivery of an Optimized and Engineered Monoclonal Antibody Provides Rapid and Prolonged Protection against Experimental Gonococcal Infection.
Academic Article Efficacy of an Experimental Gonococcal Lipooligosaccharide Mimitope Vaccine Requires Terminal Complement.
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  • Complement C6