Complement‐Dependent Synergistic Bactericidal Activity of Antibodies against Factor H–Binding Protein, a Sparsely Distributed Meningococcal Vaccine Antigen

Welsch, Jo Anne; Ram, Sanjay; Koeberling, Oliver; Granoff, Dan M.

doi:10.1086/528994

Cited by 105 publications

(152 citation statements)

References 46 publications

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“…C, surface plot of SEB shows mutated residues (red color) which are distinct from D the MHC surface (rotating 180 degrees around vertical axis) shows in cyan (residues 43, 44, 45, 46, 47, treatment of viral diseases including rabies and SARS, combination of mAbs against wild-type epitope and variant epitope can prevent the emergence of escape variants (47,48). Moreover several studies have shown that targeting more than one adhesion protein with mAb in S. aureus infection can be beneficial (49,50).…”

Section: Discussionmentioning

confidence: 99%

Generation, Characterization, and Epitope Mapping of Neutralizing and Protective Monoclonal Antibodies against Staphylococcal Enterotoxin B-induced Lethal Shock

Varshney

Wang

Cook

et al. 2011

Journal of Biological Chemistry

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T-cell stimulating activity of Staphylococcal enterotoxin B (SEB) is an important factor in the pathogenesis of certain staphylococcal diseases including SEB mediated shock. SEB is one of the most potent superantigens known and treatment of SEB induced shock remains a challenge. We generated and characterized murine monoclonal antibodies (mAbs) to SEB in mice. We tested mAbs neutralize mitogenic effects of SEB in vitro and in vivo with T-cell proliferation assays and 2 murine models for SEB induced lethal shock (SEBILS). Epitope mapping suggests that all these mAbs recognize conformational epitopes that are destroyed by deleting the C terminus of the protein. Further site-directed mutagenesis identified potential residues involved in binding to SEB that differ between Methicillin resistant and sensitive Staphylococcus aureus strains. Only mAb 20B1 was effective as a monotherapy in treating SEBILS in HLA DR3 transgenic mice, which exhibit enhanced sensitivity to SEB. It is noteworthy that mAbs, 14G8 and 6D3 were not protective when given alone in the HLA DR3 mice but their efficacy of protection could be greatly enhanced when mAbs were co-administered simultaneously. Our data suggest combinations of defined mAbs may constitute a better treatment strategy and provide a new insight for the development of passive immunotherapy. The Staphylococcal enterotoxins (SEs)2 comprise a family of distinct toxins (A-E) all of which are excreted by various strains of Staphylococcus aureus (S. aureus) (1). Staphylococcal enterotoxin B (SEB) is a well characterized 28 kDa protein that is related to SEC1-3 on the basis of sequence homology (1, 2). SEB is a superantigen that triggers cytokine production and T-cell proliferation by cross-linking MHC class II molecules on antigen presenting cells and T-cell receptors (TCR) (2-5). In humans, SEB can trigger toxic shock, profound hypotension and multi-organ failure. SEB is the major enterotoxin associated with non-menstrual toxic shock syndrome and accounts for the majority of intoxications that are not caused by toxic shock syndrome toxin 1 (TSST-1). In addition, some reports indicate that SEB induces an IgE response and thereby might contribute to the pathogenesis of asthma, chronic rhinitis, and dermatitis (6 -9). SEB is considered a select agent. The quantities needed to produce a desired effect are much lower than with synthetic chemicals. Also SEB can be easily produced in large quantities (10).Currently there are no therapies available for treating enterotoxin-induced shock, but clinical data suggests that immunoglobulins can alleviate disease (11). Moreover, passive administration of pooled human immunoglobulin, as well as murine and chicken antibodies (Abs) can protect against SEB induced lethal shock (SEBILS) in murine and primate animal models as well as against SEB triggered release of cytokines by SEB stimulated T-cells (12, 13). The efficacy of humoral immunity in protection against SEB was established by demonstrating an inverse relationship between susceptibility and an...

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Section: Discussionmentioning

confidence: 99%

Generation, Characterization, and Epitope Mapping of Neutralizing and Protective Monoclonal Antibodies against Staphylococcal Enterotoxin B-induced Lethal Shock

Varshney

Wang

Cook

et al. 2011

Journal of Biological Chemistry

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“…The role of fHBP in binding the factor H fluid phase regulator of the complement AP, enabling the meningococcus to avoid complement-mediated killing in blood, has been well documented (29,43,46,52). However, the action of complement must not be thought of as being limited to the bloodstream.…”

Section: Discussionmentioning

confidence: 99%

Expression of Factor H Binding Protein of Meningococcus Responds to Oxygen Limitation through a Dedicated FNR-Regulated Promoter

2010

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Factor H binding protein (fHBP) is a surface-exposed lipoprotein in Neisseria meningitidis, which is a component of several investigational vaccines against serogroup B meningococcus (MenB) currently in development. fHBP enables the bacterium to evade complement-mediated killing by binding factor H, a key downregulator of the complement alternative pathway, and, in addition, fHBP is important for meningococcal survival in the presence of the antimicrobial peptide LL-37. In this study, we investigate the molecular mechanisms involved in transcription and regulation of the fHBP-encoding gene, fhbp. We show that the fHBP protein is expressed from two independent transcripts: one bicistronic transcript that includes the upstream gene and a second shorter monocistronic transcript from its own dedicated promoter, P fhbp . Transcription from the promoter P fhbp responds to oxygen limitation in an FNR-dependent manner, and, accordingly, the FNR protein binds to a P fhbp probe in vitro. Furthermore, expression in meningococci of a constitutively active FNR mutant results in the overexpression of the fHBP protein. Finally, the analysis of fHBP regulation was extended to a panel of strains expressing different fHBP allelic variants at different levels, and we demonstrate that FNR is involved in the regulation of this antigen in all but one of the strains tested. Our data suggest that oxygen limitation may play an important role in inducing the expression of fHBP from a dedicated FNR-regulated promoter. This implies a role for this protein in microenvironments lacking oxygen, for instance in the submucosa or intracellularly, in addition to its demonstrated role in serum resistance in the blood.

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“…A number of studies have investigated the properties of monoclonal antibodies directed against fHBP (92)(93)(94). Diverse activities are described for these antibodies; some can inhibit fH binding, whereas others facilitate MnB killing either individually or in combination with other monoclonal antibodies (92,95).…”

Section: Biological Properties Of Monoclonal Antibodies Binding To Fhmentioning

confidence: 99%

“…Diverse activities are described for these antibodies; some can inhibit fH binding, whereas others facilitate MnB killing either individually or in combination with other monoclonal antibodies (92,95). Bactericidal killing can be observed with strains that express lower levels of fHBP using a combination of monoclonal antibodies that are synergistic (93). Recent data suggest that antibodies against two different meningococcal proteins, fHBP and neisserial heparin binding antigen (NHBA), can cooperate to induce a bactericidal response (96).…”

Section: Biological Properties Of Monoclonal Antibodies Binding To Fhmentioning

confidence: 99%

“…These include Western blotting, enzyme-linked immunosorbent assay (ELISA), flow cytometry, phage library screening, and nuclear magnetic resonance (NMR) and antibody structure modeling studies (16,92,93,95,98). Although these studies did not provide information as to whether the antibodies bind linear or conformational epitopes, they helped define the structure of fHBP on the bacterial surface.…”

Section: Biological Properties Of Monoclonal Antibodies Binding To Fhmentioning

confidence: 99%

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Role of Factor H Binding Protein in Neisseria meningitidis Virulence and Its Potential as a Vaccine Candidate To Broadly Protect against Meningococcal Disease

McNeil

Zagursky

Lin

et al. 2013

Microbiol Mol Biol Rev

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SUMMARY Neisseria meningitidis is a Gram-negative microorganism that exists exclusively in humans and can cause devastating invasive disease. Although capsular polysaccharide-based vaccines against serogroups A, C, Y, and W135 are widely available, the pathway to a broadly protective vaccine against serogroup B has been more complex. The last 11 years has seen the discovery and development of the N. meningitidis serogroup B (MnB) outer membrane protein factor H binding protein (fHBP) as a vaccine component. Since the initial discovery of fHBP, a tremendous amount of work has accumulated on the diversity, structure, and regulation of this important protein. fHBP has proved to be a virulence factor for N. meningitidis and a target for functional bactericidal antibodies. fHBP is critical for survival of meningococci in the human host, as it is responsible for the primary interaction with human factor H (fH). Binding of hfH by the meningococcus serves to downregulate the host alternative complement pathway and helps the organism evade host innate immunity. Preclinical studies have shown that an fHBP-based vaccine can elicit serum bactericidal antibodies capable of killing MnB, and the vaccine has shown very encouraging results in human clinical trials. This report reviews our current knowledge of fHBP. In particular, we discuss the recent advances in our understanding of fHBP, its importance to N. meningitidis , and its potential role as a vaccine for preventing MnB disease.

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Complement‐Dependent Synergistic Bactericidal Activity of Antibodies against Factor H–Binding Protein, a Sparsely Distributed Meningococcal Vaccine Antigen

Cited by 105 publications

References 46 publications

Generation, Characterization, and Epitope Mapping of Neutralizing and Protective Monoclonal Antibodies against Staphylococcal Enterotoxin B-induced Lethal Shock

Generation, Characterization, and Epitope Mapping of Neutralizing and Protective Monoclonal Antibodies against Staphylococcal Enterotoxin B-induced Lethal Shock

Expression of Factor H Binding Protein of Meningococcus Responds to Oxygen Limitation through a Dedicated FNR-Regulated Promoter

Role of Factor H Binding Protein in Neisseria meningitidis Virulence and Its Potential as a Vaccine Candidate To Broadly Protect against Meningococcal Disease

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