title: Identification and therapeutic potential of a vitronectin binding region of meningococcal msf.
abstract: The human pathogen Neisseria meningitides (Nm) attains serum resistance via a number of mechanisms, one of which involves binding to the host complement regulator protein vitronectin. We have shown previously that the Meningococcal surface fibril (Msf), a trimeric autotransporter, binds to the activated form of vitronectin (aVn) to increase Nm survival in human serum. In this study, we aimed to identify the aVn-binding region of Msf to assess its potential as an antigen which can elicit antibodies that block aVn binding and/or possess bactericidal properties. Using several recombinant Msf fragments spanning its surface-exposed region, the smallest aVn-binding recombinants were found to span residues 1-86 and 39-124. The use of further deletion constructs and overlapping recombinant Msf fragments suggested that a region of Msf comprising residues 39-82 may be primarily important for aVn binding and that other regions may also be involved but to a lesser extent. Molecular modelling implicated K66 and K68, conserved in all available Msf sequences, to be involved in the interaction. Recombinant fragments which bound to aVn were able to reduce the survival advantage conveyed by aVn-interaction in serum bactericidal assays. Antibodies raised against one such fragment inhibited aVn binding to Msf. In addition, the antibodies enhanced specific killing of Msf-expressing Nm in a dose-dependent manner. Overall, this study identifies an aVn-binding region of Msf, an adhesin known to impart serum resistance properties to the pathogen; and shows that this region of Msf can elicit antibodies with dual properties which reduce pathogen survival within the host and thus has potential as a vaccine antigen.
authors.affiliation: School of Cellular & Molecular Medicine, Medical Sciences Building, University Walk, University of Bristol, Bristol, BS8 ITD, United Kingdom.
authors.forename: Darryl J
authors.initials: DJ
authors.lastname: Hill
authors.affiliation: School of Cellular & Molecular Medicine, Medical Sciences Building, University Walk, University of Bristol, Bristol, BS8 ITD, United Kingdom.
authors.forename: Natalie J
authors.initials: NJ
authors.lastname: Griffiths
authors.affiliation: School of Cellular & Molecular Medicine, Medical Sciences Building, University Walk, University of Bristol, Bristol, BS8 ITD, United Kingdom.
authors.forename: Elena
authors.initials: E
authors.lastname: Borodina
authors.affiliation: School of Cellular & Molecular Medicine, Medical Sciences Building, University Walk, University of Bristol, Bristol, BS8 ITD, United Kingdom.
authors.forename: Clio A
authors.initials: CA
authors.lastname: Andreae
authors.affiliation: School of Biochemistry, Medical Sciences Building, University Walk, University of Bristol, Bristol, BS8 ITD, United Kingdom.
authors.forename: Richard B
authors.initials: RB
authors.lastname: Sessions
authors.affiliation: School of Cellular & Molecular Medicine, Medical Sciences Building, University Walk, University of Bristol, Bristol, BS8 ITD, United Kingdom.
authors.forename: Mumtaz
authors.initials: M
authors.lastname: Virji
mesh_terms: D000595:Amino Acid Sequence; D001426:Bacterial Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D001665:Binding Sites; D008969:Molecular Sequence Data; D009345:Neisseria meningitidis / Q000378:metabolism*; D019096:Vitronectin / Q000378:metabolism*
chemical_list: D001426:Bacterial Proteins; D019096:Vitronectin
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