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Title: The interaction between factor H and factor H binding protein in susceptibility to Meningococcal disease
Author: Tan, Lionel
Awarding Body: Imperial College London
Current Institution: Imperial College London
Date of Award: 2012
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Neisseria meningitidis recruits the complement regulator, factor H (fH), to its surface via factor H binding protein (fHbp), enabling it to evade the immune system. fHbp was included in vaccines prior to it being known that fHbp bound fH, potentially masking epitopes and reducing immunogenicity. fH comprises 20 short consensus repeat (SCR) domains. fHbp binds to SCRs 6 and 7 of human but not murine fH. fHbp is classified into three variant families (V1, V2 and V3). High affinity interactions between fHbp V1 and fH are dependent on two amino acids in fHbp, E283 and E304. Using modified recombinant fHbps with defined amino acid changes at E283 and E304, wild-type and transgenic mice (expressing a chimeric fH containing human SCRs 6-8) were immunised. Despite a reduction in fH binding by far Western and surface plasmon resonance analyses, the modified fHbps retained their immunogenicity and elicited variant-specific bactericidal activity equivalent to wild-type fHbp V1. fHbps V2 and V3 were shown to bind fH with high affinity; however, mutagenesis of amino acids in fHbps V2 and V3 corresponding to E283 and E304 demonstrated that these residues are less involved in interactions with fH. Furthermore, N.gonorrhoeae has an orthologue of fHbp, ngo0033; the protein, NGO0033, shares 86% amino acid identity with fHbp V3, but does not bind fH. Finally, invasive meningococcal strains in which fHbp either contained a frame shift mutation or was entirely absent were found to not express fHbp and were shown to have reduced capacity to bind fH. This suggests that expression of fHbp is not essential for virulence in these strains. Furthermore, the lack of expression of fHbp may also have implications for fHbp containing vaccines.
Supervisor: Tang, Christoph Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available