Complement Factor H Related Proteins and their Biological Role During Bacterial Infection

Lavender, Hayley Samantha (2017). Complement Factor H Related Proteins and their Biological Role During Bacterial Infection. PhD thesis The Open University.



Neisseria meningitidis is a major cause of meningitis and sepsis worldwide despite available polysaccharide and protein vaccines. Individuals with rare defects in the terminal complement pathway are susceptible to meningococcal disease but further genetic factors that contribute to disease susceptibility are less well understood. A genome wide association study has linked polymorphisms in the Complement Factor H (CFH) locus with meningococcal disease in the general population. CFH is a negative regulator of the alternative complement pathway whereas CFH-related proteins (CFHR), encoded in the CFH locus, act as antagonists of CFH. Investigations of the biological role of the CFHRs have been hampered by lack of reagents, therefore a panel of specific monoclonal antibody reagents to CFHR2-5 were generated and characterised.

Previously, N. meningitidis has been shown to bind CFH via a surface exposed lipoprotein, factor H binding protein (fHbp), at high affinity. This study demonstrates that CFHR3 binds to the bacterial surface in a fHbp dependent-manner. Furthermore, CFHR3 competes with CFH for binding to fHbp. Bound CFHR3 increases susceptibility of N. meningitidis to complement-mediated lysis which was dependent on the sequence of the fHbp variant. The ability of N. meningitidis to evade the host immune system is likely to be determined by the relative levels of CFH and CFHR3 on the bacterial surface, providing a molecular mechanism for how variation in cfhr3 may predispose individuals to meningococcal disease.

Furthermore this work demonstrates that Neisseria cinerea, which colonises the respiratory mucosa, expresses fHbp and binds CFH at similar affinities as meningococcal fHbp promoting bacterial survival in serum. The recently developed meningococcal vaccine, Bexsero®, includes fHbp as an antigen and antibodies elicited by Bexsero® are bactericidal against N. cinerea suggesting that the introduction of this vaccine could affect nasopharyngeal carriage of N. cinerea.

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