Identification of Neisseria lactamica Outer Membrane Proteins Protective against Meningococcal Disease

Setchfield, Kerry Jane (2002). Identification of Neisseria lactamica Outer Membrane Proteins Protective against Meningococcal Disease. PhD thesis The Open University.



A number of approaches have been taken towards the development of a vaccine protective against serogroup B meningococcal disease but, as yet, none have been successful. The commensal bacterium, Neisseria lactamica, shares many surface structures with N. meningitidis and N. lactamica may therefore provide an alternative approach to vaccinating against serogroup B disease. Immunological evidence suggests that carriage of N. lactamica is involved in natural protection against disease caused by N. meningitidis.

This study presents the important observation that N. lactamica vaccines protect mice against meningococcal challenge. To identify the components responsible for protection, the outer membrane proteins of N. lactamica, extracted from whole cells, were separated by preparative electrophoresis and pooled into low <43 kDa), medium (43-65 kDa) and high (>67 kDa) molecular weight protein groups. The low molecular weight group provided the best protection of these groups, and further separation of this group indicated that proteins of 25-43 kDa provided the observed protection. Serum raised against N. lactamica proteins was cross-reactive with meningococci of different serogroups, serotypes and serosubtypes. N. lactamica antisera raised in mice were not bactericidal and although sera raised in rabbits showed some bactericidal activity, titres did not correlate with protection.

Meningococcal proteins cross-reactive with N. lactamica antisera were identified using surface enhance laser-desorption ionisation time-of-flight mass spectroscopy. The cross-reactive proteins had molecular masses of approximately 11.2 kDa, 13.7 kDa, 26.8 kDa, 17.4 kDa, 28.1 kDa, 33.1 kDa, 53.2 kDa and 66.6 kDa. Several meningococcal proteins of unknown function and others that have previously been considered as vaccine antigens (PorB and TbpB) were putatively identified. Proteins with epitopes homologous to these proteins are likely to be present in N. lactamica and may be involved in protection against meningococcal challenge. The identity of the 66.6 kDa protein as TbpB was confirmed by comparing the cross-reactivity of N. meningitidis OMPs from wild-type and TbpB knockout strains with N. lactamica antisera.

Using a N. lactamica genomic expression library, the DNA sequences of recombinant N. lactamica proteins cross-reactive with N. lactamica antiserum were obtained. Meningococcal proteins with homology to the N. lactamica sequences were identified by comparison with the complete genome sequences of N. meningitidis serogroups A and B. Fifteen cross-reactive sequences coded, either partially or completely, for 23 different proteins.

This study demonstrates that N. lactamica provides an effective vaccine in mice against lethal meningococcal challenge and that N. lactamica may provide an alternative approach to vaccination against serogroup B meningococcal disease. Putative identifications of the proteins involved in this protection have been made.

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