RESUMO
Sepsis and meningitis caused by serogroup B meningococcus are devastating diseases of infants and young adults, which cannot yet be prevented by vaccination. By genome mining, we discovered GNA1870, a new surface-exposed lipoprotein of Neisseria meningitidis that induces high levels of bactericidal antibodies. The antigen is expressed by all strains of N. meningitidis tested. Sequencing of the gene in 71 strains representative of the genetic and geographic diversity of the N. meningitidis population, showed that the protein can be divided into three variants. Conservation within each variant ranges between 91.6 to 100%, while between the variants the conservation can be as low as 62.8%. The level of expression varies between strains, which can be classified as high, intermediate, and low expressors. Antibodies against a recombinant form of the protein elicit complement-mediated killing of the strains that carry the same variant and induce passive protection in the infant rat model. Bactericidal titers are highest against those strains expressing high yields of the protein; however, even the very low expressors are efficiently killed. The novel antigen is a top candidate for the development of a new vaccine against meningococcus.
Assuntos
Antígenos de Bactérias/imunologia , Lipoproteínas/imunologia , Neisseria meningitidis/imunologia , Isoformas de Proteínas/imunologia , Vacinação , Adulto , Sequência de Aminoácidos , Animais , Antígenos de Bactérias/classificação , Antígenos de Bactérias/genética , Antígenos de Bactérias/metabolismo , Sequência de Bases , Feminino , Genes Bacterianos , Humanos , Lactente , Lipoproteínas/genética , Lipoproteínas/metabolismo , Camundongos , Dados de Sequência Molecular , Neisseria meningitidis/metabolismo , Filogenia , Isoformas de Proteínas/genética , Isoformas de Proteínas/metabolismo , Proteínas Recombinantes/genética , Proteínas Recombinantes/imunologia , Proteínas Recombinantes/metabolismo , Alinhamento de SequênciaRESUMO
OBJECTIVES: To determine the association between the ability of a different strains of meningococci to survive in whole blood and the age of the donor. METHODS: A panel of serogroup B and a serogroup C strain of Neisseria meningitidis was tested in an ex vivo whole blood model. Blood from 81 healthy children and 20 adults and from children during convalescence from serogroup B (55 patients) or serogroup C (43 patients) meningococcal infection was assessed. RESULTS: Age-dependent acquisition of whole blood killing of serogroup B and C bacterial isolates was demonstrated in healthy children with an inverse relationship to the reported incidence of disease. After infection with serogroup B or C meningococci, evidence of whole blood killing of the bacteria was found even in blood from children <2 years of age, the survival of a serogroup B strain, MC58, being reduced compared with that in healthy children (median, 64% compared with 194.5% survival at 90 min). In both affected children and controls, there was a significant correlation between whole blood killing of strain MC58 and of other serogroup B and C meningococci. CONCLUSIONS: The whole blood model measures both humoral and cellular mechanisms responsible for the bactericidal activity of blood. The model was first described 80 years ago, but this is the first description of its age dependency. Acquisition of bactericidal activity was more rapid in children infected and is directed at various strains of meningococci, indicating the presence of a cross-reactive antigen(s).