Distinct Binding and Immunogenic Properties of the Gonococcal Homologue of Meningococcal Factor H Binding Protein

Neisseria meningitidis is a leading cause of sepsis and meningitis. The bacterium recruits factor H (fH), a negative regulator of the complement system, to its surface via fH binding protein (fHbp), providing a mechanism to avoid complement-mediated killing. fHbp is an important antigen that elicits protective immunity against the meningococcus and has been divided into three different variant groups, V1, V2 and V3, or families A and B. However, immunisation with fHbp V1 does not result in cross-protection against V2 and V3 and vice versa. Furthermore, high affinity binding of fH could impair immune responses against fHbp. Here, we investigate a homologue of fHbp in Neisseria gonorrhoeae, designated as Gonococcal homologue of fHbp (Ghfp) which we show is a promising vaccine candidate for N. meningitidis. We demonstrate that Gfhp is not expressed on the surface of the gonococcus and, despite its high level of identity with fHbp, does not bind fH. Substitution of only two amino acids in Ghfp is sufficient to confer fH binding, while the corresponding residues in V3 fHbp are essential for high affinity fH binding. Furthermore, immune responses against Ghfp recognise V1, V2 and V3 fHbps expressed by a range of clinical isolates, and have serum bactericidal activity against N. meningitidis expressing fHbps from all variant groups

Changes in serogroup and genotype prevalence among carried meningococci in the United Kingdom during vaccine implementation.

BACKGROUND: Herd immunity is important in the effectiveness of conjugate polysaccharide vaccines against encapsulated bacteria. A large multicenter study investigated the effect of meningococcal serogroup C conjugate vaccine introduction on the meningococcal population. METHODS: Carried meningococci in individuals aged 15-19 years attending education establishments were investigated before and for 2 years after vaccine introduction. Isolates were characterized by multilocus sequence typing, serogroup, and capsular region genotype and changes in phenotypes and genotypes assessed. RESULTS: A total of 8462 meningococci were isolated from 47 765 participants (17.7%). Serogroup prevalence was similar over the 3 years, except for decreases of 80% for serogroup C and 40% for serogroup 29E. Clonal complexes were associated with particular serogroups and their relative proportions fluctuated, with 12 statistically significant changes (6 up, 6 down). The reduction of ST-11 complex serogroup C meningococci was probably due to vaccine introduction. Reasons for a decrease in serogroup 29E ST-254 meningococci (from 1.8% to 0.7%) and an increase in serogroup B ST-213 complex meningococci (from 6.7% to 10.6%) were less clear. CONCLUSIONS: Natural fluctuations in carried meningococcal genotypes and phenotypes a can be affected by the use of conjugate vaccines, and not all of these changes are anticipatable in advance of vaccine introduction

Influence of Two Vaccination Campaigns on Genetic Diversity of Invasive Neisseria meningitidis Isolates in Northern Spain (1997–2008)

BACKGROUND: Neisseria meningitidis diversifies rapidly, due to its high recombination rates. The aim of this study was to analyze the possible impact of two vaccination campaigns (a once-off A/C polysaccharide vaccination campaign in people aged 18 months to 20 years old in 1997, and a meningococcal C conjugate vaccination campaign in children aged < or = 6 years old from 2000 to 2008) on diversification of the population of invasive isolates obtained between 1997 and 2008. All of the 461 available isolates were included (2, 319, 123, 11 and 6 belonging to serogroups A, B, C, Y and W-135, respectively). METHODOLOGY/PRINCIPAL FINDINGS: The isolates were analyzed for diversity using multilocus sequence typing, eBURST and the S.T.A.R.T.2 program. One hundred and seven sequence types (ST) and 20 clonal complexes were obtained. Five different STs (ST11, ST8, ST33, ST1163 and ST3496) included 56.4% of the isolates. With the exception of ST11, all other STs were associated with a specific serogroup. Epidemic circulation of serogroup C ST8 isolates was detected in 1997-1998, as well as epidemic circulation of ST11 isolates (serogroups B and C) in 2002-2004. The epidemic behavior of serogroup B ST11 (ST11_B:2a:P1.5) was similar, although with lesser intensity, to that of ST11 of serogroup C. Although clonality increased during epidemic years, the overall diversity of the meningococcal population did not increase throughout the 12 years of the study. CONCLUSION: The overall diversity of the meningococcal population, measured by the frequency of STs and clonal complexes, numbers of alleles, polymorphic sites, and index of association, remained relatively constant throughout the study period, contradicting previous findings by other researchers

The elusive meningococcal meningitis serogroup: a systematic review of serogroup B epidemiology

<p>Abstract</p> <p>Background</p> <p>Invasive meningococcal disease (IMD), is a widely distributed, complex human disease affecting all age categories. The causative agent, <it>Neisseria meningitidis</it>, is spread through aerosol respiratory droplets. 13 different serogroups have been identified, each with varying epidemiological features including prevalence, virulence, immunogenicity, geographical and temporal distribution. Although preventative measures are available for several of the serogroups, meningococcal disease caused by serogroup B is of particular interest due to the challenge it presents concerning vaccine development.</p> <p>Methods</p> <p>A systematic review of peer reviewed studies and reports, the collection of data from national and international health resources, along with the analysis of the Multi Locus Sequence Typing database was carried out aimed at collecting information concerning serogroup B IMD and the epidemiology attached to it.</p> <p>Results</p> <p>A continuous output of related and novel STs occurring worldwide in terms of the hypervirulent clonal complexes was observed both in published studies and the MLST database in this case using the eburst software, which highlights the genetically diverse nature of serogroup B strains.</p> <p>Conclusions</p> <p>With the recent dominance of serogroup B IMD seen in many countries, along with the presence of antibiotic resistance, vaccine development needs to target areas of the bacterium which tackle this widespread and heterogeneous aspect of meningococcal meningitis disease.</p

Progression from new methicillin-resistant Staphylococcus aureus colonisation to infection: An observational study in a hospital cohort

10.1186/1471-2334-13-491BMC Infectious Diseases131-BIDM

Vaccine Preventability of Meningococcal Clone, Greater Aachen Region, Germany

An emerging serogroup B clone can be prevented by vaccines

Neisseria meningitidis Differentially Controls Host Cell Motility through PilC1 and PilC2 Components of Type IV Pili

Neisseria meningitidis is a strictly human pathogen that has two facets since asymptomatic carriage can unpredictably turn into fulminant forms of infection. Meningococcal pathogenesis relies on the ability of the bacteria to break host epithelial or endothelial cellular barriers. Highly restrictive, yet poorly understood, mechanisms allow meningococcal adhesion to cells of only human origin. Adhesion of encapsulated and virulent meningococci to human cells relies on the expression of bacterial type four pili (T4P) that trigger intense host cell signalling. Among the components of the meningococcal T4P, the concomitantly expressed PilC1 and PilC2 proteins regulate pili exposure at the bacterial surface, and until now, PilC1 was believed to be specifically responsible for T4P-mediated meningococcal adhesion to human cells. Contrary to previous reports, we show that, like PilC1, the meningococcal PilC2 component is capable of mediating adhesion to human ME180 epithelial cells, with cortical plaque formation and F-actin condensation. However, PilC1 and PilC2 promote different effects on infected cells. Cellular tracking analysis revealed that PilC1-expressing meningococci caused a severe reduction in the motility of infected cells, which was not the case when cells were infected with PilC2-expressing strains. The amount of both total and phosphorylated forms of EGFR was dramatically reduced in cells upon PilC1-mediated infection. In contrast, PilC2-mediated infection did not notably affect the EGFR pathway, and these specificities were shared among unrelated meningococcal strains. These results suggest that meningococci have evolved a highly discriminative tool for differential adhesion in specific microenvironments where different cell types are present. Moreover, the fine-tuning of cellular control through the combined action of two concomitantly expressed, but distinctly regulated, T4P-associated variants of the same molecule (i.e. PilC1 and PilC2) brings a new model to light for the analysis of the interplay between pathogenic bacteria and human host cells

Molecular epidemiology of meningococcal disease in England and Wales 1975–1995, before the introduction of serogroup C conjugate vaccines

A comprehensive meningococcal vaccine is yet to be developed. In the absence of a vaccine that immunizes against the serogroup B capsular polysaccharide, this can only be achieved by targeting subcapsular antigens, and a number of outer-membrane proteins (OMPs) are under consideration as candidates. A major obstacle to the development of such a vaccine is the antigenic diversity of these OMPs, and obtaining population data that accurately identify and catalogue these variants is an important component of vaccine design. The recently proposed meningococcal molecular strain-typing scheme indexes the diversity of two OMPs, PorA and FetA, that are vaccine candidates, as well as the capsule and multilocus sequence type. This scheme was employed to survey 323 meningococci isolated from invasive disease in England and Wales from 1975 to 1995, before the introduction of meningococcal conjugated serogroup C polysaccharide vaccines in 1999. The eight-locus typing scheme provided high typeability (99.4 %) and discrimination (Simpson's diversity index 0.94–0.99). The data showed cycling of meningococcal genotypes and antigenic types in the absence of planned interventions. Notwithstanding high genetic and antigenic diversity, most of the isolates belonged to one of seven clonal complexes, with 11 predominant strain types. Combinations of PorA and FetA, chosen on the basis of their prevalence over time, generated vaccine recipes that included protein variants found in 80 % or more of the disease isolates for this time period. If adequate immune responses can be generated, these results suggest that control of meningococcal disease with relatively simple protein component vaccines may be possible

Differential Modulation of TNF-α–Induced Apoptosis by Neisseria meningitidis

Infections by Neisseria meningitidis show duality between frequent asymptomatic carriage and occasional life-threatening disease. Bacterial and host factors involved in this balance are not fully understood. Cytopathic effects and cell damage may prelude to pathogenesis of isolates belonging to hyper-invasive lineages. We aimed to analyze cell–bacteria interactions using both pathogenic and carriage meningococcal isolates. Several pathogenic isolates of the ST-11 clonal complex and carriage isolates were used to infect human epithelial cells. Cytopathic effect was determined and apoptosis was scored using several methods (FITC-Annexin V staining followed by FACS analysis, caspase assays and DNA fragmentation). Only pathogenic isolates were able to induce apoptosis in human epithelial cells, mainly by lipooligosaccharide (endotoxin). Bioactive TNF-α is only detected when cells were infected by pathogenic isolates. At the opposite, carriage isolates seem to provoke shedding of the TNF-α receptor I (TNF-RI) from the surface that protect cells from apoptosis by chelating TNF-α. Ability to induce apoptosis and inflammation may represent major traits in the pathogenesis of N. meningitidis. However, our data strongly suggest that carriage isolates of meningococci reduce inflammatory response and apoptosis induction, resulting in the protection of their ecological niche at the human nasopharynx

Structural Alterations in a Component of Cytochrome c Oxidase and Molecular Evolution of Pathogenic Neisseria in Humans

Three closely related bacterial species within the genus Neisseria are of importance to human disease and health. Neisseria meningitidis is a major cause of meningitis, while Neisseria gonorrhoeae is the agent of the sexually transmitted disease gonorrhea and Neisseria lactamica is a common, harmless commensal of children. Comparative genomics have yet to yield clear insights into which factors dictate the unique host-parasite relationships exhibited by each since, as a group, they display remarkable conservation at the levels of nucleotide sequence, gene content and synteny. Here, we discovered two rare alterations in the gene encoding the CcoP protein component of cytochrome cbb3 oxidase that are phylogenetically informative. One is a single nucleotide polymorphism resulting in CcoP truncation that acts as a molecular signature for the species N. meningitidis. We go on to show that the ancestral ccoP gene arose by a unique gene duplication and fusion event and is specifically and completely distributed within species of the genus Neisseria. Surprisingly, we found that strains engineered to express either of the two CcoP forms conditionally differed in their capacity to support nitrite-dependent, microaerobic growth mediated by NirK, a nitrite reductase. Thus, we propose that changes in CcoP domain architecture and ensuing alterations in function are key traits in successive, adaptive radiations within these metapopulations. These findings provide a dramatic example of how rare changes in core metabolic proteins can be connected to significant macroevolutionary shifts. They also show how evolutionary change at the molecular level can be linked to metabolic innovation and its reversal as well as demonstrating how genotype can be used to infer alterations of the fitness landscape within a single host