Fructose-1,6-bisphosphate aldolase of Neisseria meningitidis binds human plasminogen via its C-terminal lysine residue

Neisseria meningitidis is a leading cause of fatal sepsis and meningitis worldwide. As for commensal species of human neisseriae, N. meningitidis inhabits the human nasopharynx and asymptomatic colonization is ubiquitous. Only rarely does the organism invade and survive in the bloodstream leading to disease. Moonlighting proteins perform two or more autonomous, often dissimilar, functions using a single polypeptide chain. They have been increasingly reported on the surface of both prokaryotic and eukaryotic organisms and shown to interact with a variety of host ligands. In some organisms moonlighting proteins perform virulence-related functions, and they may play a role in the pathogenesis of N. meningitidis. Fructose-1,6- bisphosphate aldolase (FBA) was previously shown to be surface-exposed in meningococci and involved in adhesion to host cells. In this study, FBA was shown to be present on the surface of both pathogenic and commensal neisseriae, and surface localization and anchoring was demonstrated to be independent of aldolase activity. Importantly, meningococcal FBA was found to bind to human glu- plasminogen in a dose-dependent manner. Site-directed mutagenesis demonstrated that the C-terminal lysine residue of FBA was required for this interaction, whereas # subterminal lysine residues were not involved

Fructose-1,6-bisphosphate aldolase of Neisseria meningitidis binds human plasminogen via its C-terminal lysine residue

Neisseria meningitidis is a leading cause of fatal sepsis and meningitis worldwide. As for commensal species of human neisseriae, N. meningitidis inhabits the human nasopharynx and asymptomatic colonization is ubiquitous. Only rarely does the organism invade and survive in the bloodstream leading to disease. Moonlighting proteins perform two or more autonomous, often dissimilar, functions using a single polypeptide chain. They have been increasingly reported on the surface of both prokaryotic and eukaryotic organisms and shown to interact with a variety of host ligands. In some organisms moonlighting proteins perform virulence-related functions, and they may play a role in the pathogenesis of N. meningitidis. Fructose-1,6- bisphosphate aldolase (FBA) was previously shown to be surface-exposed in meningococci and involved in adhesion to host cells. In this study, FBA was shown to be present on the surface of both pathogenic and commensal neisseriae, and surface localization and anchoring was demonstrated to be independent of aldolase activity. Importantly, meningococcal FBA was found to bind to human glu- plasminogen in a dose-dependent manner. Site-directed mutagenesis demonstrated that the C-terminal lysine residue of FBA was required for this interaction, whereas # subterminal lysine residues were not involved

Impact of a quadrivalent meningococcal ACWY glycoconjugate or a serogroup B meningococcal vaccine on meningococcal carriage: an observer-blind, phase 3 randomised clinical trial

Background: Meningococcal conjugate vaccines protect individuals directly, but also confer herd protection by interrupting carriage transmission. This Phase III observer-blind, randomised, controlled study evaluated the effects of meningococcal quadrivalent (ACWY) glycoconjugate (MenACWY-CRM) or serogroup B (4CMenB) vaccination on meningococcal carriage rates in young adults. Methods: University students (aged 18–24 years) from ten sites in England were randomised to receive two vaccinations one month apart: two doses of Japanese Encephalitis vaccine (controls), two doses of 4CMenB (4CMenB), or one dose of MenACWY-CRM then placebo (MenACWY-CRM). Meningococci were isolated from oropharyngeal swabs collected before vaccination and at five scheduled intervals over one year. Primary analysis was cross-sectional carriage one month after the vaccine course; secondary analyses included comparison of carriage at any time point after primary analysis until study termination. Findings: 2954 subjects were randomised (control, n=987; 4CMenB, n=988; MenACWY-CRM, n=979); approximately one-third of each group was positive for meningococcal carriage at study entry. By one month, there was no significant difference in carriage between controls and 4CMenB (Odds Ratios (OR) [95% CI]; 1·2 [0·8−1·7]) or MenACWY-CRM (OR [95% CI], 0·9 [0·6–1·3]) groups. From three months after dose two, 4CMenB vaccination resulted in significantly lower carriage of any meningococcal strain (calculated efficacy 18·2% [95% CI: 3·4–30·8]) and capsular groups BCWY (calculated efficacy 26·6% [95% CI: 10·5–39·9]) compared to control vaccination. Significantly lower carriage rates were also observed in the MenACWY-CRM group compared with controls: calculated efficacies 39·0% [95%CI: 17·3-55·0] and 36.2% [95%CI: 15·6-51·7] for serogroups Y and CWY, respectively. Interpretation: MenACWY-CRM and 4CMenB vaccines reduced meningococcal carriage rates over 12 months post-vaccination and, therefore, may affect transmission where widely implemented

Limited impact of adolescent meningococcal ACWY vaccination on Neisseria meningitides serogroup W carriage in university students

Background In the UK rising disease levels due to Neisseria meningitidis serogroup W clonal complex ST-11 (MenW:cc11) strains led to introduction of conjugate MenACWY vaccination for teenagers. We investigated the impact of immunization on carriage of targeted meningococci by whole genome sequencing of isolates recovered from a cohort of vaccinated university students. Methods Strain designation data were extracted from whole genome sequence data. Genomes from carried and invasive MenW:cc11 were compared using a gene-by-gene approach. Serogrouping identified isolates expressing capsule antigens targeted by the vaccine. Results Isolates with a W: P1.5,2: F1-1: ST-11 (cc11) designation, and belonging to the emerging ‘2013-strain’ of the South American-UK MenW:cc11 sub-lineage, were responsible for an increase in carried group W. A multifocal expansion was evident with close transmission networks extending beyond individual dormitories. Carried group Y isolates were predominantly from clonal complex 23, but showed significant heterogeneity and individual strain designations were only sporadically recovered. No shifts towards acapsulate phenotypes were detected in targeted meningococcal populations. Conclusions In a setting with high levels of conjugate MenACWY vaccination, expansion of capsule-expressing isolates from the 2013-strain of MenW:cc11, but not MenY:cc23 isolates, is indicative of differential susceptibilities to vaccine-induced immunity

Rapid Transmission of a Hyper-Virulent Meningococcal Clone Due to High Effective Contact Numbers and Super Spreaders

© Copyright © 2020 Holmes, Green, Oldfield, Turner and Bayliss. Rapid transmission, a critical contributory factor in outbreaks of invasive meningococcal disease, requires naïve populations of sufficient size and intermingling. We examined genomic variability and transmission dynamics in a student population subject to an 11-fold increase in carriage of a hypervirulent Neisseria meningitidis serogroup W ST-11 clone. Phylogenetic clusters, mutation and recombination rates were derived by bioinformatic analyses of whole-genome sequencing data. Transmission dynamics were determined by combining observed carriage rates, cluster sizes and distributions with simple SIS models. Between 9 and 15 genetically-distinct clusters were detected and associated with seven residential halls. Clusters had low mutation accumulation rates and infrequent recombination events. Modeling indicated that effective contacts decreased from 10 to 2 per day between the start and mid-point of the university term. Transmission rates fluctuated between 1 and 4% while the R(t) for carriage decreased from an initial rate of 47 to 1. Decreases in transmission values correlated with a rise in vaccine-induced immunity. Observed carriage dynamics could be mimicked by populations containing 20% of super spreaders with 2.3-fold higher effective contact rates. We conclude that spread of this hypervirulent ST-11 meningococcal clone depends on the levels of effective contacts and immunity rather than genomic variability. Additionally, we propose that super-spreaders enhance meningococcal transmission and that a 70% MenACWY immunization level is sufficient to retard, but not fully prevent, meningococcal spread in close-contact populations

Rise in carriage of group W meningococci in university students in United Kingdom

MenACWY conjugate vaccination was recently introduced in the UK for adolescents and 24 young adults to reduce disease due to Neisseria meningitidis group W (MenW). We 25 conducted a cross-sectional carriage study in first year university students. Despite 71% 26 MenACWY vaccine coverage, carriage of MenW, but not MenY, rose significantly in 27 students

Phase variation mediates reductions in expression of surface proteins during persistent meningococcal carriage

Asymptomatic and persistent colonization of the upper respiratory tract by Neisseria meningitidis occurs despite elicitation of adaptive immune responses against surface antigens. A putative mechanism for facilitating host persistence of this bacterial commensal and pathogen is alterations in expression of surface antigens by simple sequence repeat (SSR)-mediated phase variation. We investigated how often phase variation occurs during persistent carriage by analyzing the SSRs of eight loci in multiple isolates from 21 carriers representative of 1 to 6 months carriage. Alterations in repeat number were detected by a GeneScan analysis and occurred at 0.06 mutations/gene/month of carriage. The expression states were determined by Western blotting and two genes, fetA and nadA, exhibited trends toward low expression states. A critical finding from our unique examination of combinatorial expression states, “phasotypes,” was for significant reductions in expression of multiple phase-variable surface proteins during persistent carriage of some strains. The immune responses in these carriers were examined by measuring variant-specific PorA IgG antibodies, capsular group Y IgG antibodies and serum bactericidal activity in concomitant serum samples. Persistent carriage was associated with high levels of specific IgG antibodies and serum bactericidal activity while recent strain acquisition correlated with a significant induction of antibodies. We conclude that phase-variable genes are driven into lower expression states during long-term persistent meningococcal carriage, in part due to continuous exposure to antibody-mediated selection, suggesting localized hypermutation has evolved to facilitate host persistence

Constraints from Inflation on Scalar-Tensor Gravity Theories

We show how observations of the perturbation spectra produced during inflation may be used to constrain the parameters of general scalar-tensor theories of gravity, which include both an inflaton and dilaton field. An interesting feature of these models is the possibility that the curvature perturbations on super-horizon scales may not be constant due to non-adiabatic perturbations of the two fields. Within a given model, the tilt and relative amplitude of the scalar and tensor perturbation spectra gives constraints on the parameters of the gravity theory, which may be comparable with those from primordial nucleosynthesis and post-Newtonian experiments.Comment: LaTeX (with RevTex) 19 pages, 8 uuencoded figures appended, also available on WWW via http://star.maps.susx.ac.uk/index.htm

Erratum: “stellar diameters and temperatures. II. main-sequence K- and M-stars” (2012, ApJ, 757, 112)

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