scholarly journals Factor H binding protein (fHbp)-mediated differential complement resistance of a serogroup C Neisseria meningitidis isolate from cerebrospinal fluid of a patient with invasive meningococcal disease

2021 ◽  
Vol 3 (9) ◽  
Author(s):  
Alessandra Facchetti ◽  
Jun X. Wheeler ◽  
Caroline Vipond ◽  
Gail Whiting ◽  
Hayley Lavender ◽  
...  
Keyword(s):  
Neisseria Meningitidis ◽  
Meningococcal Disease ◽  
Close Contact ◽  
Binding Protein ◽  
Integral Membrane Protein ◽  
Factor H ◽  
Invasive Meningococcal Disease ◽  
Content Type ◽  
Type Iv ◽  
Complement Resistance

During an outbreak of invasive meningococcal disease (IMD) at the University of Southampton, UK, in 1997, two Neisseria meningitidis serogroup C isolates were retrieved from a student (‘Case’), who died of IMD, and a close contact (‘Carrier’) who, after mouth-to-mouth resuscitation on the deceased, did not contract the disease. Genomic comparison of the isolates demonstrated extensive nucleotide sequence identity, with differences identified in eight genes. Here, comparative proteomics was used to measure differential protein expression between the isolates and investigate whether the differences contributed to the clinical outcomes. A total of six proteins were differentially expressed: four proteins (methylcitrate synthase, PrpC; hypothetical integral membrane protein, Imp; fructose-1,6-bisphosphate aldolase, Fba; aldehyde dehydrogenase A, AldA) were upregulated in the Case isolate, while one protein (Type IV pilus-associated protein, PilC2) was downregulated. Peptides for factor H binding protein (fHbp), a major virulence factor and antigenic protein, were only detected in the Case, with a single base deletion (ΔT366) in the Carrier fHbp causing lack of its expression. Expression of fHbp resulted in an increased resistance of the Case isolate to complement-mediated killing in serum. Complementation of fHbp expression in the Carrier increased its serum resistance by approximately 8-fold. Moreover, a higher serum bactericidal antibody titre was seen for the Case isolate when using sera from mice immunized with Bexsero (GlaxoSmithKline), a vaccine containing fHbp as an antigenic component. This study highlights the role of fHbp in the differential complement resistance of the Case and the Carrier isolates. Expression of fHbp in the Case resulted in its increased survival in serum, possibly leading to active proliferation of the bacteria in blood and death of the student through IMD. Moreover, enhanced killing of the Case isolate by sera raised against an fHbp-containing vaccine, Bexsero, underlines the role and importance of fHbp in infection and immunity.

scholarly journals Culture-Confirmed Invasive Meningococcal Disease in Canada, 2010 to 2014: Characterization of Serogroup B Neisseria meningitidis Strains and Their Predicted Coverage by the 4CMenB Vaccine

mSphere ◽  
2020 ◽  
Vol 5 (2) ◽  
Author(s):  
Raymond S. W. Tsang ◽  
Dennis K. S. Law ◽  
Rosita De Paola ◽  
Maria Giuliani ◽  
Maria Stella ◽  
...  
Keyword(s):  
Molecular Epidemiology ◽  
Neisseria Meningitidis ◽  
Meningococcal Disease ◽  
Factor H ◽  
Invasive Meningococcal Disease ◽  
Effective Control ◽  
Atlantic Region ◽  
Content Type ◽  
Laboratory Surveillance ◽  
4Cmenb Vaccine

ABSTRACT The molecular epidemiology of culture-confirmed invasive meningococcal disease (IMD) in Canada from 2010 to 2014 was studied with an emphasis on serogroup B Neisseria meningitidis (MenB) isolates, including their predicted coverage by the 4CMenB vaccine. The mean annual incidence rates of culture confirmed IMD varied from 0.19/100,000 in Ontario to 0.50/100,000 in New Brunswick and 0.59/100,000 in Quebec. In both Quebec and Atlantic region, MenB was significantly more common than other serogroups, while in other provinces, both MenB and serogroup Y (MenY) were almost equally common. The majority of MenB cases (67.0%) were in those aged ≤24 years, while most MenC (75.0%) and MenY (69.6%) cases were in adults more than 24 years old. The 349 MenB isolates were grouped into 103 sequence types (STs), 90 of which belonged to 13 clonal complexes (CCs). A large number of 4CMenB antigen genes were found among the Canadian MenB, which is predicted to encode 50 factor H binding protein (fHbp) types, 40 NHBA types, and 55 PorA genotypes. Provinces and regions were found to have their own unique MenB STs. A meningococcal antigen typing system assay predicted an overall MenB coverage by 4CMenB to be 73.6%, with higher coverage predicted for the two most common STs: 100% for ST154 and 95.9% for ST269, leading to higher coverage in both the Atlantic region and Quebec. Higher coverage (81.4%) was also found for MenB recovered from persons aged 15 to 24 years, followed by strains from infants and children ≤4 years old (75.2%) and those aged 5 to 14 years (75.0%). IMPORTANCE Laboratory surveillance of invasive meningococcal disease (IMD) is important to our understanding of the evolving nature of the Neisseria meningitidis strain types causing the disease and the potential coverage of disease strains by the newly developed vaccines. This study examined the molecular epidemiology of culture-confirmed IMD cases in Canada by examining the strain types and the potential coverage of a newly licensed 4CMenB vaccine on Canadian serogroup B N. meningitidis strains. The strain types identified in different parts of Canada appeared to be unique as well as their predicted coverage by the 4CMenB vaccine. These data were compared to data obtained from previous studies done in Canada and elsewhere globally. For effective control of IMD, laboratory surveillance of this type was found to be essential and useful to understand the dynamic nature of this disease.

scholarly journals Susceptibility to Invasive Meningococcal Disease: Polymorphism of Complement System Genes and Neisseria meningitidis Factor H Binding Protein

PLoS ONE ◽  
2015 ◽  
Vol 10 (3) ◽  
pp. e0120757 ◽  
Author(s):  
Declan T. Bradley ◽  
Thomas W. Bourke ◽  
Derek J. Fairley ◽  
Raymond Borrow ◽  
Michael D. Shields ◽  
...  
Keyword(s):  
Neisseria Meningitidis ◽  
Complement System ◽  
Meningococcal Disease ◽  
Binding Protein ◽  
Factor H ◽  
Invasive Meningococcal Disease

scholarly journals Genomic Characterization of Invasive Meningococcal Serogroup B Isolates and Estimation of 4CMenB Vaccine Coverage in Finland

mSphere ◽  
2020 ◽  
Vol 5 (5) ◽  
Author(s):  
Margherita Bodini ◽  
Alessandro Brozzi ◽  
Maria Giuliani ◽  
Hanna Nohynek ◽  
Anni Vainio ◽  
...  
Keyword(s):  
Genetic Variability ◽  
Neisseria Meningitidis ◽  
Meningococcal Disease ◽  
Vaccine Coverage ◽  
Factor H ◽  
Invasive Meningococcal Disease ◽  
Heparin Binding ◽  
Protein Variant ◽  
Content Type ◽  
Typing System

ABSTRACT Invasive meningococcal disease (IMD) caused by Neisseria meningitidis is a significant cause of morbidity and mortality worldwide. In Finland, the incidence rate of IMD is low, with meningococcal serogroup B (MenB) accounting for around one-third of IMD cases annually. The aim of this study was to investigate the genetic variability of invasive MenB isolates collected in Finland between 2010 and 2017 (n = 81), including the genes encoding the 4-component MenB vaccine (4CMenB; Bexsero; GSK) antigens and their promoters, and to evaluate the 4CMenB potential coverage. Whole-genome sequencing was performed. The meningococcal antigen typing system (MATS) was used to characterize MenB isolates and predict the potential coverage of 4CMenB. MATS was complemented by genetic MATS (gMATS) through association of antigen genotyping and phenotypic MATS results. Multilocus sequence typing revealed predominance of the ST-41/44 clonal complex among which sequence type (ST)-303 was the most common and was predicted to be covered by 4CMenB. Of the 4 major vaccine antigens, the factor H-binding protein variant 1, neisserial heparin binding antigen peptide 2, and the PorA P1.4 antigen were predominant, whereas Neisseria adhesin A was present in only 4% of the 81 isolates. MATS and gMATS 4CMenB strain coverage predictions were 78% and 86%, respectively, in a subpanel of 60 isolates collected during 2010 to 2014, with a gMATS prediction of 84% for all 81 isolates. The results suggest that 4CMenB could reduce the burden of IMD in Finland and that gMATS could be applied to monitor vaccine strain coverage and predict vaccine effectiveness. IMPORTANCE 4CMenB is a 4-component vaccine used against invasive meningococcal disease (IMD) caused by Neisseria meningitidis serogroup B (MenB). We investigated the genetic variability of MenB in Finland and evaluated 4CMenB strain coverage by 2 different methods: MATS (meningococcal antigen typing system) and gMATS (genetic MATS). In a set of MenB isolates, 78% (MATS) and 86% (gMATS) were predicted as covered by 4CMenB, suggesting that use of 4CMenB would help reduce IMD incidence in Finland. MATS has been used in 13 countries worldwide, generating information on phenotypic characteristics that could infer protection by 4CMenB. Based on these data and genetic information, gMATS coverage predictions can be made. gMATS predicts coverage consistent with MATS for about 94% of tested strains. Unlike MATS, gMATS does not require live isolates, thus allowing the analysis also of noncultivable strains, making the coverage predictions more accurate. Therefore, gMATS can replace MATS to assess 4CMenB coverage, including in regions with no prior MATS data.

Prevalence and genetic diversity of two adhesion-related genes, pilE and nadA, in Neisseria meningitidis in China

2013 ◽  
Vol 141 (10) ◽  
pp. 2163-2172 ◽  
Author(s):  
X. SUN ◽  
H. ZHOU ◽  
L. XU ◽  
H. YANG ◽  
Y. GAO ◽  
...  
Keyword(s):  
Genetic Diversity ◽  
Neisseria Meningitidis ◽  
Adhesion Molecules ◽  
Meningococcal Disease ◽  
Class Ii ◽  
Type Iv Pili ◽  
Invasive Meningococcal Disease ◽  
Class I ◽  
Type Iv

SUMMARYThe main Neisseria meningitidis adhesion molecules, type IV pili (Tfp) and Neisseria adhesion A (NadA), play important roles in the pathogenesis of invasive meningococcal disease. PilE is the major Tfp subunit. In this study, the prevalence and genetic diversity of pilE and nadA were investigated in the prevalent serogroups and clonal complexes (CC) of N. meningitidis isolated in China. All serogroup A strains belonging to CC1 and CC5 and all CC11 serogroup W135 strains were clustered into class II PilE clades. All serogroup C and most of serogroup B isolates except CC8 and ST5642 were class I PilE clades. Class II pilE sequences were highly conserved. All isolates belonging to class I PilE isolates were nadA negative. However, nadA-positive strains were exclusively found in CC5 and CC11 isolates (class II PilE). This study showed that PilE and NadA may be related to epidemic or endemic meningococcal disease.

scholarly journals Insights on Population Structure and Within-Host Genetic Changes among Meningococcal Carriage Isolates from U.S. Universities

mSphere ◽  
2020 ◽  
Vol 5 (2) ◽  
Author(s):  
Sandeep J. Joseph ◽  
Nadav Topaz ◽  
How-Yi Chang ◽  
Melissa J. Whaley ◽  
Jeni T. Vuong ◽  
...  
Keyword(s):  
General Population ◽  
Neisseria Meningitidis ◽  
Meningococcal Disease ◽  
Mass Vaccination ◽  
Invasive Meningococcal Disease ◽  
Whole Genome ◽  
Genetic Changes ◽  
Content Type ◽  
Host Genetic ◽  
Vaccination Campaigns

ABSTRACT In 2015 and 2016, meningococcal carriage evaluations were conducted at two universities in the United States following mass vaccination campaigns in response to Neisseria meningitidis serogroup B (NmB) disease outbreaks. A simultaneous carriage evaluation was also conducted at a university near one of the outbreaks, where no NmB cases were reported and no mass vaccination occurred. A total of ten cross-sectional carriage evaluation rounds were conducted, resulting in 1,514 meningococcal carriage isolates collected from 7,001 unique participants; 1,587 individuals were swabbed at multiple time points (repeat participants). All isolates underwent whole-genome sequencing. The most frequently observed clonal complexes (CC) were CC198 (27.3%), followed by CC1157 (17.4%), CC41/44 (9.8%), CC35 (7.4%), and CC32 (5.6%). Phylogenetic analysis identified carriage isolates that were highly similar to the NmB outbreak strains; comparative genomics between these outbreak and carriage isolates revealed genetic changes in virulence genes. Among repeat participants, 348 individuals carried meningococcal bacteria during at least one carriage evaluation round; 50.3% retained N. meningitidis carriage of a strain with the same sequence type (ST) and CC across rounds, 44.3% only carried N. meningitidis in one round, and 5.4% acquired a new N. meningitidis strain between rounds. Recombination, point mutations, deletions, and simple sequence repeats were the most frequent genetic mechanisms found in isolates collected from hosts carrying a strain of the same ST and CC across rounds. Our findings provide insight on the dynamics of meningococcal carriage among a population that is at higher risk for invasive meningococcal disease than the general population. IMPORTANCE U.S. university students are at a higher risk of invasive meningococcal disease than the general population. The responsible pathogen, Neisseria meningitidis, can be carried asymptomatically in the oropharynx; the dynamics of meningococcal carriage and the genetic features that distinguish carriage versus disease states are not completely understood. Through our analyses, we aimed to provide data to address these topics. We whole-genome sequenced 1,514 meningococcal carriage isolates from individuals at three U.S. universities, two of which underwent mass vaccination campaigns following recent meningococcal outbreaks. We describe the within-host genetic changes among individuals carrying a strain with the same molecular type over time, the primary strains being carried in this population, and the genetic differences between closely related outbreak and carriage strains. Our results provide detailed information on the dynamics of meningococcal carriage and the genetic differences in carriage and outbreak strains, which can inform future efforts to reduce the incidence of invasive meningococcal disease.

scholarly journals Genome Sequence of a Neisseria meningitidis Capsule Null Locus Strain from the Clonal Complex of Sequence Type 198

2012 ◽  
Vol 194 (18) ◽  
pp. 5144-5145 ◽  
Author(s):  
Sabine Schork ◽  
Andreas Schlüter ◽  
Jochen Blom ◽  
Susanne Schneiker-Bekel ◽  
Alfred Pühler ◽  
...  
Keyword(s):  
Neisseria Meningitidis ◽  
Genome Sequence ◽  
Meningococcal Disease ◽  
Clonal Complex ◽  
Sequence Type ◽  
Invasive Meningococcal Disease ◽  
Content Type ◽  
Polysaccharide Capsules

ABSTRACTNeisseria meningitidisis a commensal and accidental pathogen exclusively of humans. Although the production of polysaccharide capsules is considered to be essential for meningococcal virulence, there have been reports of constitutively unencapsulated strains causing invasive meningococcal disease (IMD). Here we report the genome sequence of a capsule null locus (cnl) strain of sequence type 198 (ST-198), which is found in half of the reported cases of IMD caused bycnlmeningococcal strains.

scholarly journals Disease-Associated Neisseria meningitidis Isolates Inhibit Wound Repair in Respiratory Epithelial Cells in a Type IV Pilus-Independent Manner

2014 ◽  
Vol 82 (12) ◽  
pp. 5023-5034 ◽  
Author(s):  
Xiaoyun Ren ◽  
Joanna K. MacKichan
Keyword(s):  
Cell Migration ◽  
Neisseria Meningitidis ◽  
Meningococcal Disease ◽  
Wound Repair ◽  
Disease Onset ◽  
Independent Manner ◽  
Content Type ◽  
Type Iv ◽  
Respiratory Epithelial

ABSTRACTNeisseria meningitidisis the causative agent of meningococcal disease. Onset of meningococcal disease can be extremely rapid and can kill within a matter of hours. However, although a much-feared pathogen,Neisseria meningitidisis frequently found in the nasopharyngeal mucosae of healthy carriers. The bacterial factors that distinguish disease- from carriage-associated meningococci are incompletely understood. Evidence suggesting that disruptions to the nasopharynx may increase the risk of acquiring meningococcal disease led us to evaluate the ability of disease- and carriage-associated meningococcal isolates to inhibit cell migration, using anin vitroassay for wound repair. We found that disease-associated isolates in our collection inhibited wound closure, while carriage-associated isolates were more variable, with many isolates not inhibiting wound repair at all. For isolates selected for further study, we found that actin morphology, such as presence of lamellipodia, correlated with cell migration. We demonstrated that multiple meningococcal virulence factors, including the type IV pili, are dispensable for inhibition of wound repair. Inhibition of wound repair was also shown to be an active process, i.e., requiring live bacteria undergoing active protein synthesis.

scholarly journals Characterization of Neisseria meningitidis Isolates That Do Not Express the Virulence Factor and Vaccine Antigen Factor H Binding Protein

2011 ◽  
Vol 18 (6) ◽  
pp. 1002-1014 ◽  
Author(s):  
Jay Lucidarme ◽  
Lionel Tan ◽  
Rachel M. Exley ◽  
Jamie Findlow ◽  
Ray Borrow ◽  
...  
Keyword(s):  
Neisseria Meningitidis ◽  
Binding Protein ◽  
Factor H ◽  
Negative Regulator ◽  
Vaccine Antigen ◽  
Natural Immunity ◽  
Content Type ◽  
Reading Frame ◽  
Flanking Sequences

ABSTRACTNeisseria meningitidisremains a leading cause of bacterial sepsis and meningitis. Complement is a key component of natural immunity against this important human pathogen, which has evolved multiple mechanisms to evade complement-mediated lysis. One approach adopted by the meningococcus is to recruit a human negative regulator of the complement system, factor H (fH), to its surface via a lipoprotein, factor H binding protein (fHbp). Additionally, fHbp is a key antigen in vaccines currently being evaluated in clinical trials. Here we characterize strains ofN. meningitidisfrom several distinct clonal complexes which do not express fHbp; all strains were recovered from patients with disseminated meningococcal disease. We demonstrate that these strains have either a frameshift mutation in thefHbpopen reading frame or have entirely lostfHbpand some flanking sequences. No fH binding was detected to other ligands among thefHbp-negative strains. The implications of these findings for meningococcal pathogenesis and prevention are discussed.

scholarly journals Unveiling New Aspects of Meningococcal Carriage and Disease Prevention

2015 ◽  
Vol 54 (1) ◽  
pp. 2-4
Author(s):  
Magnus Gottfredsson
Keyword(s):  
Disease Prevention ◽  
Neisseria Meningitidis ◽  
Whole Genome Sequencing ◽  
Genome Sequencing ◽  
Meningococcal Disease ◽  
Invasive Meningococcal Disease ◽  
Whole Genome ◽  
Traditional Methods ◽  
Content Type ◽  
Phenotypic Methods

Recently, two protein-based vaccines have been approved for the prevention of invasive meningococcal disease caused byNeisseria meningitidisserogroup B (MenB). It is therefore important to study carefully if and how these pathogens respond to widespread vaccination. Traditionally, meningococci have been classified on the basis of capsular phenotypes, but variable levels of capsule expression can influence the results, mainly among MenB strains. In this issue, Jones and colleagues (J Clin Microbiol 54:25–34, 2016,http://dx.doi.org/10.1128/JCM.01447-15) compare whole-genome sequencing to traditional phenotypic methods of classifying meningococci. They demonstrate that for MenB in particular, sequencing-based methods are far superior to traditional methods, especially when it comes to characterizing carriage isolates. This has important implications for future surveillance.

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