scholarly journals Influence of the combination and phase variation status of the haemoglobin receptors HmbR and HpuAB on meningococcal virulence

Microbiology ◽  
2011 ◽  
Vol 157 (5) ◽  
pp. 1446-1456 ◽  
Author(s):  
Isfahan Tauseef ◽  
Odile B. Harrison ◽  
Karl G. Wooldridge ◽  
Ian M. Feavers ◽  
Keith R. Neal ◽  
...  
Keyword(s):  
Neisseria Meningitidis ◽  
Meningococcal Disease ◽  
Systemic Disease ◽  
Phase Variation ◽  
Phase Variable ◽  
Insertion Element ◽  
Systemic Spread ◽  
High Level ◽  
Complete Deletion

Neisseria meningitidis can utilize haem, haemoglobin and haemoglobin–haptoglobin complexes as sources of iron via two TonB-dependent phase variable haemoglobin receptors, HmbR and HpuAB. HmbR is over-represented in disease isolates, suggesting a link between haemoglobin acquisition and meningococcal disease. This study compared the distribution of HpuAB and phase variation (PV) status of both receptors in disease and carriage isolates. Meningococcal disease (n = 214) and carriage (n = 305) isolates representative of multiple clonal complexes (CCs) were investigated for the distribution, polyG tract lengths and ON/OFF status of both haemoglobin receptors, and for the deletion mechanism for HpuAB. Strains with both receptors or only hmbR were present at similar frequencies among meningococcal disease isolates as compared with carriage isolates. However, >90 % of isolates from the three CCs CC5, CC8 and CC11 with the highest disease to carriage ratios contained both receptors. Strains with an hpuAB-only phenotype were under-represented among disease isolates, suggesting selection against this receptor during systemic disease, possibly due to the receptor having a high level of immunogenicity or being inefficient in acquisition of iron during systemic spread. Absence of hpuAB resulted from either complete deletion or replacement by an insertion element. In an examination of PV status, one or both receptors were found in an ON state in 91 % of disease and 71 % of carriage isolates. We suggest that expression of a haemoglobin receptor, either HmbR or HpuAB, is of major importance for systemic spread of meningococci, and that the presence of both receptors contributes to virulence in some strains.

scholarly journals Phase Variation of NadA in Invasive Neisseria meningitidis Isolates Impacts on Coverage Estimates for 4C-MenB, a MenB Vaccine

2018 ◽  
Vol 56 (9) ◽  
Author(s):  
Luke R. Green ◽  
Jay Lucidarme ◽  
Neelam Dave ◽  
Hannah Chan ◽  
Stephen Clark ◽  
...  
Keyword(s):  
Neisseria Meningitidis ◽  
High Throughput ◽  
Meningococcal Disease ◽  
Regulatory Region ◽  
Phase Variation ◽  
Enzyme Linked Immunosorbent Assay ◽  
Phase Variable ◽  
Content Type ◽  
Protective Antigens ◽  
Low Expression

ABSTRACT A recombinant NadA protein is one of the four major protective antigens of 4C-MenB (Bexsero), a vaccine developed for serogroup B Neisseria meningitidis (MenB). The meningococcal antigen typing system (MATS) is utilized as a high-throughput assay for assessing the invasive MenB strain coverage of 4C-MenB. Where present, the nadA gene is subject to phase-variable changes in transcription due to a 5′TAAA repeat tract located in a regulatory region. The promoter-containing intergenic region (IGR) sequences and 5′TAAA repeat numbers were determined for 906 invasive meningococcal disease isolates possessing the nadA gene. Exclusion of the 5′TAAA repeats reduced the number of IGR alleles from 82 to 23. Repeat numbers were associated with low and high levels of NadA expression by Western blotting and enzyme-linked immunosorbent assay (ELISA). Low-expression repeat numbers were present in 83% of 179 MenB isolates with NadA-2/3 or NadA-1 peptide variants and 68% of 480 MenW ST-11 complex isolates with NadA-2/3 peptide variants. For isolates with vaccine-compatible NadA variants, 93% of MATS-negative isolates were associated with low-expression repeat numbers, whereas 63% of isolates with MATS relative potency (RP) scores above the 95% confidence interval for the positive bactericidal threshold had high-expression repeat numbers. Analysis of 5′TAAA repeat numbers has potential as a rapid, high-throughput method for assessing strain coverage for the NadA component of 4C-MenB. A key application will be assessing coverage in meningococcal disease cases where confirmation is by PCR only and MATS cannot be applied.

scholarly journals Meningococcal Disease Caused by Neisseria meningitidis Serogroup B Serotype 4 in São Paulo, Brazil, 1990 to 1996

1998 ◽  
Vol 40 (2) ◽  
pp. 65-70 ◽  
Author(s):  
Claudio Tavares Sacchi ◽  
Ana Paula Silva de Lemos ◽  
Maria Claudia C. Camargo ◽  
Anne M. Whitney ◽  
Carmo Elias A. Melles ◽  
...  
Keyword(s):  
Neisseria Meningitidis ◽  
Meningococcal Disease ◽  
Fragment Length Polymorphism ◽  
Systemic Disease ◽  
Sao Paulo ◽  
Frequent Pattern ◽  
Rrna Genes ◽  
São Paulo ◽  
Vaccination Trial ◽  
Prevalent Strain

A large epidemic of serogroup B meningococcal disease (MD), has been occurring in greater São Paulo, Brazil, since 1988.21 A Cuban-produced vaccine, based on outer-membrane-protein (OMP) from serogroup B: serotype 4: serosubtype P1.15 (B:4:P1.15) Neisseria meningitidis, was given to about 2.4 million children aged from 3 months to 6 years during 1989 and 1990. The administration of vaccine had little or no measurable effects on this outbreak. In order to detect clonal changes that could explain the continued increase in the incidence of disease after the vaccination, we serotyped isolates recovered between 1990 and 1996 from 834 patients with systemic disease. Strains B:4:P1.15, which was detected in the area as early as 1977, has been the most prevalent phenotype since 1988. These strains are still prevalent in the area and were responsible for about 68% of 834 serogroup B cases in the last 7 years. We analyzed 438 (52%) of these strains by restriction fragment length polymorphism (RFLPs) of rRNA genes (ribotyping). The most frequent pattern obtained was referred to as Rb1 (68%). We concluded that the same clone of B:4:P1.15-Rb1 strains was the most prevalent strain and responsible for the continued increase of incidence of serogroup B MD cases in greater São Paulo during the last 7 years in spite of the vaccination trial.

scholarly journals Necessity of Molecular Techniques To Distinguish between Neisseria meningitidis Strains Isolated from Patients with Meningococcal Disease and from Their Healthy Contacts

1998 ◽  
Vol 36 (9) ◽  
pp. 2465-2470 ◽  
Author(s):  
Ulrich Vogel ◽  
Giovanna Morelli ◽  
Kerstin Zurth ◽  
Heike Claus ◽  
Eugen Kriener ◽  
...  
Keyword(s):  
Czech Republic ◽  
Neisseria Meningitidis ◽  
Meningococcal Disease ◽  
Capsular Polysaccharide ◽  
Molecular Techniques ◽  
Blood Isolate ◽  
The Czech Republic ◽  
Specific Pcr ◽  
Systemic Spread ◽  
Sequence Types

Serogroup C strains of Neisseria meningitidis were isolated from a Germany patient with severe meningococcal disease after a trip to the Czech Republic. These strains (case isolates) were characterized by classical and molecular techniques, as were other strains (carrier isolates) isolated from healthy contacts. Five of 10 carrier isolates had switched off the expression of capsular polysaccharide, as demonstrated by a serogroup-specific PCR. The two case isolates were indistinguishable by multilocus sequence typing and belonged to the ET-37 complex. The carrier isolates belonged to four different sequence types, all unrelated to that of the case strains. Pulsed-field gel electrophoresis showed that the case isolates differed from reference ET-37 complex strains from the Czech Republic and Canada as well as from all the carrier isolates. The isolate from the patient’s nasopharynx was indistinguishable from the blood isolate except for a 40,000-bp chromosomal deletion that had occurred during systemic spread.

scholarly journals The Phosphorylcholine Epitope Undergoes Phase Variation on a 43-Kilodalton Protein in Pseudomonas aeruginosa and on Pili of Neisseria meningitidis and Neisseria gonorrhoeae

1998 ◽  
Vol 66 (9) ◽  
pp. 4263-4267 ◽  
Author(s):  
Jeffrey N. Weiser ◽  
Joanna B. Goldberg ◽  
Nina Pan ◽  
Lynn Wilson ◽  
Mumtaz Virji
Keyword(s):  
Pseudomonas Aeruginosa ◽  
Monoclonal Antibodies ◽  
Streptococcus Pneumoniae ◽  
Respiratory Tract ◽  
Neisseria Meningitidis ◽  
Phase Variation ◽  
Phase Variable ◽  
Human Respiratory Tract ◽  
Lower Growth ◽  
Gram Negative

ABSTRACT Phosphorylcholine (ChoP) is a component of the teichoic acids ofStreptococcus pneumoniae and has been recently identified on the lipopolysaccharide of Haemophilus influenzae, also a major pathogen of the human respiratory tract. Other gram-negative pathogens that frequently infect the human respiratory tract were surveyed for the presence of the ChoP epitope as indicated by binding to monoclonal antibodies (MAbs) recognizing this structure. The ChoP epitope was found on a 43-kDa protein on all clinical isolates ofPseudomonas aeruginosa examined and on several class I and II pili of Neisseria meningitidis. The specificity of the anti-ChoP MAb was demonstrated by the inhibition of binding in the presence of ChoP but not structural analogs. As in the case of H. influenzae, the expression of this epitope was phase variable on these species. In P. aeruginosa, this epitope was expressed at detectable levels only at lower growth temperatures. Expression of the ChoP epitope on piliated neisseriae displayed phase variation, both linked to pilus expression and independently of fully piliated bacteria.

scholarly journals Genotypic and Phenotypic Characterization of theO-Linked Protein Glycosylation System Reveals High Glycan Diversity in Paired Meningococcal Carriage Isolates

2018 ◽  
Vol 200 (16) ◽  
Author(s):  
Bente Børud ◽  
Guro K. Bårnes ◽  
Ola Brønstad Brynildsrud ◽  
Elisabeth Fritzsønn ◽  
Dominique A. Caugant
Keyword(s):  
Neisseria Meningitidis ◽  
Phase Variation ◽  
Protein Glycosylation ◽  
Phase Variable ◽  
Upper Respiratory Tract ◽  
Content Type ◽  
Variable Expression ◽  
Evolutionary Forces ◽  
Strain Collection

ABSTRACTSpecies within the genusNeisseriadisplay significant glycan diversity associated with theO-linked protein glycosylation (pgl) systems due to phase variation and polymorphic genes and gene content. The aim of this study was to examine in detail thepglgenotype and glycosylation phenotype in meningococcal isolates and the changes occurring during short-term asymptomatic carriage. Paired meningococcal isolates derived from 50 asymptomatic meningococcal carriers, taken about 2 months apart, were analyzed with whole-genome sequencing. TheO-linked protein glycosylation genes were characterized in detail using the Genome Comparator tool at the https://pubmlst.org/ database. Immunoblotting with glycan-specific antibodies (Abs) was used to investigate the protein glycosylation phenotype. All majorpgllocus polymorphisms identified inNeisseria meningitidisto date were present in our isolate collection, with the variable presence ofpglGandpglH, both in combination with eitherpglBorpglB2. We identified significant changes and diversity in thepglgenotype and/or glycan phenotype in 96% of the paired isolates. There was also a high degree of glycan microheterogeneity, in which different variants of glycan structures were found at a given glycoprotein. The main mechanism responsible for the observed differences was phase-variable expression of the involved glycosyltransferases and theO-acetyltransferase. To our knowledge, this is the first characterization of thepglgenotype and glycosylation phenotype in a larger strain collection. This report thus provides important insight into glycan diversity inN. meningitidisand into the phase variability changes that influence the expressed glycoform repertoire during meningococcal carriage.IMPORTANCEBacterial meningitis is a serious global health problem, and one of the major causative organisms isNeisseria meningitidis, which is also a common commensal in the upper respiratory tract of healthy humans. In bacteria, numerous loci involved in biosynthesis of surface-exposed antigenic structures that are involved in the interaction between bacteria and host are frequently subjected to homologous recombination and phase variation. These mechanisms are well described inNeisseria, and phase variation provides the ability to change these structures reversibly in response to the environment. Protein glycosylation systems are becoming widely identified in bacteria, and yet little is known about the mechanisms and evolutionary forces influencing glycan composition during carriage and disease.

scholarly journals Potentiation of Phase Variation in Multiple Outer-Membrane Proteins During Spread of the Hyperinvasive Neisseria meningitidis Serogroup W ST-11 Lineage

2019 ◽  
Vol 220 (7) ◽  
pp. 1109-1117 ◽  
Author(s):  
Luke R Green ◽  
Neelam Dave ◽  
Adeolu B Adewoye ◽  
Jay Lucidarme ◽  
Stephen A Clark ◽  
...  
Keyword(s):  
Membrane Proteins ◽  
Neisseria Meningitidis ◽  
Outer Membrane ◽  
Polymerase Chain Reaction Amplification ◽  
Outer Membrane Proteins ◽  
Phase Variation ◽  
Rapid Expansion ◽  
Whole Genome Sequencing Data ◽  
Phase Variable ◽  
Sequencing Data

AbstractBackgroundSince 2009, increases in the incidence of invasive meningococcal disease have occurred in the United Kingdom due to a sublineage of the Neisseria meningitidis serogroup W ST-11 clonal complex (hereafter, the “original UK strain”). In 2013, a descendent substrain (hereafter, the “2013 strain”) became the dominant disease-causing variant. Multiple outer-membrane proteins of meningococci are subject to phase-variable switches in expression due to hypermutable simple-sequence repeats. We investigated whether alterations in phase-variable genes may have influenced the relative prevalence of the original UK and 2013 substrains, using multiple disease and carriage isolates.MethodsRepeat numbers were determined by either bioinformatics analysis of whole-genome sequencing data or polymerase chain reaction amplification and sizing of fragments from genomic DNA extracts. Immunoblotting and sequence-translation analysis was performed to identify expression states.ResultsSignificant increases in repeat numbers were detected between the original UK and 2013 strains in genes encoding PorA, NadA, and 2 Opa variants. Invasive and carriage isolates exhibited similar repeat numbers, but the absence of pilC gene expression was frequently associated with disease.ConclusionsElevated repeat numbers in outer-membrane protein genes of the 2013 strain are indicative of higher phase-variation rates, suggesting that rapid expansion of this strain was due to a heightened ability to evade host immune responses during transmission and asymptomatic carriage.

scholarly journals Opacity-Associated Adhesin Repertoire in Hyperinvasive Neisseria meningitidis

2006 ◽  
Vol 74 (9) ◽  
pp. 5085-5094 ◽  
Author(s):  
Martin J. Callaghan ◽  
Keith A. Jolley ◽  
Martin C. J. Maiden
Keyword(s):  
Genetic Diversity ◽  
Neisseria Meningitidis ◽  
Meningococcal Disease ◽  
Sequence Diversity ◽  
Central Importance ◽  
Global Spread ◽  
Time Periods ◽  
High Level ◽  
Protein Variants ◽  
Over Time

ABSTRACT The opacity (Opa) proteins mediate a variety of interactions between the bacterium Neisseria meningitidis and its human host. These interactions are thought to be of central importance in both the asymptomatic colonization of the nasopharynx and the sporadic occurrence of meningococcal disease. The receptor specificities of a limited number of Opa protein variants have been explored, but the high level of amino acid sequence diversity among variants has complicated the assignment of specific roles to individual Opa variants or combinations of variants. In addition, the distribution of Opa protein variants among diverse meningococci, information that is potentially informative for studies of Opa function, is poorly understood. A systematic survey of the genetic diversity in the four opa gene loci in each of 77 meningococcal isolates was undertaken. These isolates were representative of the seven hyperinvasive meningococcal clonal complexes that caused the majority of meningococcal disease over the last 50 years. Consistent with previous studies, a high level of sequence diversity was observed among the opa genes and the proteins that they encoded; however, particular sets of Opa protein variants were consistently associated with each of the clonal complexes over time periods often spanning decades and during global spread. These observations were consistent with the postulate that particular combinations of Opa proteins confer fitness advantages to individual clonal complexes and have implications for studies of Opa function and the inclusion of Opa proteins in novel meningococcal vaccines.

scholarly journals Role of Lipopolysaccharide Sialylation in Serum Resistance of Serogroup B and C Meningococcal Disease Isolates

1999 ◽  
Vol 67 (2) ◽  
pp. 954-957 ◽  
Author(s):  
Ulrich Vogel ◽  
Heike Claus ◽  
Gabriele Heinze ◽  
Matthias Frosch
Keyword(s):  
Neisseria Meningitidis ◽  
Human Serum ◽  
Meningococcal Disease ◽  
Serum Resistance ◽  
Minor Importance ◽  
Infant Rat ◽  
Systemic Spread

ABSTRACT α-2,3-Sialyltransferase mutants of three genetically and phenotypically diverse Neisseria meningitidis strains were compared with regard to resistance to human serum and systemic spread in the infant rat. Lipopolysaccharide sialylation was found to be of minor importance for the resistance of serogroup B and C meningococcal disease isolates to complement attack.

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