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Genome-based characterization of Neisseria meningitidis with focus on the emergent serogroup Y disease
Örebro University, School of Health and Medical Sciences, Örebro University, Sweden.
2014 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Neisseria meningitidis, also referred to as meningococcus, is one of the leading causes of epidemic meningitis and septicaemia worldwide. Despite modern treatment, meningococcal disease remains associated with a high mortality (about 10%). Meningococcal disease is mainly restricted to specific hypervirulent lineages and specific capsular groups (serogroups), which have a changing global distribution over time. At the end of the 2000s, the previously unusual serogroup Y emerged, corresponding to half of all of the invasive meningococcal disease (IMD) cases in Sweden by the beginning of the 2010s. The aim of this thesis is to describe the emergence of serogroup Y meningococci genetically in an effort to understand some of the factors involved in the successful spread of this group throughout Sweden. In addition, genetic typing schemes were evaluated for surveillance and outbreak investigation.

Our results indicate that the currently recommended typing for surveillance of meningococci could be altered to include the factor H-binding protein (fHbp). A highly variable multilocus variable number tandem repeat analysis (HV-MLVA) was able to confirm connected cases in a suspected small outbreak. In addition, a strain type sharing the same porA, fetA, porB, fHbp, penA and multilocus sequence type was found to be the principal cause of the increase in serogroup Y disease. However, a deeper resolution obtained from the core genomes revealed a subtype of this strain, which was mainly responsible for the increase. Finally, when the Swedish serogroup Y genomes were compared internationally, different strains seemed to dominate in different regions. This indicates that the increase was probably not due to one or more point introductions of a strain previously known internationally but more probably multifactorial.

Place, publisher, year, edition, pages
Örebro: Örebro university , 2014. , 92 p.
Series
Örebro Studies in Medicine, ISSN 1652-4063 ; 109
Keyword [en]
Neisseria meningitidis, meningococcal disease, serogroup Y, molecular characterization, epidemiology, genome sequencing
National Category
Medical and Health Sciences Biomedical Laboratory Science/Technology
Research subject
Biomedicine
Identifiers
URN: urn:nbn:se:oru:diva-35997OAI: oai:DiVA.org:oru-35997DiVA: diva2:739448
Public defence
2014-09-26, Universitetssjukhuset, hörsal C3, Södra Grev Rosengatan, Örebro, 09:00 (English)
Opponent
Supervisors
Available from: 2014-08-21 Created: 2014-08-21 Last updated: 2015-12-28Bibliographically approved
List of papers
1. Evaluation of molecular typing methods for identification of outbreak-associated Neisseria meningitidis isolates
Open this publication in new window or tab >>Evaluation of molecular typing methods for identification of outbreak-associated Neisseria meningitidis isolates
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2013 (English)In: Acta Pathologica, Microbiologica et Immunologica Scandinavica (APMIS), ISSN 0903-4641, E-ISSN 1600-0463, Vol. 121, no 6, 503-510 p.Article in journal (Refereed) Published
Abstract [en]

It is essential in an outbreak investigation that strain characterization of Neisseria meningitidis is performed in a rapid and accurate manner. This study evaluated two new molecular typing methods, multiple- locus variable number tandem repeat analysis (MLVA) and repetitive sequence-based PCR (rep-PCR) (DiversiLab; bioMe´rieux) and compared them with current recommended methodologies. This retrospective study included 36 invasive N. meningitidis serogroup C isolates collected in Sweden 2001 through 2009 and previously subjected to outbreak investigation. All strains were typed with highly variable- MLVA (HV-MLVA) and rep-PCR. The isolates were further characterized by multilocus sequence typing (MLST) and sequencing of the fetA, fHbp, penA, porA and porB genes. The results showed that HVMLVA had the highest index of diversity (0.99) and rep-PCR had the highest congruence (40%) with the currently recommended typing methods. The HV MLVA correlated best to the spatiotemporal connections and had the overall highest Adjusted Wallace coefficients, suggesting that HV-MLVA can predict the results of the other typing methods in the study. We therefore suggest that after initial confirmation of species, serogroup and genosubtype, HV-MLVA should be used asthe most discriminatorymethod for first hand investigation of N. meningitidis serogroup C isolates.

Keyword
Neisseria meningitidis, molecular typing, repetitive sequence-based PCR, MLVA, epidemiology.
National Category
Medical Biotechnology (with a focus on Cell Biology (including Stem Cell Biology), Molecular Biology, Microbiology, Biochemistry or Biopharmacy)
Research subject
Microbiology
Identifiers
urn:nbn:se:oru:diva-36111 (URN)10.1111/apm.12022 (DOI)000319427100004 ()
Available from: 2014-08-25 Created: 2014-08-25 Last updated: 2017-03-27Bibliographically approved
2. Genetic characterisation of the emerging invasive Neisseria meningitidis serogroup Y in Sweden, 2000 to 2010
Open this publication in new window or tab >>Genetic characterisation of the emerging invasive Neisseria meningitidis serogroup Y in Sweden, 2000 to 2010
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2011 (English)In: Eurosurveillance, ISSN 1025-496X, E-ISSN 1560-7917, Vol. 16, no 23, 19885Article in journal (Refereed) Published
Abstract [en]

Neisseria meningitidis serogroups B and C have beenresponsible for the majority of invasive meningococcaldisease in Europe. Recently, an increase of N. meningitidisdisease due to serogroup Y has been notedin Sweden (in 2010, the proportion was 39%, with anincidence of 0.23 per 100,000 population), as well as inother northern European countries. We aimed to investigatethe clonal pattern of the emerging serogroup Yin Sweden during 2000 to 2010. The serogroup Y isolatesidentified during this time (n=85) were characterisedby multilocus sequence typing and sequencing ofthe fetA, fHbp, penA, porA and porB genes. The mostfrequent clone (comprising 28 isolates) with identicalallele combinations of the investigated genes, waspartly responsible for the observed increased numberof N. meningitidis serogroup Y isolates. It was sulfadiazineresistant, with genosubtype P1.5-2,10-1,36-2,sequence type 23, clonal complex 23, porB allele 3-36,fetA allele F4-1, fHbp allele 25 and penA allele 22. Thefirst case with disease due to this clone was identifiedin 2002: there was a further case in 2004, six during2006 to 2007, eight during 2008 to 2009, with a peakof 12 cases in 2010. An unusual increase of invasivedisease in young adults (aged 20–29 years) caused bythis clone was shown, but no increase in mortality ratewas observed.

Place, publisher, year, edition, pages
Saint-Maurice, France: European Centre for the Epidemiological Monitoring of AIDS, 2011
National Category
Biomedical Laboratory Science/Technology
Research subject
Biomedicine
Identifiers
urn:nbn:se:oru:diva-36113 (URN)000291586300002 ()21679677 (PubMedID)2-s2.0-79959480972 (Scopus ID)
Available from: 2014-08-25 Created: 2014-08-25 Last updated: 2017-03-27Bibliographically approved
3. Surveillance of invasive Neisseria meningitidis with a serogroup Y update, Sweden 2010 to 2012
Open this publication in new window or tab >>Surveillance of invasive Neisseria meningitidis with a serogroup Y update, Sweden 2010 to 2012
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(English)Manuscript (preprint) (Other academic)
Abstract [en]

As previously described in this journal, an increase of invasive meningococcal disease caused by Neisseria meningitidis serogroup Y has been noted in Sweden, and to a lower extent throughout Europe. In the present study, we aimed to describe the current epidemiology of invasive N. meningitidis isolates in Sweden, with focus on the still increasing serogroup Y, and to find an optimal molecular typing scheme for both surveillance and outbreak investigations.

All invasive N. meningitidis isolates in Sweden from 2010 to 2012 (n=208) were genetically characterized.

The predominant serogroup in Sweden is still serogroup Y, in 2010, 2011 and 2012 corresponding to 22/57, 31/61 and 44/90of all invasive isolates (incidence 0.23, 0.33 and 0.46 per 100,000 population). Of the serogroup Y isolates in 2010, 2011 and 2012: 15/22, 23/32 and 19/44 were genetically clonal (Y: P1.5-2,10-1,36-2: F4-1: ST-23 (cc23), ‘porB allele 3- 36, fHbp allele 25 and penA allele 22), respectively. Our findings further support those of others that currently recommended FetA typing could be replaced by FHbp. Moreover, in line with our previous study, the current results indicate that highly variable multiple-locus variable number tandem repeat analysis (HV-MLVA) can be used as a first-hand rapid method for small outbreak investigations.

National Category
Biomedical Laboratory Science/Technology
Research subject
Biomedicine
Identifiers
urn:nbn:se:oru:diva-36118 (URN)
Available from: 2014-08-25 Created: 2014-08-25 Last updated: 2014-08-25Bibliographically approved
4. Whole-genome characterization of emergent invasive Neisseria meningitidis serogroup Y in Sweden from the two recent decades
Open this publication in new window or tab >>Whole-genome characterization of emergent invasive Neisseria meningitidis serogroup Y in Sweden from the two recent decades
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(English)Manuscript (preprint) (Other academic)
Abstract [en]

Background and Objective: Invasive meningococcal disease (IMD) caused by Neisseria meningitidis serogroup Y has increased in Europe, especially in Scandinavia. In Sweden, serogroup Y is the dominating serogroup and in 2012 the serogroup Y disease incidence was 0.46/100,000 population. We have previously shown that a strain type belonging to ST-23 is responsible for the emergence of this serogroup in Sweden. The objective of this study was to compare the meningococcal population structure and phylogeography of Swedish invasive serogroup Y strains to other countries with different disease incidence.

Materials and Methods: Whole-genome sequencing was performed on invasive serogroup Y isolates from 1995 to 2012 in Sweden (n=186). A comparison of serogroup Y isolates was performed using a collection of isolates from England, Wales and Northern Ireland (n=143), which has relatively low incidence, and two isolates from the USA, where serogroup Y remains one of the major causes of IMD.

Results: The meningococcal population structures were similar in the investigated regions; however, different strain types were dominating in each geographic region. A number of genes, known or hypothesized to have an impact on meningococcal virulence, were shown to be associated with different strain types and subtypes.

Conclusions: The emergence of serogroup Y is most likely not associated with a previously described strain type that has been introduced into the Swedish meningococcal population. The reasons for the disease increase are most probably multifactorial; both increased virulence and host adaptive immunity influence infection and transmission. Future genomewide association studies could reveal additional genes associated with serogroup Y meningococcal disease.

Keyword
Neisseria meningitidis, genome sequencing, epidemiology, serogroup Y, invasive meningococcal disease
National Category
Biomedical Laboratory Science/Technology
Research subject
Biomedicine
Identifiers
urn:nbn:se:oru:diva-36120 (URN)
Available from: 2014-08-25 Created: 2014-08-25 Last updated: 2014-08-25Bibliographically approved

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