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Hedberg, Sara [Thulin]
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Publications (10 of 13) Show all publications
Törös, B., Hedberg, S. T., Unemo, M., Jacobsson, S., Hill, D. M. C., Olcén, P., . . . Mölling, P. (2015). Genome-based characterization of emergent invasive Neisseria meningitidis serogroup Y isolates in Sweden from 1995 to 2012. Journal of Clinical Microbiology, 53(7), 2154-2162
Open this publication in new window or tab >>Genome-based characterization of emergent invasive Neisseria meningitidis serogroup Y isolates in Sweden from 1995 to 2012
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2015 (English)In: Journal of Clinical Microbiology, ISSN 0095-1137, E-ISSN 1098-660X, Vol. 53, no 7, p. 2154-2162Article in journal (Refereed) Published
Abstract [en]

Invasive meningococcal disease (IMD) caused by Neisseria meningitidis serogroup Y has increased in Europe, especially in Scandinavia. In Sweden, serogroup Y is now the dominating serogroup, and in 2012, the serogroup Y disease incidence was 0.46/100,000 population. We previously showed that a strain type belonging to sequence type 23 was responsible for the increased prevalence of this serogroup in Sweden. The objective of this study was to investigate the serogroup Y emergence by whole-genome sequencing and compare the meningococcal population structure of Swedish invasive serogroup Y strains to those of other countries with different IMD incidence. Whole-genome sequencing was performed on invasive serogroup Y isolates from 1995 to 2012 in Sweden (n = 186). These isolates were compared to a collection of serogroup Y isolates from England, Wales, and Northern Ireland from 2010 to 2012 (n = 143), which had relatively low serogroup Y incidence, and two isolates obtained in 1999 in the United States, where serogroup Y remains one of the major causes of IMD. The meningococcal population structures were similar in the investigated regions; however, different strain types were prevalent 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. The reasons for the IMD increase are multifactorial and are influenced by increased virulence, host adaptive immunity, and transmission. Future genome-wide association studies are needed to reveal additional genes associated with serogroup Y meningococcal disease, and this work would benefit from a complete serogroup Y meningococcal reference genome.

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-45585 (URN)10.1128/JCM.03524-14 (DOI)000358287700023 ()25926489 (PubMedID)2-s2.0-84932634694 (Scopus ID)
Note

Funding Agencies:

Meningitis Research Foundation

Wellcome Trust

European Union

Örebro County Council Research Committee

Available from: 2015-08-18 Created: 2015-08-18 Last updated: 2019-03-26Bibliographically approved
Törös, B., Hedberg, S. T., Jacobsson, S., Fredlund, H., Olcén, P. & Mölling, P. (2013). Evaluation of molecular typing methods for identification of outbreak-associated Neisseria meningitidis isolates. Acta Pathologica, Microbiologica et Immunologica Scandinavica (APMIS), 121(6), 503-510
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, p. 503-510Article 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.

Keywords
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: 2019-03-26Bibliographically approved
Hedberg, S. ., Törös, B., Fredlund, H., Olcén, P. & Mölling, P. (2011). Genetic characterisation of the emerging invasive Neisseria meningitidis serogroup Y in Sweden, 2000 to 2010. Eurosurveillance, 16(23), Article ID 19885.
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, article id 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: 2019-03-26Bibliographically approved
Hedberg, S. T., Olcén, P., Fredlund, H. & Unemo, M. (2010). Antibiotic susceptibility of invasive Neisseria meningitidis isolates from 1995 to 2008 in Sweden: the meningococcal population remains susceptible. Scandinavian Journal of Infectious Diseases, 42(1), 61-64
Open this publication in new window or tab >>Antibiotic susceptibility of invasive Neisseria meningitidis isolates from 1995 to 2008 in Sweden: the meningococcal population remains susceptible
2010 (English)In: Scandinavian Journal of Infectious Diseases, ISSN 0036-5548, E-ISSN 1651-1980, Vol. 42, no 1, p. 61-64Article in journal (Refereed) Published
Abstract [en]

The susceptibility to 7 antibiotics was determined for all Swedish invasive Neisseria meningitidis isolates from 1995 to 2008 (N=717). In general, these remain highly susceptible to the antibiotics recommended for use. Accordingly, penicillin G remains effective for the treatment of invasive meningococcal disease and ciprofloxacin appropriate for prophylaxis.

National Category
Medical and Health Sciences
Research subject
Medicine
Identifiers
urn:nbn:se:oru:diva-8532 (URN)10.3109/00365540903292682 (DOI)000274210500009 ()19883157 (PubMedID)
Available from: 2009-11-25 Created: 2009-11-12 Last updated: 2018-02-23Bibliographically approved
Hedberg, S. T., Fredlund, H., Nicolas, P., Caugant, D. A., Olcén, P. & Unemo, M. (2009). Antibiotic susceptibility and characteristics of Neisseria meningitidis isolates from the African meningitis belt, 2000 to 2006: phenotypic and genotypic perspectives. Antimicrobial Agents and Chemotherapy, 53(4), 1561-1566
Open this publication in new window or tab >>Antibiotic susceptibility and characteristics of Neisseria meningitidis isolates from the African meningitis belt, 2000 to 2006: phenotypic and genotypic perspectives
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2009 (English)In: Antimicrobial Agents and Chemotherapy, ISSN 0066-4804, E-ISSN 1098-6596, Vol. 53, no 4, p. 1561-1566Article in journal (Refereed) Published
Abstract [en]

Up-to-date information regarding the antibiotic susceptibility of Neisseria meningitidis strains from African countries is highly limited. Our aim was to comprehensively describe the antibiotic susceptibilities of a selection of N. meningitidis isolates recovered between 2000 and 2006 from 18 African countries, mainly those within the meningitis belt. Susceptibilities to 11 antibiotics were determined using Etest for 137 N. meningitidis isolates (stringently selected from 693 available isolates). The isolates were also characterized by serogrouping, multilocus sequence typing, genosubtyping, and penA allele identification. All N. meningitidis isolates were susceptible to ceftriaxone, chloramphenicol, and ciprofloxacin. No isolate produced beta-lactamase. Only three isolates (2%) displayed reduced susceptibility to penicillin G. The two isolates with the highest penicillin G MICs were the only isolates showing reduced susceptibility to ampicillin and cefuroxime. One of these isolates was also resistant to penicillin V. One percent of isolates displayed reduced susceptibility to rifampin, while 52% of the isolates were resistant to tetracycline, 74% were resistant to erythromycin, and 94% were resistant to sulfadiazine. The MICs of rifampin and tetracycline seemed to be associated with the serogroup of the isolates. In total, 18 sequence types (STs), 10 genosubtypes, and 8 different penA alleles were identified; the most common were ST-7, P1.20,9,35-1, and penA4, respectively. A high level of correlation was found between ST, genosubtype, and penA allele. In conclusion, N. meningitidis isolates from the African meningitis belt remain highly susceptible to the antibiotics used. Regarding beta-lactam antibiotics, rare isolates showed a reduced susceptibility to penicillins, but the expanded-spectrum cephalosporins are not affected at present.

National Category
Medical and Health Sciences Microbiology in the medical area
Research subject
Microbiology; Physiology; Biomedicine
Identifiers
urn:nbn:se:oru:diva-8630 (URN)10.1128/AAC.00994-08 (DOI)19188396 (PubMedID)
Available from: 2009-11-25 Created: 2009-11-23 Last updated: 2018-01-12Bibliographically approved
Thulin Hedberg, S. (2009). Antibiotic susceptibility and resistance in Neisseria meningitidis: phenotypic and genotypic characteristics. (Doctoral dissertation). Örebro: Örebro universitet
Open this publication in new window or tab >>Antibiotic susceptibility and resistance in Neisseria meningitidis: phenotypic and genotypic characteristics
2009 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Neisseria meningitidis, also known as the meningococcus, is a globally spread obligate human bacterium causing meningitis and/or septicaemia. It is responsible for epidemics in both developed and developing countries. Untreated invasive meningococcal disease is often fatal, and despite modern intensive care units, the mortality is still remarkably high (approximately 10%). The continuously increasing antibiotic resistance in many bacterial pathogens is a serious public health threat worldwide and there have been numerous reports of emerging resistance in meningococci during the past decades.

In paper I, the gene linked to reduced susceptibility to penicillins, the penA gene, was examined. The totally reported variation in all published penA genes was described. The penA gene was highly variable (in total 130 variants were identified). By examination of clinical meningococcal isolates, the association between penA gene sequences and penicillin susceptibility could be determined. Isolates with reduced susceptibility displayed mosaic structures in the penA gene. Two closely positioned nucleotide polymorphisms were identified in all isolates with reduced penicillin susceptibility and mosaic structured penA genes. These alterations were absent in all susceptible isolates and were successfully used to detect reduced penicillin susceptibility by real-time PCR and pyrosequencing in paper II. In papers III and IV, antibiotic susceptibility and characteristics of Swedish and African meningitis belt meningococcal isolates were comprehensively described. Although both populations were mainly susceptible to the antibiotics used for treatment and prophylaxis, the proportion of meningococci with reduced penicillin susceptibility was slightly higher in Sweden. A large proportion of the African isolates was resistant to tetracycline and erythromycin. In paper V, the gene linked to rifampicin resistance, the rpoB gene, was examined in meningococci from 12 mainly European countries. Alterations of three amino acids in the RpoB protein were found to always and directly lead to rifampicin resistance. A new breakpoint for rifampicin resistance in meningococci was suggested. The biological cost of the RpoB alterations was investigated in mice. The pathogenicity/virulence was significantly lower in rifampicin resistant mutants as compared with susceptible wild-type bacteria.

Place, publisher, year, edition, pages
Örebro: Örebro universitet, 2009. p. 94
Series
Örebro Studies in Medicine, ISSN 1652-4063 ; 38
Keywords
Neisseria meningitidis, meningococcal disease, antibiotic resistance, antibiotic susceptbility, biological cost, PCR, sequencing
National Category
Cell and Molecular Biology Microbiology in the medical area Microbiology in the medical area Microbiology in the medical area
Research subject
Biomedicine; Medicine
Identifiers
urn:nbn:se:oru:diva-8652 (URN)978-91-7668-702-4 (ISBN)
Public defence
2009-12-18, Wilandersalen, Universitetssjukhuset Örebro, Örebro, 09:00 (English)
Opponent
Supervisors
Available from: 2009-11-25 Created: 2009-11-25 Last updated: 2018-01-12Bibliographically approved
Taha, M.-K., Thulin Hedberg, S., Szatanik, M., Hong, E., Ruckly, C., Abad, R., . . . Wasko, I. (2009). Defining the breakpoint for resistance to rifampicin in Neisseria meningitidis by rpoB sequencing.
Open this publication in new window or tab >>Defining the breakpoint for resistance to rifampicin in Neisseria meningitidis by rpoB sequencing
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2009 (English)Manuscript (preprint) (Other academic)
Abstract [en]

Clinical isolates of Neisseria meningitidis resistant to rifampicin are important to identify asthey lead to failure of chemoprophylaxis of meningococcal disease. However, theidentification of these isolates is hindered by the absence of a harmonized breakpoint despiteefforts of standardization. In the present study, a large number (n=352) of clinical N.meningitidis isolates from 12 mainly European countries and spanning over 25 years (1984 to2009) were examined. The collection comprised all clinical isolates with MIC 0.25 mg/lreceived by the national reference laboratories for meningococci in the participating countries(n=161). In addition, representative isolates displaying MIC of rifampicin <0.25 mg/l wereexamined (n=191). Phenotyping and genotyping of isolates were performed and a 660 bpDNA fragment of the rpoB gene was sequenced in all the included isolates. Sequencesdiffering by at least one nucleotide were defined as a unique rpoB allele (n=55). Geometricmeans of MIC were calculated for isolates displaying the same allele. All the clinical isolatesdisplaying MIC >1 mg/l of rifampicin possessed rpoB alleles with critical mutations (in total21 alleles), resulting in substitutions at the codon H552 and less frequently at nearby codons(S548 and S557). These alterations were absent in the alleles (n=34) found in all isolates withMIC 1 mg/l. Based on these findings, rifampicin susceptible isolates could be defined asthose with MIC 1 mg/l. A new web site was created based on the data from this work (http://neisseria.org/nm/typing/rpoB). The rifampicin resistant isolates belonged to diversegenetic lineages and provoked lower bacteremia levels in mice. This biological cost mayexplain the non-expansion of the rifampicin resistant isolates.

National Category
Medical and Health Sciences
Research subject
Medicine
Identifiers
urn:nbn:se:oru:diva-8655 (URN)
Available from: 2009-11-25 Created: 2009-11-25 Last updated: 2017-10-18Bibliographically approved
Hedberg, S. T., Olcén, P., Fredlund, H. & Mölling, P. (2009). Real-time PCR detection of five prevalent bacteria causing acute meningitis. Acta Pathologica, Microbiologica et Immunologica Scandinavica (APMIS), 117(11), 856-860
Open this publication in new window or tab >>Real-time PCR detection of five prevalent bacteria causing acute meningitis
2009 (English)In: Acta Pathologica, Microbiologica et Immunologica Scandinavica (APMIS), ISSN 0903-4641, E-ISSN 1600-0463, Vol. 117, no 11, p. 856-860Article in journal (Refereed) Published
National Category
Medical and Health Sciences Microbiology in the medical area
Research subject
Medicine
Identifiers
urn:nbn:se:oru:diva-12129 (URN)10.1111/j.1600-0463.2009.02539.x (DOI)19845537 (PubMedID)
Note

Letter to the editor.

Available from: 2010-10-07 Created: 2010-10-07 Last updated: 2018-01-12Bibliographically approved
Hedberg, S. T., Olcén, P., Fredlund, H. & Unemo, M. (2008). Combined real-time PCR and pyrosequencing strategy for objective, sensitive, specific, and high throughput identification of reduced susceptibility to penicillins in Neisseria meningitidis. Antimicrobial Agents and Chemotherapy, 52(2), 753-756
Open this publication in new window or tab >>Combined real-time PCR and pyrosequencing strategy for objective, sensitive, specific, and high throughput identification of reduced susceptibility to penicillins in Neisseria meningitidis
2008 (English)In: Antimicrobial Agents and Chemotherapy, ISSN 0066-4804, E-ISSN 1098-6596, Vol. 52, no 2, p. 753-756Article in journal (Refereed) Published
Abstract [en]

A segment of penA in Neisseria meningitidis strains (n = 127), including two nucleotide sites closely associated to reduced susceptibility to penicillins, was amplified and pyrosequenced. All results were in concordance with Sanger sequencing, and a high correlation between alterations in the two Pen(i)-specific sites and reduced susceptibility to penicillins was identified.

Place, publisher, year, edition, pages
Washington, DC: American Society for Microbiology, 2008
Keywords
Anti-Bacterial Agents/pharmacology, Bacterial Proteins/chemistry/genetics, Base Sequence, Humans, Microbial Sensitivity Tests/methods, Molecular Sequence Data, Neisseria meningitidis/*drug effects, Penicillin Resistance, Penicillin-Binding Proteins/chemistry/genetics, Penicillins/*pharmacology, Polymerase Chain Reaction/methods, Sensitivity and Specificity, Sequence Analysis; DNA
National Category
Medical and Health Sciences Infectious Medicine
Research subject
Infectious Diseases; Medicine
Identifiers
urn:nbn:se:oru:diva-3451 (URN)10.1128/AAC.00914-07 (DOI)18070955 (PubMedID)
Available from: 2008-12-08 Created: 2008-12-08 Last updated: 2017-12-14Bibliographically approved
Unemo, M., Olcén, P., Fredlund, H. & Hedberg, S. T. (2008). Real-time PCR and subsequent pyrosequencing for screening of penA mosaic alleles and prediction of reduced susceptibility to expanded-spectrum cephalosporins in Neisseria gonorrhoeae. Acta Pathologica, Microbiologica et Immunologica Scandinavica (APMIS), 116(11), 1004-1008
Open this publication in new window or tab >>Real-time PCR and subsequent pyrosequencing for screening of penA mosaic alleles and prediction of reduced susceptibility to expanded-spectrum cephalosporins in Neisseria gonorrhoeae
2008 (English)In: Acta Pathologica, Microbiologica et Immunologica Scandinavica (APMIS), ISSN 0903-4641, E-ISSN 1600-0463, Vol. 116, no 11, p. 1004-1008Article in journal (Refereed) Published
Place, publisher, year, edition, pages
Oxford: Blackwell, 2008
National Category
Medical and Health Sciences Microbiology in the medical area
Research subject
Infectious Diseases
Identifiers
urn:nbn:se:oru:diva-7010 (URN)10.1111/j.1600-0463.2008.01062.x (DOI)19132998 (PubMedID)
Note

Letter to the editor

Available from: 2009-05-28 Created: 2009-05-28 Last updated: 2018-01-13Bibliographically approved
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