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Exploring genomic and phenotypic differences in Neisseria meningitidis: understanding carriage and invasive disease
Örebro universitet, Institutionen för medicinska vetenskaper.
2024 (Engelska)Doktorsavhandling, sammanläggning (Övrigt vetenskapligt)
Abstract [en]

Neisseria meningitidis can colonise the nasopharynx in humans and is also the cause of invasive meningococcal disease (IMD), which often presents as septicaemia and meningitis with high mortality rates. Invasive disease is often associated with specific capsular serogroups and clonal complexes (CC). In Sweden, serogroups Y and W have had a high incidence in recent years, but were previously considered rare causes of IMD, suggesting a change in the virulence potential of these serogroups. Currently, no specific genes exist that can reliably predict whether an N. meningitidis isolate will result in invasive disease or remain in the carriage state. Genetically similar isolates can be found during carriage and IMD, and it is more common for the carriage isolates to lack a capsule. The aim of this thesis was to investigate how genetic and phenotypic differences in N. meningitidis, can affect the virulence and the transition from a carriage state to invasive disease.

The results indicate that the increase of serogroup W in Sweden is due to a specific lineage of CC11. This CC is rarely found among carriers and is considered highly virulent. Infections in transgenic mice with serogroup W CC11 isolates showed a greater virulence compared to serogroup Y isolates from other CCs. Although both serogroups are common causes of IMD in Sweden, they differ in virulence in transgenic mice. A genome-wide association study comparing carriage and invasive isolates, revealed that there were genetic variants in genes associated with virulence between these isolates. Among these variants were pilE/pilS, which are involved in the type IV pili. Comparison of pilE gene expression between carriage and invasive isolates showed no significant difference between these isolates. However, a difference in the class of the PilE protein was found between invasive and carriage isolates. Further research is needed to understand the impact of these genetic variations on the transition from carriage to invasive disease, also considering how factors in the human host and the environment that may contribute to the development of invasive disease.

Ort, förlag, år, upplaga, sidor
Örebro: Örebro University , 2024. , s. 81
Serie
Örebro Studies in Medicine, ISSN 1652-4063 ; 292
Nyckelord [en]
Neisseria meningitidis, invasive meningococcal disease, carriage, virulence, whole genome sequencing, genome wide association study
Nationell ämneskategori
Annan medicinsk grundvetenskap
Identifikatorer
URN: urn:nbn:se:oru:diva-112752ISBN: 9789175295572 (tryckt)ISBN: 9789175295589 (digital)OAI: oai:DiVA.org:oru-112752DiVA, id: diva2:1848177
Disputation
2024-05-31, Örebro universitet, Campus USÖ, hörsal X3, Södra Grev Rosengatan 32, Örebro, 09:00 (Svenska)
Opponent
Handledare
Tillgänglig från: 2024-04-02 Skapad: 2024-04-02 Senast uppdaterad: 2024-05-27Bibliografiskt granskad
Delarbeten
1. Whole-Genome Sequencing of Emerging Invasive Neisseria meningitidis Serogroup W in Sweden
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2018 (Engelska)Ingår i: Journal of Clinical Microbiology, ISSN 0095-1137, E-ISSN 1098-660X, Vol. 56, nr 4, artikel-id e01409-17Artikel i tidskrift (Refereegranskat) Published
Abstract [en]

Invasive disease caused by Neisseria meningitidis serogroup W (MenW) has historically had a low incidence in Sweden, with an average incidence of 0.03 case/100,000 population from 1995 to 2014. In recent years, a significant increase in the incidence of MenW has been noted in Sweden, to an average incidence of 0.15 case/100,000 population in 2015 to 2016. In 2017 (1 January to 30 June), 33% of invasive meningococcal disease cases (7/21 cases) were caused by MenW. In the present study, all invasive MenW isolates from Sweden collected in 1995 to June 2017 (n = 86) were subjected to whole-genome sequencing to determine the population structure and to compare isolates from Sweden with historical and international cases. The increase of MenW in Sweden was determined to be due to isolates belonging to the South American sublineage of MenW clonal complex 11, namely, the novel U.K. 2013 lineage. This lineage was introduced in Sweden in 2013 and has since been the dominant lineage of MenW.

Ort, förlag, år, upplaga, sidor
American Society for Microbiology, 2018
Nyckelord
CC11, Neisseria meningitidis, invasive meningococcal disease, serogroup W, whole-genome sequencing
Nationell ämneskategori
Infektionsmedicin
Identifikatorer
urn:nbn:se:oru:diva-66477 (URN)10.1128/JCM.01409-17 (DOI)000429718700010 ()29321195 (PubMedID)2-s2.0-85044717735 (Scopus ID)
Anmärkning

Funding Agencies:

Örebro County Council Research Committee

Nyckelfonden

Wellcome Trust

European Union

Tillgänglig från: 2018-04-13 Skapad: 2018-04-13 Senast uppdaterad: 2024-05-06Bibliografiskt granskad
2. Difference in virulence between Neisseria meningitidis serogroups W and Y in transgenic mice
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2020 (Engelska)Ingår i: BMC Microbiology, E-ISSN 1471-2180, Vol. 20, nr 1, artikel-id 92Artikel i tidskrift (Refereegranskat) Published
Abstract [en]

BACKGROUND: Neisseria meningitidis serogroups W and Y are the most common serogroups causing invasive meningococcal disease in Sweden. The majority of cases are caused by the serogroup W UK 2013 strain of clonal complex (cc) 11, and subtype 1 of the serogroup Y, YI strain of cc23. In this study, virulence factors of several lineages within cc11 and cc23 were investigated in transgenic BALB/c mice expressing human transferrin. Transgenic mice were infected intraperitoneally with serogroup W and Y isolates. Levels of bacteria and the proinflammatory cytokine CXCL1 were determined in blood collected 3 h and 24 h post-infection. Apoptosis was investigated in immune cells from peritoneal washes of infected mice. Adhesion and induction of apoptosis in human epithelial cells were also scored.

RESULTS: The levels of bacteraemia, CXCL1, and apoptosis were higher in serogroup W infected mice than in serogroup Y infected mice. Serogroup W isolates also induced higher levels of apoptosis and adhesion in human epithelial cells. No significant differences were observed between different lineages within cc11 and cc23.

CONCLUSIONS: N. meningitidis Serogroup W displayed a higher virulence in vivo in transgenic mice, compared to serogroup Y. This was reflected by higher bacteremia, proinflammatory activity, and ability to induce apoptosis in mouse immune cells and human epithelial cells.

Ort, förlag, år, upplaga, sidor
BioMed Central, 2020
Nyckelord
Neisseria meningitidis, Serogroup W, Serogroup Y, Transgenic mice, Virulence
Nationell ämneskategori
Infektionsmedicin
Identifikatorer
urn:nbn:se:oru:diva-81345 (URN)10.1186/s12866-020-01760-4 (DOI)000528725400001 ()32295520 (PubMedID)2-s2.0-85083478167 (Scopus ID)
Anmärkning

Funding Agencies:

Örebro County Council Research Committee  

Nyckelfonden, Örebro University Hospital, Örebro, Sweden  

Institut Pasteur, Paris, France  

Örebro University 

Tillgänglig från: 2020-04-29 Skapad: 2020-04-29 Senast uppdaterad: 2024-05-06Bibliografiskt granskad
3. Genetic variants linked to the phenotypic outcome of invasive disease and carriage of Neisseria meningitidis
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2023 (Engelska)Ingår i: Microbial Genomics, E-ISSN 2057-5858, Vol. 9, nr 10, artikel-id 001124Artikel i tidskrift (Refereegranskat) Published
Abstract [en]

Neisseria meningitidis can be a human commensal in the upper respiratory tract but is also capable of causing invasive diseases such as meningococcal meningitis and septicaemia. No specific genetic markers have been detected to distinguish carriage from disease isolates. The aim here was to find genetic traits that could be linked to phenotypic outcomes associated with carriage versus invasive N. meningitidis disease through a bacterial genome-wide association study (GWAS). In this study, invasive N. meningitidis isolates collected in Sweden (n=103) and carriage isolates collected at Örebro University, Sweden (n=213) 2018-2019 were analysed. The GWAS analysis, treeWAS, was applied to single-nucleotide polymorphisms (SNPs), genes and k-mers. One gene and one non-synonymous SNP were associated with invasive disease and seven genes and one non-synonymous SNP were associated with carriage isolates. The gene associated with invasive disease encodes a phage transposase (NEIS1048), and the associated invasive SNP glmU S373C encodes the enzyme N-acetylglucosamine 1-phosphate (GlcNAC 1-P) uridyltransferase. Of the genes associated with carriage isolates, a gene variant of porB encoding PorB class 3, the genes pilE/pilS and tspB have known functions. The SNP associated with carriage was fkbp D33N, encoding a FK506-binding protein (FKBP). K-mers from PilS, tbpB and tspB were found to be associated with carriage, while k-mers from mtrD and tbpA were associated with invasiveness. In the genes fkbp, glmU, PilC and pilE, k-mers were found that were associated with both carriage and invasive isolates, indicating that specific variations within these genes could play a role in invasiveness. The data presented here highlight genetic traits that are significantly associated with invasive or carriage N. meningitidis across the species population. These traits could prove essential to our understanding of the pathogenicity of N. meningitidis and could help to identify future vaccine targets.

Ort, förlag, år, upplaga, sidor
Microbiology Society, 2023
Nyckelord
Carriage, Genome-wide association study, Invasive meningococcal disease, Neisseria meningitidis
Nationell ämneskategori
Medicinsk genetik och genomik
Identifikatorer
urn:nbn:se:oru:diva-109425 (URN)10.1099/mgen.0.001124 (DOI)001107086200005 ()37874326 (PubMedID)2-s2.0-85175126623 (Scopus ID)
Forskningsfinansiär
Region Örebro län, OLL-967424
Tillgänglig från: 2023-10-25 Skapad: 2023-10-25 Senast uppdaterad: 2025-02-10Bibliografiskt granskad
4. pilE expression and copy number dynamics in carriage and invasive Neisseria meningitidis
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(Engelska)Manuskript (preprint) (Övrigt vetenskapligt)
Nationell ämneskategori
Annan hälsovetenskap
Identifikatorer
urn:nbn:se:oru:diva-113539 (URN)
Tillgänglig från: 2024-05-06 Skapad: 2024-05-06 Senast uppdaterad: 2024-05-27Bibliografiskt granskad

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