| 1. |
- Eriksson, Lorraine, 1990-
(author)
-
Exploring genomic and phenotypic differences in Neisseria meningitidis : understanding carriage and invasive disease
- 2024
-
Doctoral thesis (other academic/artistic)abstract
- 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.
|
|
| 2. |
- Fagerström, Anna, 1980-
(author)
-
Long-term molecular epidemiology of extended-spectrum β-lactamase producing Escherichia coli in a low-endemic setting
- 2020
-
Doctoral thesis (other academic/artistic)abstract
- Escherichia coli is a commensal inhabitant in the gastro-intestinal tract of humans and animals but it is also the most common bacterial species causing urinary tract infection, which ranges in severity from distal cystitis to urosepsis and septic shock. During the past decades, the prevalence of antibiotic resistant E. coli has increased worldwide. Extended-spectrum β-lactamases (ESBL) causes resistance to β-lactam antibiotics, the most widely used class of antibiotics. The genes encoding ESBL, bla, are usually carried on conjugative plasmids, which can be transferred between different bacterial lineages and different species. These plasmids frequently also carry resistance genes to additional antibiotic classes, and ESBL-producing E. coli are therefore often multidrug-resistant. The aim of this thesis was to describe the long-term molecular epidemiology of ESBL-producing E. coli in Örebro County during the time when they first started to emerge. In addition, potential transmission to the environment was investigated by performing a comparative analysis on ESBL-producing E. coli isolated from patients and from the aquatic environment in Örebro city. In general, the E. coli population was genetically diverse, but the pandemic lineage ST131, first identified in 2004, appears to have been responsible for the dramatic increase of CTX-M-15-producing E.coli observed during the late 2000s. CTX-M-15 was the most prevalent ESBL-type followed by CTX-M-14 and these genes were mainly found on plasmids belonging to the IncF or IncI1 families. Continuous horizontal transmission of IncI1 ST31 and ST37 plasmids between diverse E. coli lineages have also contributed to the dissemination of blaCTX-M-15 in Örebro County. Extended spectrum β-lactamase-producing E. coli were found to be common in the aquatic environment in Örebro city and E. coli lineages genetically similar to those causing infections in humans were present in environmental waters indicating that transmission of ESBL-producing E. colifrom humans to the aquatic environment likely has occurred.
|
|
| 3. |
- Ziegler, Ingrid, 1976-
(author)
-
Quantitative detection of bacterial DNA in whole blood in bloodstream infection
- 2018
-
Doctoral thesis (other academic/artistic)abstract
- This thesis aims to increase the knowledge on how quantitative PCR can be used in the diagnostics of bloodstream infections, with an emphasis on quantitative elements.In Papers I and II, we evaluated quantitative data from two commercial PCR tests for pathogen detection directly in blood, Magicplex Sepsis (I) and SeptiFast (II), from patients with suspected sepsis. We found that high quantification cycle (Cq) values, indicating low DNA loads, were associated with findings of pathogens with doubtful clinical relevance, whereas low Cq values, indicating high DNA loads, were correlated with sepsis and septic shock, as well as with positive blood culture results.In Paper III, we aimed to study the bacterial DNA load during Staphylococcus aureus bacteremia, in relation to different clinical factors. For this purpose, we developed a droplet digital PCR (ddPCR) for precise DNA quantification, targeting S. aureus specifically. We found that a high initial S. aureus DNA load was associated with laboratory markers for immune dysregulation as well as with sepsis, endocarditis, and mortality.In Paper IV, we aimed to develop a tool for repeated DNA quantification during bloodstream infection. For this purpose, we optimized a ddPCR, targeting the universal bacterial 16S rDNA, and performed a comparison with species-specific ddPCRs on spiked blood, and on clinical samples. The performance of the16S rDNA ddPCR was adequate, and we found that a high 16S rDNA load was associated with sepsis and mortality.In conclusion, our results indicate that the pathogen DNA load in blood plays an important role in the clinical picture in BSI. In future research on molecular BSI diagnostics, studies on DNA loads and clearance should be included.
|
|
| 4. |
- Jacobsson, Susanne, 1974-
(author)
-
Characterisation of Neisseria meningitidis from a virulence and immunogenic perspective that includes variations in novel vaccine antigens
- 2009
-
Doctoral thesis (other academic/artistic)abstract
- Neisseria meningitidis, also referred to as meningococcus, is a Gram-negative diplococcal bacterium best known as an important cause of meningitis and septicaemia worldwide. Meningococcal disease is a rare but life-threatening illness that may progress to death despite optimal medical care including appropriate antibiotic therapy. Case fatality remains high and survivors may suffer from significant sequelae because of impaired circulation and/or damages to the central nervous system. Prevention through vaccination remains a most effective approach to control disease. The main problem, however, is the absence of an effective vaccine against disease caused by a broad spectrum of group B isolates. Understanding how the meningococcus can be both a common commensal and a devastating human pathogen is a major task for researchers in the area of meningococcal disease. In paper I, we investigated and described the characteristics of fatal meningococcal isolates and compared these with non-fatal invasive meningococcal isolates. The diversity was high within the isolates from both patient groups. Group Y, serotypes 14 and 15 and genosubtypes P1.7,16-29,35 and P1.5-1,10-4,36-2 were more common in fatal cases as were being elderly and female. The second major task in the area of meningococcal disease is to develop a group B vaccine. Six genes encoding antigens identified as promising vaccine candidates were examined in papers II & III. Based on our results, the prevalence of these genes and their sequence variation have the potential to constitute a meningococcal vaccine of broad range that also cover group B isolates in Sweden and other countries with a similar distribution of disease causing meningococci. In paper IV, we investigated the levels of IgG antibodies in serum directed against fHbp and NadA, two of the antigens included in papers II & III. Overall, the immune response to fHbp seems to be higher than the immune response to NadA, with a clear rise of anti-fHbp in the young adult groups (20-29 years).
|
|
| 5. |
- Säll, Olof, 1980-
(author)
-
Infections in the central nervous system with focus on meningococcal disease : clinical and epidemiological aspects
- 2022
-
Doctoral thesis (other academic/artistic)abstract
- Infections in the central nervous system (CNS) include meningitis and encephalitis and are associated with high mortality and morbidity. A large number of different pathogens can cause these infections, including Neisseria meningitidis. It’s crucial to find the causative pathogen in order to provide the best treatment to the patient and for disease surveillance. In Paper I, molecular methods were used to investigate the microbial etiology in patients presenting with CNS infections at United Mission Hospital in Tansen, Nepal. Although the cerebrospinal fluid samples were analyzed for a large number of microbes using two commercial multiplex PCR panels and additional in-house real-time PCR, the etiology of the infections was still unknown in a large number of patients. This calls for further development of diagnostic methods for CNS infections.Neisseria meningitidis, the meningococcus, is a strictly human commensal but also capable to cause severe disease, typically in the form of sepsis and meningitis. The aim of Paper II and III was to study the clinical presentation of N. meningitidis serogroup Y and W infections, which increased unexpectedlyin Sweden from 2007 and 2014, respectively. By reviewing medical records of these infection episodes, the conclusion was drawn that atypical presentations with respiratory and gastrointestinal symptoms were common, rather than meningitis and petechiae.In Paper IV, meningococcal carriage was studied among students at Örebro University. Age ≤22 years, smoking, previous tonsillectomy, frequent partying and male gender were associated with higher carrier rates. The so far longest observation of carriage of the same meningococcal strain was presented, with a duration of at least one year.In conclusion, the results from these studies highlight the importance of early detection of meningococcal infections with atypical presentations and the need of improved diagnostics for CNS infections
|
|
| 6. |
- Törös, Bianca, 1987-
(author)
-
Genome-based characterization of Neisseria meningitidis with focus on the emergent serogroup Y disease
- 2014
-
Doctoral thesis (other academic/artistic)abstract
- 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.
|
|
