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- Jacobsson, Susanne, 1974-
(author)
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Characterisation of Neisseria meningitidis from a virulence and immunogenic perspective that includes variations in novel vaccine antigens
- 2009
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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).
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| 2. |
- Thulin Hedberg, Sara
(author)
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Antibiotic susceptibility and resistance in Neisseria meningitidis : phenotypic and genotypic characteristics
- 2009
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Doctoral thesis (other academic/artistic)abstract
- 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.
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| 3. |
- Törös, Bianca, 1987-
(author)
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Genome-based characterization of Neisseria meningitidis with focus on the emergent serogroup Y disease
- 2014
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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.
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