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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. |
- Thunberg, Ulrica, 1967-
(author)
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Aspects of Staphylococcus aureus in Chronic Rhinosinusitis
- 2020
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Doctoral thesis (other academic/artistic)abstract
- Chronic rhinosinusitis (CRS) affects about 10% of the European population, and is considered a great scourge. Its cause is not clear. Findings of Staphylococcus aureus in the maxillary sinus are common in CRS patients, but are usually regarded as insignificant due to the bacterium’s attribute as a commensal elsewhere. S. aureus has the ability to cause both mild disease and serious conditions, due to its wide armoury of secreted components such as staphylococcal enterotoxins and cell-surface-associated virulence components. This thesis focuses on the clinical features and importance of S. aureus in CRS, including a long-term perspective on the disease, through studying a cohort of CRS patients. S. aureus was found to be highly prevalent in the maxillary sinus and nares of CRS patients, which might indicate an impact on the disease. A sheltered sampling technique for maxillary sinus culture reduced the contamination rate but did not significantly improve the diagnostic reliability. Whole genome sequencing showed that 95% of paired S. aureus isolates collected simultaneously from the nares and maxillary sinus were from identical lineages, indicating colonization of the maxillary sinus from the nares as one joint milieu. A decade-long persistence of S. aureus in the nares and maxillary sinus was established in 20% of CRS patients. The vast majority of S. aureus isolates were susceptible to all tested antibiotics, including the strains that had persisted for a decade. No significant differences in the prevalence of gene determinants were seen for selected virulence factors and MSCRAMMs in S. aureus isolates sampled from CRS patients and healthy controls. The overall alterations of anti-staphylococcal antibodies over time showed great variability and minor support for an impact of S. aureus on CRS. At the long-term follow-up, symptoms were generally reduced and VAS quality of life in terms of fatigue was improved. The subgroup of CRS patients without nasal polyposis had a greater chance of symptom relief than their counterparts with nasal polyposis in this longterm perspective. There was no correlation between severity of symptoms for CRS patients and S. aureus growth in the maxillary sinus to support a role for S. aureus in CRS.
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