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Staphylococcus aureus bacteremia, molecular epidemiology and host immune response
Örebro University, School of Medical Sciences.
2017 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Staphylococcus aureus is a major pathogen responsible for a considerable disease burden worldwide. It may cause a wide array of infections, from superficial skin infections to invasive bacteremia and complications such as infective endocarditis (IE) and osteomyelitis. This thesis aimed to investigate aspects of the molecular epidemiology of S. aureus and host immune response in relation to disease manifestation, severity, and over time during S. aureus bacteremia (SAB).

Genotypic characteristics in isolates causing colonization, bacteremia, and bacteremia with IE were studied. The S. aureus population was genetically diverse and certain clones with their set of often lineage-specific virulence genes were associated with invasive disease. Characterization of the long-term molecular epidemiology of MSSA bacteremia showed an increased prevalence of CC5 and CC15, while CC8, CC25 and CC30 declined. Antibiotic resistance pattern was favorable and unaffected.

Further, different aspects of host immune response were explored in patients with SAB during the acute phase of bacteremia. When investigating the NLRP3 inflammasome signaling, induced caspase-1 activity was found, with a great inter-individual variation between patients, and subsequent release of IL-18, indicating inflammasome activity. Finally, the dynamics of MHC class II related genes HLA-DRA and CD74 were analyzed as markers of immunosuppression. Patients with complicated SAB had significantly lower HLA-DRA expression than patients with uncomplicated bacteremia, demonstrating an association between complicated SAB and impaired immune function.

In conclusion, the S. aureus genotype, as well as host factors reflected by inter-individual variations in inflammasome signaling and immune function, may all contribute to disease manifestation and outcome during SAB. An ability to measure the immune response early and continuously during the hospital stay and course of bacteremia could offer a way to tailor patient management and treatment in an individualized way.

Place, publisher, year, edition, pages
Örebro: Örebro University , 2017. , 75 p.
Series
Örebro Studies in Medicine, ISSN 1652-4063 ; 158
Keyword [en]
Staphylococcus aureus, molecular epidemiology, DNAmicroarray, bacteremia, sepsis, NLRP3, inflammasome, caspase-1, HLA-DR, HLA-DRA, CD74
National Category
Family Medicine
Identifiers
URN: urn:nbn:se:oru:diva-54675ISBN: 978-91-7529-181-9 (print)OAI: oai:DiVA.org:oru-54675DiVA: diva2:1064802
Public defence
2017-03-31, Campus USÖ, hörsal C3, Södra Grev Rosengatan 32, Örebro, 09:00 (Swedish)
Opponent
Supervisors
Available from: 2017-01-13 Created: 2017-01-13 Last updated: 2017-03-08Bibliographically approved
List of papers
1. Prevalence of Clonal Complexes and Virulence Genes among Commensal and Invasive Staphylococcus aureus Isolates in Sweden
Open this publication in new window or tab >>Prevalence of Clonal Complexes and Virulence Genes among Commensal and Invasive Staphylococcus aureus Isolates in Sweden
2013 (English)In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 8, no 10, e77477Article in journal (Refereed) Published
Abstract [en]

Staphylococcus aureus encodes a remarkable number of virulence factors which may contribute to its pathogenicity and ability to cause invasive disease. The main objective of this study was to evaluate the association between S. aureus invasiveness and bacterial genotype, in terms of the presence of virulence genes and affiliation to clonal complexes. Also, the significance of different virulence genes, mainly adhesins, for the development of infective endocarditis was investigated.

DNA microarray technology was used to analyze 134 S. aureus isolates, all methicillin-susceptible, derived from three groups of clinically well-characterized patients: nasal carriers (n=46), bacteremia (n=55), and bacteremia with infective endocarditis (n=33).

Invasive isolates were dominant in four of the major clonal complexes: 5, 8, 15, and 25. Of the 170 virulence genes examined, those encoding accessory gene regulator group II (agr II), capsule polysaccharide serotype 5 (cap5), and adhesins such as S. aureus surface protein G (sasG) and fibronectin-binding protein B (fnbB) were found to be associated with invasive disease. The same was shown for the leukocidin genes lukD/lukE, as well as the genes encoding serine protease A and B (splA/splB), staphylococcal complement inhibitor (scn) and the staphylococcal exotoxin-like protein (setC or selX). In addition, there was a trend of higher prevalence of certain genes or gene clusters (sasG, agr II, cap5) among isolates causing infective endocarditis compared to other invasive isolates. In most cases, the presence of virulence genes was linked to clonal complex affiliation.

In conclusion, certain S. aureus clonal lineages harboring specific sets of virulence genes seem to be more successful in causing invasive disease.

Place, publisher, year, edition, pages
San Francisco, USA: Public Library of Science, 2013
National Category
Infectious Medicine
Research subject
Medicine
Identifiers
urn:nbn:se:oru:diva-32536 (URN)10.1371/journal.pone.0077477 (DOI)000325810900138 ()24130888 (PubMedID)2-s2.0-84885169766 (Scopus ID)
Note

Funding Agency: Research Comitte of the County Council of Orebro University Hospital

Available from: 2013-11-26 Created: 2013-11-26 Last updated: 2017-03-22Bibliographically approved
2. Long term molecular epidemiology of methicillin-susceptible staphylococcus aureus bacteremia isolates in Sweden
Open this publication in new window or tab >>Long term molecular epidemiology of methicillin-susceptible staphylococcus aureus bacteremia isolates in Sweden
Show others...
2014 (English)In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 9, no 12, e114276Article in journal (Refereed) Published
Abstract [en]

Staphylococcus aureus is one of the major pathogens that causes bacteremia; therefore, it is important to understand the long-term molecular epidemiology of S. aureus bacteremia infections. In particular, little is known about the population structure of methicillin-sensitive S. aureus (MSSA) compared to that of methicillin-resistant S. aureus. We investigated potential changes in the MSSA molecular epidemiology in Örebro County, Sweden, from 1980 through 2010. 400 MSSA bacteremia isolates, the first 100 isolated each decade from 1980 through 2010, were retrospectively identified and analyzed regarding assignment to clonal complexes (CCs), presence of virulence genes and antibiotic resistant determinants with DNA microarray-based genotyping. 24 different CCs were identified. Most isolates (80%) belonged to 6 predominant lineages. Of those, the number of isolates assigned to CC5 and CC15 increased, and those assigned to CC8, CC25, and CC30 decreased. The most prevalent clone, CC45, did not show a significant change in prevalence during the study period. A change in prevalence was observed for some of the virulence genes, mainly attributed with their association to certain CCs. With the exception of the common blaZ gene (encoding penicillinase), antibiotic resistance genes were only sporadically detected. In conclusion, the MSSA population structure was genetically diverse. We observed decadal changes in assignments to five predominant clones, and corresponding changes in the prevalence of some virulence genes linked to CC affiliation. In light of the restrictive antibiotics prescriptions and extensive infection control procedures in Sweden, antibiotic resistance genes were rarely detected and their prevalence unaffected during the study period.

Place, publisher, year, edition, pages
San Francisco, USA: Public Library Science, 2014
National Category
Infectious Medicine Orthopedics Clinical Laboratory Medicine
Research subject
Medicine
Identifiers
urn:nbn:se:oru:diva-39966 (URN)10.1371/journal.pone.0114276 (DOI)000346907200063 ()25479442 (PubMedID)2-s2.0-84917739022 (Scopus ID)
Note

Funding Agency:

Research Committee of the County Council of Örebro University Hospital

Available from: 2014-12-22 Created: 2014-12-22 Last updated: 2017-03-22Bibliographically approved
3. Caspase-1 Inflammasome Activity in Patients with Staphylococcus aureus Bacteraemia
Open this publication in new window or tab >>Caspase-1 Inflammasome Activity in Patients with Staphylococcus aureus Bacteraemia
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(English)Manuscript (preprint) (Other academic)
National Category
Family Medicine
Identifiers
urn:nbn:se:oru:diva-56197 (URN)
Available from: 2017-03-08 Created: 2017-03-08 Last updated: 2017-03-08Bibliographically approved
4. Expression of HLA-DRA and CD74 mRNA in whole blood during the course of complicated and uncomplicated Staphylococcus aureus bacteraemia
Open this publication in new window or tab >>Expression of HLA-DRA and CD74 mRNA in whole blood during the course of complicated and uncomplicated Staphylococcus aureus bacteraemia
Show others...
(English)Manuscript (preprint) (Other academic)
National Category
Family Medicine
Identifiers
urn:nbn:se:oru:diva-56198 (URN)
Available from: 2017-03-08 Created: 2017-03-08 Last updated: 2017-04-25Bibliographically approved

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