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C10X polymorphism in the CARD8 gene is associated with bacteraemia
Örebro University, School of Health and Medical Sciences, Örebro University, Sweden.
Örebro University, School of Health and Medical Sciences, Örebro University, Sweden.
Örebro University, School of Health and Medical Sciences, Örebro University, Sweden.
Örebro University, School of Health and Medical Sciences, Örebro University, Sweden.
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(English)Manuscript (preprint) (Other academic)
Abstract [en]

Introduction:: The NLRP3 inflammasome is an intracellular multi-protein complex that triggers caspase-1 mediated maturation of interleukin-1β (IL-1β); one of the most potent mediators of inflammation and a major cytokine produced during severe infections, like sepsis. However, the excessive cytokine levels seem to stage for tissue injury and organ failure, and high levels of IL-1β correlates with severity and mortality of sepsis. Instead, recent data suggest caspase- 1 to function as a guardian against severe infections. CARD8 has been implied to regulate the synthesis of IL-1β via interaction to caspase-1. In recent years, polymorphism of CARD8 (C10X) per se or in combination with NLRP3 (Q705K) has been implicated with increased risk of inflammation. The aim was to investigate the correlation of these polymorphisms with severe blood stream infection.

Methods:: Human DNA was extracted from blood culture bottles that were found to be positive for microbial growth (i.e. patients with bacteraemia). Polymorphisms Q705K in the NLRP3 gene and C10X in the CARD8 gene were genotyped using TaqMan genotyping assay. The results were compared to healthy controls and to samples from patients with negative cultures.

Results:: The polymorphism C10X was significantly over-represented among patients with bacteraemia as compared to healthy controls, whereas patients with negative blood culture were not associated with a higher prevalence. No association was observed with polymorphism Q705K of NLRP3 in eithergroup of patients.

Conclusions:: Patients carrying polymorphism C10X in the CARD8 gene are at increased risk of developing bacteraemia and severe inflammation.

Keywords [en]
bacteraemia, blood culture, gene variants, infection, inflammasomes, inflammation, innate immunity, leukocytes, polymorphisms, sepsis
National Category
Medical and Health Sciences
Research subject
Biomedicine
Identifiers
URN: urn:nbn:se:oru:diva-32015OAI: oai:DiVA.org:oru-32015DiVA, id: diva2:656222
Available from: 2013-10-15 Created: 2013-10-15 Last updated: 2017-10-17Bibliographically approved
In thesis
1. Inflammasomes: defense guardians in host-microbe defence
Open this publication in new window or tab >>Inflammasomes: defense guardians in host-microbe defence
2013 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

The inflammasomes are emerging as key regulators of the innate immune response as they response to cellular infection, tissue damage and/or stress. Activated inflammasomes provide a signalling platform for caspase-1 activation which subsequently processes the maturation of interleukin (IL)-1β and IL-18, and in addition promotes cell death, named pyroptosis. These effector mechanisms of the inflammasome constitute an important part of the innate immune response in host-defence.

The aims of this thesis were to elucidate if the inflammasome is activated by specific pathogens, and if genetic variations lead to susceptibility to severe inflammatory diseases, such as blood stream infections. We found that the commensal pathogens Staphylococcus aureus and Propionibacterium acnes induce caspase-1 activation, the latter being a stronger activator. The data also propose that it is rather the bacterial ligands than the secreted toxins of P. acnes that induce inflammasome activation. Even though the S. aureus PVL-toxin induces a caspase-1 activation, involvement of other virulence factors are of importance. Upon S. aureus and P. acnes stimulation, inter-individual variations were found, implying that the characteristics of the host innate immune system, rather than the properties of the bacteria, are decisive for the inflammatory response. Indeed, healthy individuals with the combined polymorphisms of the NLRP3 inflammasome (C10X/Q705K) have higher levels of spontaneous IL-1β, and most intriguingly C10X polymorphism showed a strong correlation with patients with bacteremia.

In conclusion, these studies suggest that different pathogens activate the inflammasomes to various degrees. The genetics of the host innate immune system, rather than the properties of the bacteria, define the inflammatory response against these bacteria, and specific genetic variations such as C10X polymorphism can increase the susceptibility for disease development.

Place, publisher, year, edition, pages
Örebro: Örebro universitet, 2013. p. 76
Series
Örebro Studies in Medicine, ISSN 1652-4063 ; 88
Keywords
Innate immunity, inflammasome, leukocytes, cytokines, Staphylococcus aureus, Propionibacterium acnes, inflammation, infection, gene variants, polymorphism.
National Category
Medical and Health Sciences
Research subject
Biomedicine
Identifiers
urn:nbn:se:oru:diva-28523 (URN)978-91-7668-923-3 (ISBN)
Public defence
2013-06-05, Wilandersalen, M-huset, Universitetetssjukhuset Örebro, Grev Rosen gatan 18, Örebro, 09:00 (Swedish)
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Available from: 2013-04-02 Created: 2013-04-02 Last updated: 2017-10-17Bibliographically approved

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Idosa, Berhane AsfawSahdo, BerollaKelly, AnneSöderquist, BoSärndahl, Eva

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