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CD46 contributes to the severity of group A streptococcal infection
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
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2008 (English)In: Infection and Immunity, ISSN 0019-9567, E-ISSN 1098-5522, Vol. 76, no 9, 3951-3958 p.Article in journal (Refereed) Published
Abstract [en]

Streptococcus pyogenes (group A Streptococcus) is a human pathogen that causes a wide variety of diseases ranging from uncomplicated superficial infections to severe infections such as streptococcal toxic shock syndrome and necrotizing fasciitis. These bacteria interact with several host cell receptors, one of which is the cell surface complement regulator CD46. In this study, we demonstrate that infection of epithelial cells with S. pyogenes leads to the shedding of CD46 at the same time as the bacteria induce apoptosis and cell death. Soluble CD46 attached to the streptococcal surface, suggesting that bacteria might bind available extracellular CD46 as a strategy to survive and avoid host defenses. The protective role of human CD46 was demonstrated in ex vivo whole-blood assays showing that the growth of S. pyogenes was enhanced in blood from mice expressing human CD46. Finally, in vivo experimental infection showed that bacteremia levels, arthritis frequency, and mortality were higher in CD46 transgenic mice than in nontransgenic mice. Taken together, these results argue that bacterial exploitation of human CD46 enhances bacterial survival and represents a novel pathogenic mechanism that contributes to the severity of group A streptococcal disease.

Place, publisher, year, edition, pages
2008. Vol. 76, no 9, 3951-3958 p.
National Category
Medical and Health Sciences
Identifiers
URN: urn:nbn:se:uu:diva-95666DOI: 10.1128/IAI.00109-08ISI: 000258667500013PubMedID: 18573902OAI: oai:DiVA.org:uu-95666DiVA: diva2:169972
Available from: 2007-04-03 Created: 2007-04-03 Last updated: 2017-12-14Bibliographically approved
In thesis
1. Receptor Interactions Between Pathogenic Bacteria and Host Cells
Open this publication in new window or tab >>Receptor Interactions Between Pathogenic Bacteria and Host Cells
2007 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

This thesis focuses on host and pathogen specific interactions during invasive disease. We have investigated the role and impact of different virulence factors of Neisseria gonorrhoeae, N. meningitidis and Streptococcus pyogenes on host epithelial cells and in vivo.

N. gonorrhoeae cause the sexually transmitted disease gonorrhoea and N. meningitidis is the most common cause of bacterial meningitis and may be leathal to the host within hours of infection. The neisserial type IV pili were shown to have an important impact on host cells for the induction of pro-inflammatory and other cellular defence transcriptional responses. Furthermore, N. meningitidis generally induced an earlier response compared to N. gonorrhoeae, probably as a result of the meningococcal capsule. The role of N. meningitidis serogroup B lipooliogsaccharide was investigated during invasive disease. Bacterial invasion of host cells and blood survival as well as virulence in vivo was dependent on the integrity of the LOS structure.

S. pyogenes may cause a variety of diseases ranging from uncomplicated diseases such as 'strep-throat' to more severe invasive diseases such as necrotizing fasciitis and streptococcal toxic shock syndrome. S. pyogenes ScpC protease degrade interleukin 8 during necrotizing fasciitis. We investigated the role of ScpC in systemic disease and observed enhanced virulence by bacteria unable to degrade IL-8. Following an intravenous infection of mice pro-inflammatory cytokines and complement activation was induced by the ScpC negative mutant compared to the wild-type and correlated with higher bacteremia. These data indicate that the precense of the ScpC protease has an important impact on the host for the outcome of streptococcal sepsis. Another phagocytic escape mechanism of S. pyogenes is their ability to coat themselves with host proteins. We observed that released complement control protein, CD46, bound to the streptococcal cell surface. CD46 has been shown to interact with the streptococcal M protein and have now been found to bind to the surface of the bacteria in a growth phase dependent manner. We observed a more aggressive disease development in CD46 transgenic mice after an intravenous infection with an M6 serotype, resulting in higher mortality of CD46 transgenic mice compared with control mice. These data indicate that CD46 may confer a protection to the streptococci during early stage of systemic infection and contributes to the understanding of immune evsion of S. pyogenes.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2007. 78 p.
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 247
Keyword
Microbiology, Type IV pili, Lipooligosaccharide, ScpC protease, CD46, Mikrobiologi
Identifiers
urn:nbn:se:uu:diva-7782 (URN)978-91-554-6847-7 (ISBN)
Public defence
2007-04-26, B7: 101a, Biomedicinskt Centrum, Husargatan 3, Uppsala, 10:00
Opponent
Supervisors
Available from: 2007-04-03 Created: 2007-04-03Bibliographically approved

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