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Superantigens in group A streptococcus: gene diversity and humoral immune response
Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Biomedical Laboratory Science.
2011 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Group A streptococcus (GAS) is a strictly human pathogen that causes infections ranging from asymptomatic carriage to the highly lethal streptococcal toxic shock syndrome (STSS). GAS are classified according to the sequence of the variable 5’ end of the emm-gene that encodes the surface associated M-protein. In the late 1980s, outbreaks of GAS infections with high rates of STSS were reported in several parts of the world, including Sweden. Superantigens (SAgs), a group of exotoxins, have been described as key mediators of STSS due to their capacity to polyclonally activate T-cells and induce a massive release of inflammatory cytokines. Previous reports have revealed that sera from STSS patients have lower capacity to neutralize this SAg-mediated immune stimulation and a higher prevalence of GAS isolates with specific emm-genotypes during disease outbreaks. The aims of this thesis were to analyse the protective antibody response mounted by the host against SAgs produced by the infecting GAS isolate and to characterise the isolates emm-genotypes and SAg gene profiles. The clinical material examined was collected from patients with STSS, sepsis, erysipelas, or tonsillitis in Sweden between 1986 and 2001. Both acute- and convalescence-phase sera were analyzed, along with the infecting GAS isolates. The 92 clinical GAS isolates examined were found to exhibit a high degree of genetic diversity in terms of the number and identity of their SAg genes. Isolates with a given emm-genotype could be divided into subgroups on the basis of their SAg gene profiles. Ten different SAg gene profiles were identified in the 45 emm1 isolates examined; one of these ten was highly persistent, being observed in 22 isolates collected over 14 years. Two of the 11 known SAg genes in GAS, smeZ-1 and speA, were more prevalent in the emm1 associated profiles than in the SAg gene profiles of isolates with other emm-genotypes. Patients infected by GAS with the emm1-genotype were less likely to produce acute-phase sera that could effectively neutralize the T-cell mitogenicity induced by the infecting isolate’s extracellular products (EP). Sepsis patients whose sera exhibited this lack of neutralizing ability were more prone to developing STSS. Most patients whose acute-phase sera did not effectively neutralize the EP from the infecting isolate lacked protective antibodies in their convalescent-phase sera despite having elevated ELISA titers. The results reported herein show that combining SAg gene profiling with emm-genotyping may be useful for tracking the spread of GAS clones in the community. It was also shown that a lack of neutralizing activity in convalescence-phase sera might be due to an inability of those patients to mount a protective immune response against SAgs produced by the infecting GAS isolate.

Place, publisher, year, edition, pages
Umeå: Umeå University , 2011. , 60 p.
Series
Umeå University medical dissertations, ISSN 0346-6612 ; 1432
Keyword [en]
Group A streptococcus, Streptococcus pyogenes, superantigen (SAg), SAg-gene profile, M-protein, emm-genotype
National Category
Microbiology in the medical area Biomedical Laboratory Science/Technology
Research subject
biomedicinsk laboratorievetenskap
Identifiers
URN: urn:nbn:se:umu:diva-46454ISBN: 978-91-7459-239-9 (print)OAI: oai:DiVA.org:umu-46454DiVA: diva2:441042
Public defence
2011-10-07, E04, byggnad 6A, Norrlands Universitets Sjukhus, Umeå, 09:00 (English)
Opponent
Supervisors
Available from: 2011-09-16 Created: 2011-09-02 Last updated: 2011-09-16Bibliographically approved
List of papers
1. Characterization of mitogenic and DNase activity of recombinantly produced mitogenic factor from group A streptococcus
Open this publication in new window or tab >>Characterization of mitogenic and DNase activity of recombinantly produced mitogenic factor from group A streptococcus
(English)Manuscript (preprint) (Other academic)
National Category
Microbiology in the medical area
Identifiers
urn:nbn:se:umu:diva-46952 (URN)
Available from: 2011-09-16 Created: 2011-09-16 Last updated: 2011-09-16Bibliographically approved
2. Superantigen gene profile diversity among clinical group A streptococcal isolates.
Open this publication in new window or tab >>Superantigen gene profile diversity among clinical group A streptococcal isolates.
2008 (English)In: FEMS Immunology and Medical Microbiology, ISSN 0928-8244, E-ISSN 1574-695X, Vol. 54, no 2, 236-44 p.Article in journal (Refereed) Published
Abstract [en]

This study examines the diversity of superantigen gene profiles between and within emm-genotypes of 92 clinical group A streptococcal isolates (30 STSS, 24 sepsis, 25 erysipelas, and 12 tonsillitis) collected in Sweden between 1986 and 2001. The emm-genotype and the distribution of smeZ, speG, speJ, speA, speC, speH, speI, speK/L, speL/M, speM, and ssa genes, and the smeZ allelic variant were determined using PCR and DNA sequencing. Forty-five emm1 isolates revealed 10 superantigen gene profiles. One profile dominated and was identified in 22 isolates collected over 14 years. The results indicate that a selective advantage maintained this genotype in circulation. The superantigen content among the emm1 isolates ranged from three to seven, with smeZ-1, speG, and speA present in all but one profile. The 47 isolates of 27 other emm-genotypes exhibited 29 superantigen gene profiles. Thus, the distribution of superantigen genes was highly variable within isolates regardless of emm-genotype. Two novel emm1 subtypes and 14 novel smeZ allelic variants were identified. The 22 smeZ alleles were generally linked to the emm-genotype. The results of the investigation show that superantigen gene profiling is useful for tracking spread of clones in the community.

Identifiers
urn:nbn:se:umu:diva-21725 (URN)10.1111/j.1574-695X.2008.00469.x (DOI)18754783 (PubMedID)
Available from: 2009-04-17 Created: 2009-04-17 Last updated: 2017-12-13
3. Dynamics of the immune response against extracellular products of group A streptococci during infection.
Open this publication in new window or tab >>Dynamics of the immune response against extracellular products of group A streptococci during infection.
Show others...
2007 (English)In: Clinical and Vaccine Immunology, ISSN 1556-6811, E-ISSN 1556-679X, Vol. 14, no 1, 44-51 p.Article in journal (Refereed) Published
Abstract [en]

The immune response against the infecting group A streptococcus (GAS) extracellular products (EP) was determined in acute- and convalescent-phase sera from 75 patients with different clinical manifestations of GAS infection. All EP elicited a high proliferative response in human peripheral blood mononuclear cells. In patients with bacteremia, low neutralization in acute-phase sera was associated with development of streptococcal toxic shock syndrome. Lack of neutralization in acute-phase sera was more common in patients infected with the T1emm1 serotype. The majority of patients did not develop the ability to neutralize the mitogenic activity of their infecting isolate despite a significant increase in enzyme-linked immunosorbent assay titer in early convalescent-phase sera. In patients with the ability to neutralize GAS EP, the immune response remained high over at least 3 years. In contrast, the neutralization capacity conferred by intravenous immunoglobulin and/or plasma treatment disappeared within 3 months.

Identifiers
urn:nbn:se:umu:diva-21777 (URN)10.1128/CVI.00271-06 (DOI)17093101 (PubMedID)
Available from: 2009-04-20 Created: 2009-04-20 Last updated: 2017-12-13

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