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The streptococcal protease IdeS modulates bacterial IgGFc binding and generates 1/2Fc fragments with the ability to prime polymorphonuclear leucocytes
Umeå universitet, Medicinska fakulteten, Institutionen för molekylärbiologi (Medicinska fakulteten). (Pawel)
Umeå universitet, Medicinska fakulteten, Institutionen för molekylärbiologi (Medicinska fakulteten). (Pawel)
2008 (Engelska)Ingår i: Molecular Immunology, ISSN 0161-5890, E-ISSN 1872-9142, Vol. 45, nr 12, s. 3347-3353Artikel i tidskrift (Refereegranskat) Published
Abstract [en]

The important human bacterial pathogen Streptococcus pyogenes has evolved a variety of mechanisms to evade the actions of the human immune system. M protein and M-like proteins are major virulence factors that bind with high affinity to the Fc-part of IgG. However, the contribution of non-immune binding of IgG to bacterial virulence is not fully established. Importantly, the capacity of S. pyogenes to bind IgG is limited and due to the presence of large amounts of IgG present in vivo, the majority of IgGFc binding sites at the streptococcal surface are likely to be occupied by non-specific IgG. S. pyogenes also secretes a highly effective IgG-endopeptidase, IdeS that inhibits phagocytic killing by cleavage of specific IgG creating F(ab')2 and 1/2Fc fragments. In the present work, IgG and 1/2Fc binding to the streptococcal surface was studied and correlated to IdeS activity. Binding of IgG to the streptococcal surface is shown to be equilibrium and thus not designed to mediate a lasting protection against specific antibodies. However, non-immune binding of IgG to the bacterial surface is followed by the proteolytic cleavage of the antibody by the IgG-endopeptidase IdeS. IdeS generated 1/2Fc fragments do not compete efficiently with intact IgG in binding to the bacterial surface and rapid dissociation of 1/2Fc allows binding of new IgG. Thus, a correlated binding and proteolytic cleavage of IgG also increases the probability that the bacteria can resist specific IgG, despite the presence of a large excess of non-specific IgG in the circulation. As a consequence of IdeS activity, circulating 1/2Fc fragments are generated. These 1/2Fc fragments were shown to be biological active by acting as priming agents for polymorphonuclear leucocytes, suggesting a new mechanism of immune evasion employed by S. pyogenes.

Ort, förlag, år, upplaga, sidor
2008. Vol. 45, nr 12, s. 3347-3353
Nyckelord [en]
IgG; Fc-binding; S. pyogenes; IgG-endopeptidase; Priming
Nationell ämneskategori
Cell- och molekylärbiologi
Identifikatorer
URN: urn:nbn:se:umu:diva-20794DOI: 10.1016/j.molimm.2008.04.013PubMedID: 18533265OAI: oai:DiVA.org:umu-20794DiVA, id: diva2:209563
Tillgänglig från: 2009-03-25 Skapad: 2009-03-25 Senast uppdaterad: 2018-06-09Bibliografiskt granskad
Ingår i avhandling
1. The streptococcal IgG degrading enzyme IdeS: studies on host-pathogen interactions
Öppna denna publikation i ny flik eller fönster >>The streptococcal IgG degrading enzyme IdeS: studies on host-pathogen interactions
2012 (Engelska)Doktorsavhandling, sammanläggning (Övrigt vetenskapligt)
Abstract [en]

The important human pathogen Streptococcus pyogenes causes both mild infections such as pharyngitis and impetigo but also severe life threatening invasive infections.  Specific antibodies (IgG) recognize pathogens and are important mediators for pathogen clearance by the immune defence. S.ipyogenes expresses a highly effective and specific IgG endopeptidase called IdeS (immunoglobulin degrading enzyme of S.ipyogenes). IdeS rescues bacteria from opsonising IgG by cleavage of IgG generating two fragments F(ab´)2 and ½Fc. Moreover, IdeS block ROS production by neutrophils. In this thesis I have studied (i) allelic variants of IdeS and their biological potential, (ii) consequences of ½Fc production for host-pathogen interactions and (iii) IdeS processing by streptococcal and neutrophil proteases.

When investigating the allelic variants of IdeS we could show that in respect to IgG degradation and inhibition of ROS production the allelic variants where indistinguishable, however the allelic variant of serotype M28 appears to be an unique exception as this protein was deficient in IgG cleavage but still inhibited ROS production. Further, the ½Fc fragments produced when IgG is cleaved by IdeS were shown to prime human neutrophils and under ex vivo experimental conditions this increased the bactericidal activity of the neutrophils. Finally, we made the interesting finding that IdeS is N-terminally processed by neutrophil proteases and by the streptococcal protease SpeB, but retain enzymatic activity and was less immunogenic compared to the full length protein.

Ort, förlag, år, upplaga, sidor
Umeå: Umeå universitet, 2012. s. 43
Serie
Umeå University medical dissertations, ISSN 0346-6612 ; 1491
Nyckelord
streptococcus pyogenes, IdeS
Nationell ämneskategori
Mikrobiologi
Forskningsämne
molekylärbiologi
Identifikatorer
urn:nbn:se:umu:diva-53706 (URN)978-91-7459-404-1 (ISBN)
Disputation
2012-05-03, Bergasalen, NUS By 27, Umeå, 10:00 (Engelska)
Opponent
Handledare
Tillgänglig från: 2012-04-12 Skapad: 2012-04-04 Senast uppdaterad: 2018-06-08Bibliografiskt granskad

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