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Streptococcus pyogenes secreted enzymes interacting with the human host

by Collin, Mattias, PhD

Abstract (Summary)
Streptococcus pyogenes is one of the most common bacteria infecting humans. One of the factors contributing to the disease-causing properties is the secreted streptococcal cysteine proteinase, SpeB, which degrades several host proteins in connective tissue and circulation. SpeB activity depends on the transformation from an inactive precursor, zymogen, into a mature proteinase. We show that the important cell wall-anchored M protein is involved in the unfolding and maturation of SpeB. An engineered strain lacking M protein secreted the SpeB zymogen in a conformational state that did not allow the maturation to proceed normally. Furthermore, we identified genes that were regulated by environmental changes using RNA fingerprinting. One of the identified glucose-induced genes encodes a phosphotransferase system that could be involved in the signaling leading to down-regulation of virulence genes in response to the nutritional status. Moreover, a novel secreted endoglycosidase, EndoS, has been identified. Purified EndoS removes the glycan from native human immunoglobulin G (IgG).This glycan is known to be important for IgG effector functions such as complement activation and binding to Fc receptors on phagocytic cells. Furthermore, it was discovered that SpeB cleaves the heavy chain of IgG resulting in distinct fragments separating the antigen-binding Fab portions from the effector-triggering Fc portion. SpeB also degrades the heavy chains of IgA, IgM, IgD and IgE. Finally, it was shown that both these enzymatic activities on human IgG have functional consequences with significantly impaired antibody-mediated killing of S. pyogenes in an ex vivo model.
Bibliographical Information:

Advisor:

School:Lunds universitet

School Location:Sweden

Source Type:Doctoral Dissertation

Keywords:MEDICINE; Streptococcus pyogenes; RNA fingerprinting; Clinical biology; immunoglobulins; Klinisk biologi; autoimmunity; endoglycosidase; cysteine proteinase; glycosylation

ISBN:91-628-4966-2

Date of Publication:01/01/2001

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