The M protein of Streptococcus pyogenes is a major bacterial virulence factor that confers resistance to phagocytosis. To analyze how M protein allows evasion of phagocytosis, we used the M22 protein, which has features typical of many M proteins and has two well-characterized regions binding human plasma proteins: the hypervariable NH2-terminal region binds C4b-binding protein (C4BP), which inhibits the classical pathway of complement activation; and an adjacent semivariable region binds IgA-Fc. Characterization of chromosomal S. pyogenes mutants demonstrated that each of the ligand-binding regions contributed to phagocytosis resistance, which could be fully explained as cooperation between the two regions. Deposition of complement on S. pyogenes occurred almost exclusively via the classical pathway, even under nonimmune conditions, but was down-regulated by bacteria-bound C4BP, providing an explanation for the ability of bound C4BP to inhibit phagocytosis. Different opsonizing antisera shared the ability to block binding of both C4BP and IgA, suggesting that the two regions in M22 play important roles also under immune conditions, as targets for protective antibodies. These data indicate that M22 and similar M proteins confer resistance to phagocytosis through ability to bind two components of the human immune system.
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6 October 2003
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September 29 2003
Evasion of Phagocytosis through Cooperation between Two Ligand-binding Regions in Streptococcus pyogenes M Protein
Fredric Carlsson,
Fredric Carlsson
Department of Medical Microbiology, Dermatology, and Infection, Lund University, SE-22362 Lund, Sweden
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Karin Berggård,
Karin Berggård
Department of Medical Microbiology, Dermatology, and Infection, Lund University, SE-22362 Lund, Sweden
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Margaretha Stålhammar-Carlemalm,
Margaretha Stålhammar-Carlemalm
Department of Medical Microbiology, Dermatology, and Infection, Lund University, SE-22362 Lund, Sweden
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Gunnar Lindahl
Gunnar Lindahl
Department of Medical Microbiology, Dermatology, and Infection, Lund University, SE-22362 Lund, Sweden
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Fredric Carlsson
Department of Medical Microbiology, Dermatology, and Infection, Lund University, SE-22362 Lund, Sweden
Karin Berggård
Department of Medical Microbiology, Dermatology, and Infection, Lund University, SE-22362 Lund, Sweden
Margaretha Stålhammar-Carlemalm
Department of Medical Microbiology, Dermatology, and Infection, Lund University, SE-22362 Lund, Sweden
Gunnar Lindahl
Department of Medical Microbiology, Dermatology, and Infection, Lund University, SE-22362 Lund, Sweden
Address correspondence to Gunnar Lindahl, Dept. of Medical Microbiology, Dermatology, and Infection, Lund University, Sölvegatan 23, SE-22362 Lund, Sweden. Phone: 46-46-173244; Fax: 46-46-189117; email: [email protected]
Abbreviations used in this paper: C4BP, C4b-binding protein; HVR, hypervariable region; TH, Todd-Hewitt.
Received:
April 03 2003
Revision Received:
August 08 2003
Accepted:
August 08 2003
Online ISSN: 1540-9538
Print ISSN: 0022-1007
The Rockefeller University Press
2003
J Exp Med (2003) 198 (7): 1057–1068.
Article history
Received:
April 03 2003
Revision Received:
August 08 2003
Accepted:
August 08 2003
Citation
Fredric Carlsson, Karin Berggård, Margaretha Stålhammar-Carlemalm, Gunnar Lindahl; Evasion of Phagocytosis through Cooperation between Two Ligand-binding Regions in Streptococcus pyogenes M Protein . J Exp Med 6 October 2003; 198 (7): 1057–1068. doi: https://doi.org/10.1084/jem.20030543
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