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Role of the hypervariable region in streptococcal M proteins: binding of a human complement inhibitor
E Johnsson1, K Berggård, H Kotarsky
1Department of Medical Microbiology, Lund University, Sweden.
Abstract:
Antigenic variation allows pathogenic microorganisms to evade the immune system of the infected host. The variable structure must play an important role in pathogenesis, but its function is in most cases unknown. Here, we identify a function for the surface-exposed hypervariable region of streptococcal M5 protein, a virulence factor that inhibits phagocytosis. The hypervariable region of M5 was found to bind the human complement inhibitor FHL-1 (factor H-like protein 1), a 42-kDa plasma protein. Plasma absorption experiments with M5-expressing bacteria showed that the interaction with FHL-1 occurs also under physiologic conditions. Studies of another extensively characterized M protein, M6, indicated that this protein also has a binding site for FHL-1 in the hypervariable region. The complement-inhibitory function of FHL-1 was retained after binding to streptococci, suggesting that bound FHL-1 protects bacteria against complement attack. All available data now indicate that FHL-1, or another human complement inhibitor, binds to the hypervariable region of M proteins. These findings provide insights into the forces that drive antigenic variation and may explain why the hypervariable region of M protein is essential for phagocytosis resistance. Moreover, these data add to a growing body of evidence that human complement inhibitors are major targets for pathogenic microorganisms.
Insights
Pathogenic bacteria like Streptococcus evade immune responses by altering their surface proteins. Researchers found that the M protein
Area of Science:
- Microbiology
- Immunology
- Biochemistry
Background:
- Pathogenic microorganisms utilize antigenic variation to evade host immune systems.
- The specific functions of variable structures in pathogenesis are often unknown.
- Streptococcal M proteins are key virulence factors involved in inhibiting phagocytosis.
Purpose of the Study:
- To identify the function of the hypervariable region of streptococcal M5 protein.
- To investigate the interaction between M5 protein and human complement inhibitors.
- To understand the role of M protein-complement interactions in bacterial pathogenesis.
Main Methods:
- Binding assays to detect interactions between M5 protein and FHL-1.
- Plasma absorption experiments using M5-expressing bacteria.
- Analysis of M6 protein for similar binding capabilities.
Main Results:
- The hypervariable region of M5 protein binds to the human complement inhibitor FHL-1 (factor H-like protein 1).
- This interaction was confirmed to occur under physiological conditions.
- M6 protein also demonstrated a binding site for FHL-1 in its hypervariable region.
- Bound FHL-1 retained its complement-inhibitory function, protecting bacteria from complement attack.
Conclusions:
- The hypervariable region of M proteins binds human complement inhibitors like FHL-1.
- This interaction is crucial for protecting bacteria against complement-mediated attack.
- These findings provide insights into antigenic variation and the essential role of M protein's hypervariable region in evading phagocytosis.
- Human complement inhibitors are significant targets for pathogenic microorganisms.