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Biomimetic Materials to Characterize Bacteria-host Interactions
Published on: November 16, 2015
Group A streptococci induce stronger M protein-fibronectin interaction when specific human antibodies are bound
Sebastian Wrighton1, Vibha Kumra Ahnlide1, Oscar André1
1Division of Infection Medicine, Department of Clinical Sciences, Faculty of Medicine, Lund University, Lund, Sweden.
Abstract:
Group A streptococcus (GAS) is a highly adapted, human-specific pathogen that is known to manipulate the immune system through various mechanisms. GAS' M protein constitutes a primary target of the immune system due to its spatial configuration and dominance on the bacterial surface. Antibody responses targeting the M protein have been shown to favor the conserved C region. Such antibodies (Abs) circumvent antigenic escape and efficiently bind to various M types. The ability of GAS to bind to fibronectin (Fn), a high molecular weight glycoprotein of the extracellular matrix, has long been known to be essential for the pathogen's evolutionary success and fitness. However, some strains lack the ability to efficiently bind Fn. Instead, they have been found to additionally bind Fn via the A-B domains of their M proteins. Here, we show that human Abs can induce increased Fn-binding affinity in M proteins, likely by enhancing the weak A-B domain binding. We found that this enhanced Fn binding leads to a reduction in Ab-mediated phagocytosis, indicating that this constitutes a GAS immune escape mechanism. We could show that the Fc domain of Abs is necessary to trigger this phenomenon and that Ab flexibility may also play a key role. We, moreover, saw that our Abs could enhance Fn binding in 3 out of 5 emm type strains tested, belonging to different clades, making it likely that this is a more generalizable phenomenon. Together our results suggest a novel synergistic interplay of GAS and host proteins which ultimately benefits the bacterium.
Insights
Group A Streptococcus (GAS) manipulates host antibodies to increase fibronectin binding, hindering immune cell clearance. This novel immune evasion strategy benefits the pathogen by reducing antibody-mediated phagocytosis.
Area of Science:
- Microbiology
- Immunology
- Molecular Biology
Background:
- Group A Streptococcus (GAS) is a human-specific pathogen that employs various immune evasion mechanisms.
- The GAS M protein is a key surface antigen targeted by antibodies, with responses often directed towards the conserved C region.
- GAS utilizes fibronectin (Fn) binding for survival and fitness, though binding mechanisms vary among strains.
Purpose of the Study:
- To investigate the interaction between human antibodies and GAS M proteins regarding fibronectin binding.
- To elucidate the role of antibody-induced fibronectin binding in GAS immune evasion.
- To determine the specific antibody domains and properties involved in this phenomenon.
Main Methods:
- Characterization of antibody interactions with GAS M proteins from different emm types.
- Assessment of fibronectin binding affinity in the presence of human antibodies.
- Measurement of antibody-mediated phagocytosis of GAS strains.
- Investigation of the role of antibody Fc domain and flexibility.
Main Results:
- Human antibodies can enhance the fibronectin-binding affinity of GAS M proteins, particularly through A-B domain interactions.
- Enhanced fibronectin binding significantly reduces antibody-mediated phagocytosis, indicating an immune escape mechanism.
- The Fc domain of antibodies is crucial for triggering this enhanced fibronectin binding, with antibody flexibility potentially playing a role.
- This phenomenon was observed in multiple GAS emm type strains from different clades, suggesting broad applicability.
Conclusions:
- A novel mechanism of GAS immune evasion involves host antibodies inadvertently enhancing bacterial fibronectin binding.
- This antibody-driven enhancement of fibronectin binding impedes phagocytosis, providing a survival advantage to GAS.
- The findings reveal a complex interplay between GAS, host proteins, and antibodies, highlighting a previously unrecognized synergistic relationship that benefits the pathogen.
