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The Complement Binding and Inhibitory Protein CbiA of Borrelia miyamotoi Degrades Extracellular Matrix Components by
Ngoc T T Nguyen1, Florian Röttgerding1, Gayatri Devraj1
1Institute of Medical Microbiology and Infection Control, University Hospital of Frankfurt, Frankfurt, Germany.
Abstract:
The emerging relapsing fever spirochete Borrelia (B.) miyamotoi is transmitted by ixodid ticks and causes the so-called hard tick-borne relapsing fever or B. miyamotoi disease (BMD). More recently, we identified a surface-exposed molecule, CbiA exhibiting complement binding and inhibitory capacity and rendering spirochetes resistant to complement-mediated lysis. To gain deeper insight into the molecular principles of B. miyamotoi-host interaction, we examined CbiA as a plasmin(ogen) receptor that enables B. miyamotoi to interact with the serine protease plasmin(ogen). Recombinant CbiA was able to bind plasminogen in a dose-dependent fashion. Moreover, lysine residues appear to play a crucial role in the protein-protein interaction as binding of plasminogen was inhibited by the lysine analog tranexamic acid as well as increasing ionic strength. Of relevance, plasminogen bound to CbiA can be converted by urokinase-type plasminogen activator (uPa) to active plasmin which cleaved both, the chromogenic substrate S-2251 and its physiologic substrate fibrinogen. Concerning the involvement of specific amino acids in the interaction with plasminogen, lysine residues located at the C-terminus are frequently involved in the binding as reported for various other plasminogen-interacting proteins of Lyme disease spirochetes. Lysine residues located within the C-terminal domain were substituted with alanine to generate single, double, triple, and quadruple point mutants. However, binding of plasminogen to the mutated CbiA proteins was not affected, suggesting that lysine residues distant from the C-terminus might be involved in the interaction.
Insights
Borrelia miyamotoi uses the CbiA molecule to bind plasminogen, a key step in host interaction. This interaction, crucial for Borrelia miyamotoi disease (BMD) pathogenesis, may involve lysine residues distant from the C-terminus.
Area of Science:
- Microbiology and Immunology
- Molecular Biology
- Infectious Diseases
Background:
- Borrelia miyamotoi (B. miyamotoi) is a relapsing fever spirochete transmitted by ticks, causing hard tick-borne relapsing fever or B. miyamotoi disease (BMD).
- The surface protein CbiA was previously identified for its complement-binding and inhibitory properties, conferring resistance to complement-mediated lysis.
- Understanding B. miyamotoi-host interactions is crucial for deciphering disease mechanisms.
Purpose of the Study:
- To investigate the role of CbiA as a plasmin(ogen) receptor for B. miyamotoi.
- To elucidate the molecular mechanisms underlying CbiA's interaction with plasminogen.
- To identify specific amino acid residues involved in CbiA-plasminogen binding.
Main Methods:
- Recombinant CbiA protein was used to assess plasminogen binding capacity.
- The effect of tranexamic acid and ionic strength on plasminogen binding was evaluated.
- Plasminogen bound to CbiA was activated to plasmin, and its enzymatic activity was tested.
- Site-directed mutagenesis of C-terminal lysine residues in CbiA was performed to analyze their role in binding.
Main Results:
- Recombinant CbiA demonstrated dose-dependent binding to plasminogen.
- Plasminogen binding was inhibited by tranexamic acid and increased ionic strength, suggesting the involvement of lysine residues.
- Bound plasminogen could be converted to active plasmin by urokinase-type plasminogen activator (uPa), which cleaved fibrinogen.
- Mutagenesis of C-terminal lysine residues did not affect plasminogen binding, indicating potential involvement of other lysine residues.
Conclusions:
- CbiA functions as a plasmin(ogen) receptor for B. miyamotoi, facilitating interaction with the host serine protease plasmin(ogen).
- The interaction involves lysine residues, but likely not those located at the C-terminus, suggesting alternative binding sites.
- This interaction may contribute to B. miyamotoi pathogenesis by enabling conversion to active plasmin.
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