Binding and activation of the human plasma kinin-forming system on the cell walls of Candida albicans and Candida tropicalis

Bacterial infections often upregulate the plasma kinin-forming cascade of the host (the ‘contact system’) which is triggered by adsorption of high molecular mass kininogen (HK), coagulation factor XII (FXII) and prekallikrein (pHPK) on the host or pathogen cell surfaces. A possible activation of the contact system upon infection of the human host by major fungal pathogens of Candida species has not been extensively explored until a recent report of tight binding of HK to the cell walls of these fungi. In the current study, the adsorption of the other contact system components to the cell surfaces of Candida albicans and Candida tropicalis was characterized. FXII was found to be tightly bound by Candida germ tube forms, to a level 5-fold higher than that for HK. In contrast, pHPK bound poorly but its additional amounts could dock to the cell wall through the surface-bound HK. It was also shown that within the complex of these proteins assembled on the cell walls of fungal hyphae, pHPK could be activated by FXIIa and the active HPK effectively produced kinins from HK. It is suggested that kinins, released at the Candida cell wall, can promote host colonization by the pathogen and the development of infection.

The assembly and activation of kinin-forming systems on the surface of human U-937 macrophage-like cells

A complex of three plasma proteins, including the high molecular mass kininogen (HK), prekallikrein (PK), and factor XII (FXII), is known to assemble on cell surfaces to release bradykinin-related proinflammatory peptides (kinins). Only recently, the binding of HK to human macrophages was described in the U-937 cell line model. In the present study, the adsorption of the other components of plasma kinin-generating system to these cells was characterized. FXII was found to tightly bind to U-937 cells and was also shown to partially compete with HK for the same binding sites on the macrophage surface. The Mac-1 and gC1qR proteins were found to be receptors for FXII on the cell surface. PK indirectly docked to the macrophages via the cell-bound HK and FXII. Within the complex of these proteins assembled on the macrophage, PK could be activated by FXII/FXIIa or independently of this factor, and the active PK effectively released kinins from HK. The cell surface-bound HK could also be the substrate for tissue kallikrein approaching the cell from the bulk fluid. The kinins released at the surface are suggested to induce secondary responses in the macrophages, leading to further propagation of the inflammatory state.