Serum Amyloid P Component Bound to Fungal Functional Amyloid Is Anti-Phagocytic and Anti-inflammatory

Abstract

Abstract Invasive fungal disease is often characterized by a sparse cellular inflammatory response, and we have proposed that deposition of serum amyloid P component (SAP, also called PTX2) on fungal surfaces dampens the innate immune response. Binding of SAP to fungi was dependent upon fungal expression of cell surface functional amyloid, with 92% of Candida albicans yeast cells binding SAP, whereas only 18% of yeasts of an amyloid-depleted strain of Saccharomyces cerevisiae bound SAP. Furthermore, SAP bound to 40% of S. cerevisiae cells expressing the amyloidogenic C. albicans adhesin Als5pWT, but only 19% of cells expressing a non-amyloidogenic single site mutant, Als5pV326N. Macrophages phagocytosed fungi in proportion to expression of surface amyloid: C. albicans > S. cerevisiae expressing Als5pWT >>>S. cerevisiae expressing Als5pV326N or S. cerevisiae. Macrophages incubated with C. albicans yeasts secreted significantly increased amounts of IFNγ, IL-6, TNFα and IL-10. Pre-treatment of macrophages with SAP or yeasts with SAP reduced C. albicans phagocytosis by more than 80% within 30 minutes, and led to reductions of IFNγ, IL-6, TNFα, but to an increase in the secretion of the anti-inflammatory cytokine IL-10. The structurally similar pentraxin, C-reactive protein, demonstrated negligible binding to Candida (7% on flow cytometry) and slightly increased macrophage phagocytosis of yeasts. Thus SAP, whether added exogenously to macrophages or coating fungi, rapidly dampened the host cellular immune response. These findings support the hypothesis that amyloid-dependent SAP binding diminishes cellular innate immunity in invasive candidiasis in humans.