Serum Amyloid P Component Binds Fungal Surface Amyloid and Decreases Human Macrophage Phagocytosis and Secretion of Inflammatory Cytokines

Abstract

In patients with invasive fungal diseases, there is often little cellular inflammatory response. We tested the idea that binding of the human constitutive plasma protein serum amyloid P component (SAP) (also called PTX2) to Candida albicans dampens the innate immune response to this fungus. Many pathogenic fungi have cell surface amyloid-like structures important for adhesion and biofilm formation. Human SAP bound to fungi that expressed functional cell surface amyloid, but SAP had minimal binding to fungi with reduced expression of cell surface amyloid. In the absence of SAP, phagocytosis of fungi by human macrophages was potentiated by expression of amyloid on the fungi. SAP binding to fungi inhibited their phagocytosis by macrophages. Macrophages pretreated with SAP displayed reduced fungal phagocytosis, reduced secretion of inflammatory cytokines (IFN-γ, IL-6, and TNF-α), and increased secretion of the anti-inflammatory cytokine IL-10. SAP bound to fungi or added to the medium upregulated the expression of the anti-inflammatory receptor CD206 on macrophages. These findings suggest that SAP bound to amyloid-like structures on fungal cells dampens the host cellular immune response in fungal diseases such as invasive candidiasis. IMPORTANCE Macrophages are a key part of our innate immune system and are responsible for recognizing invading microbes, ingesting them, and sending appropriate signals to other immune cells. We have found that human macrophages can recognize invading yeast pathogens that have a specific molecular pattern of proteins on their surfaces: these proteins have structures similar to the structures of amyloid aggregates in neurodegenerative diseases like Alzheimer’s disease. However, this surface pattern also causes the fungi to bind a serum protein called serum amyloid P component (SAP). In turn, the SAP-coated yeasts are poorly recognized and seldom ingested by the macrophages, and the macrophages have a more tolerant and less inflammatory response in the presence of SAP. Therefore, we find that surface structures on the yeast can alter how the macrophages react to invading microbes.

Antifungal Activity of Mammalian Serum Amyloid A1 against Candida albicans

“…Plasma proteins have multiple roles in controlling infections. A recent study demonstrated that human plasma protein serum amyloid P component (SAP) was able to bind to surface amyloid-like structures of C. albicans and resulted in poor recognition and ingestion of yeast cells by host macrophages (26). Combined with this previous finding, our study implies that this innate immune protein could play a critical role in defense against C. albicans infections either through indirect induction of degranulation and phagocytosis or directly by killing the pathogen.…”

An Amyloid Core Sequence in the Major Candida albicans Adhesin Als1p Mediates Cell-Cell Adhesion

“…Als1p is highly expressed in mouse models of infection and in artificial biofilms (14, 45). In contrast, Als5p is moderately expressed, and its expression can skew human macrophages toward the tolerant M2 state or lead to commensal-like interactions in a Caenorhabditis elegans infection model (46, 47). These independent biological roles are reflected in differences in the activities of Als1p and Als5p in vitro.…”

Human serum proteins bind to Sporothrix schenckii conidia with differential effects on phagocytosis

“…Interestingly, SAP binds to functional amyloid displayed in the fungal surface in several deep infections [26,27]. In invasive candidiasis, SAP binds to functional amyloid on the surface of the fungi; this inhibits macrophage phagocytosis and reduces the secretion of inflammatory cytokines [28].…”