Immune Interactions with Pathogenic and Commensal Fungi: A Two-Way Street

Abstract

We are exposed to a wide spectrum of fungi including innocuous environmental organisms, opportunistic pathogens, commensal organisms, and fungi that can actively and explicitly cause disease. Much less is understood about effective host immunity to fungi than is generally known about immunity to bacterial and viral pathogens. Innate and adaptive arms of the immune system are required for effective host defense against Candida, Aspergillus, Cryptococcus, and others, with specific elements of the host response regulating specific types of fungal infections (e.g., mucocutaneous versus systemic). Here we will review themes and controversies that are currently shaping investigation of antifungal immunity (primarily to Candida and Aspergillus) and will also examine the emerging field of the role of fungi in the gut microbiome.

Figure 1. Dectin-1 Signaling Pathways

Dectin-1 binds to β-glucan exposed at the surface of fungal cell walls. Clustering of Dectin-1 receptors and the exclusion of inhibitory protein phosphatases (CD45 and CD148) allows for sustained phosphorylation of the intracellular stalk of Dectin-1 that has a hemi-ITAM motif. Subsequent recruitment and phosphorylation of Syk induces signaling through the Syk-dependent, Raf-1-dependent, and NFAT pathways leading to activation of cellular responses that include phagocytosis, respiratory burst, and production of pro-inflammatory cytokines and chemokines. Red dots indicate phosphorylation. Diagram based on Goodridge et al. (2011).

Figure 2. Distinct T Cell Responses Based on Dendritic Cell Recognition of Candida Yeast Versus Pseudo-hyphae

β-glucan exposed on the surface of Candida yeast in the epidermis is recognized by Dectin-1 on Langerhans cells, inducing production of IL-6 and the generation of a Th17-dominated adaptive immune response that is effective against reinfection of the skin. In contrast, Candida pseudo-hyphae penetrated into the deeper layers of the skin. These filaments expose little or no β-glucan and are recognized by dendritic cells in the dermis by receptors other than Dectin-1. This recognition translates into a more Th1 cell-dominated response that is effective against systemic infection with Candida. Diagram based on Kashem et al. (2015).

Figure 3. Autocrine Activity of Neutrophil IL-17 in Fungal Infections

Exposure of macrophages and dendritic cells to germinating spores or yeast induces production of IL-6 and IL-23, which activate a sub-population of bone marrow neutrophils that constitutively express IL-6 and IL-23 receptors on the cell surface and the RORγt transcription factor in the cytoplasm. RORγt translocates to the nucleus to initiate IL-17 gene expression. IL-6 and IL-23 also induce expression of cell surface IL-17RC, and as IL-17RA is constitutively expressed, neutrophils can be activated by autocrine or paracrine IL-17. These activated neutrophils also express Dectin-2 and Dectin-3 (MCL), and subsequent exposure to hyphae results in increased production of reactive oxygen species that promotes fungal killing. Diagram based on Taylor et al. (2014b).