Mendelian genetics of human susceptibility to fungal infection

Abstract

A recent surge in newly described inborn errors of immune function-related genes that result in susceptibility to fungal disease has greatly enhanced our understanding of the cellular and molecular basis of antifungal immune responses. Characterization of single-gene defects that predispose to various combinations of superficial and deep-seated infections caused by yeasts, molds, and dimorphic fungi has unmasked the critical role of novel molecules and signaling pathways in mucosal and systemic antifungal host defense. These experiments of nature offer a unique opportunity for developing new knowledge in immunological research and form the foundation for devising immune-based therapeutic approaches for patients infected with fungal pathogens.

Figure 1.

Disorders associated with systemic fungal disease. The generation of superoxide by the NADPH oxidase complex and of hypochlorous acid by myeloperixodase within phagocytes is critical for the killing of filamentous molds and yeasts. The interaction between monocytes/macrophages and T/NK lymphocytes is important for control of infections by intracellular dimorphic fungi. Specifically, interleukin-12 is released by monocytes/macrophages in response to fungal ingestion and binds to its cognate receptor on T/NK cells. This, in turn, results in STAT4-dependent release of interferon-γ, which acts on monocytes/macrophages to enhance fungal killing via activation of STAT1. IRF8 is critical for myeloid cell differentiation and interleukin-12 production, and GATA2 plays a significant role in monocyte, dendritic cell and NK cell maintenance and effector function. Activation of NEMO, downstream from CD40, interleukin-1 receptor, and TNF-receptor signaling, is important for control of Pneumocystis infection.

Figure 2.

Disorders associated with mucocutaneous fungal disease. Candida recognition by myeloid cell C-type lectin receptors such as dectin-1 results in activation of the CARD9/BCL-10/MALT1 signaling complex. This in turn orchestrates the production of proinflammatory cytokines that direct T-lymphocyte differentiation toward the Th17 program, a STAT3-dependent process. DOCK8 and IRF8 also contribute to Th17 differentiation, and gain-of-function STAT1 mutations that lead to STAT1 hyperphosphorylation create a cytokine milieu that inhibits the generation of Th17 cells. STK4 is crucial for T-cell survival. Th17 cells produce interleukin-17 and interleukin-22, which recruit phagocytes to the site of fungal infection and induce the generation of potent antifungal antimicrobial peptides by epithelial cells. Mucocutaneous candidiasis is seen in patients with mutations in interleukin-17F, interleukin-17RA, and the adaptor protein ACT1, which impair interleukin-17-dependent signaling, and in patients with autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy who have neutralizing autoantibodies against interleukin-17 and interleukin-22.