Immunity against fungi

Abstract

Pathogenic fungi cause a wide range of syndromes in immune-competent and immune-compromised individuals, with life-threatening disease primarily seen in humans with HIV/AIDS and in patients receiving immunosuppressive therapies for cancer, autoimmunity, and end-organ failure. The discovery that specific primary immune deficiencies manifest with fungal infections and the development of animal models of mucosal and invasive mycoses have facilitated insight into fungus-specific recognition, signaling, effector pathways, and adaptive immune responses. Progress in deciphering the molecular and cellular basis of immunity against fungi is guiding preclinical studies into vaccine and immune reconstitution strategies for vulnerable patient groups. Furthermore, recent work has begun to address the role of endogenous fungal communities in human health and disease. In this review, we summarize a contemporary understanding of protective immunity against fungi.

Figure 1. Human fungal diseases.

The figure depicts the anatomic sites that are most commonly affected by the fungal genera listed below each organ system. At several sites, fungal disease occurs due to inoculation at the site. For example, humans inhale infectious conidia or desiccated fungal cells of all genera listed under lungs and respiratory tree. For other sites, such as the liver, spleen, and blood stream, disease is the result of dissemination of the indicated fungus from the initial inoculation site. Illustrated by Mao Miyamoto.

Figure 2. Model of fungus-induced CLR signaling in antifungal defense.

At the site of inoculation, particulate fungal polysaccharides bind C-type lectin receptors (CLRs) and Fc receptors (FcRs), resulting in SYK activation via ITAM signaling in the receptor tail, the FcRγ signaling adaptor, or integrin receptor activation. The ensuing PKCδ and CARD9 activation is critical for caspase-1 and caspase-8 activity, MAP kinase signaling (not shown), NF-κB activation, and cytokine production. SYK-dependent PLCγ2 activation is linked to NADPH oxidase assembly and calcineurin-dependent NFAT activation. Dectin/SYK signaling controls IRF5-dependent IFN-γ production. VAV1 and BTK can interact with dectin-1 to mediate phagocytosis of Candida albicans in macrophages. BTK may also promote calcineurin activation and the production of NFAT-regulated cytokines. The model depicts fungal killing in the phagosome. Myeloid cell–derived cytokines promote the differentiation of both Th1 cells and Th17 cells. Th17 and innately derived IL-17 activate epithelial responses that coordinate clearance of fungal cells at mucosal surfaces. The asterisks indicate genetic or humoral defects that predispose humans to a spectrum of fungal disease. Myeloid and epithelial cells collaborate to regulate CXCR2-dependent neutrophil recruitment to portals of infection. Illustrated by Mao Miyamoto.