A Fun-Guide to Innate Immune Responses to Fungal Infections

Abstract

Immunocompromised individuals are at high risk of developing severe fungal infections with high mortality rates, while fungal pathogens pose little risk to most healthy people. Poor therapeutic outcomes and growing antifungal resistance pose further challenges for treatments. Identifying specific immunomodulatory mechanisms exploited by fungal pathogens is critical for our understanding of fungal diseases and development of new therapies. A gap currently exists between the large body of literature concerning the innate immune response to fungal infections and the potential manipulation of host immune responses to aid clearance of infection. This review considers the innate immune mechanisms the host deploys to prevent fungal infection and how these mechanisms fail in immunocompromised hosts. Three clinically relevant fungal pathogens (Candida albicans, Cryptococcus spp. and Aspergillus spp.) will be explored. This review will also examine potential mechanisms of targeting the host therapeutically to improve outcomes of fungal infection.

Keywords: antifungal immunity; fungal infections; host-directed therapy; host–pathogen interaction; immune dysregulation.

Figure 1

Cellular Innate Immune Control of Fungal Infections. Various mechanisms exist for the control of fungal infections by the innate immune system. Macrophages phagocytose fungi, undergo macrophage clustering or fold phagocytosed hyphae. Recognition of fungal ligands, such as candidalysin, stimulates production of IL-1β, triggering neutrophil recruitment [70]. Increased expression of IL-33 in C. albicans infection triggers neutrophil recruitment and phagocytosis [71]. Neutrophils may also release reactive oxygen species (ROS) or neutrophil extracellular traps, degranulate, phagocytose fungi or undergo swarming. Eosinophils have antifungal effects through degranulation [72] and production of IL-17, which stimulates pro-inflammatory signalling, production of antimicrobial peptides and Th17 cell differentiation [73,74].

Figure 2

Failures of innate immunity in fungal infection. Examples of specific failures of innate immunity which lead to susceptibility to fungal infection. STAT1 gain of function mutations increase sensitivity to IFNs, leading to increased susceptibility to fungal infections [131]. OTUD1 or MyD88 deficiencies result in reduced transcription of NF-κB, resulting in reduced inflammatory response and increased C. albicans burden [135,138]. CARD9 deficiency causes reduced NF-κB transcription, resulting in reduced inflammatory response and increased A. fumigatus burden [147]. NADPH oxidase deficiency in CGD patients reduced production of ROS, reducing the ability to kill A. fumigatus and removing ROS-mediated inhibition of NF-κB, resulting in excess TNF production and host injury [41,131]. Anti-GM-CSF antibodies prevent macrophage differentiation and activation, resulting in inability to control C. neoformans infection [148].