Immunity to Commensal Fungi: Detente and Disease

Abstract

Fungi are ubiquitous in our environment, and a healthy immune system is essential to maintain adequate protection from fungal infections. When this protection breaks down, superficial and invasive fungal infections cause diseases that range from irritating to life-threatening. Millions of people worldwide develop invasive infections during their lives, and mortality for these infections often exceeds 50%. Nevertheless, we are normally colonized with many of the same disease-causing fungi (e.g., on the skin or in the gut). Recent research is dramatically expanding our understanding of the mechanisms by which our immune systems interact with these organisms in health and disease. In this review, we discuss what is currently known about where and how the immune system interacts with common fungi.

Keywords: Aspergillus; Candida; Dectin-1; Malassezia; innate immunity; microbiome; mycobiome.

Figure 1.. Distribution of common commensal fungi.

Fungal representation at various sites and sources are indicated. Relative prevalence across multiple studies at each site are represented by the size of the fungal genera name.

Figure 2.. Interaction of commensal fungi with the mucosal immune system during homeostasis and disseminated fungal infection.

Top panel depicts normal homeostatic conditions. (A) Probiotic Saccharomyces boosts intestinal IgA, directly inhibits intestinal pathogen infection, and also limits pathological inflammatory responses. (B) Commensal Saccharomyces induces monocyte training that limits pathological Candida infection. (C) Commensal Candida being sampled by Langerin⁺ intestinal dendritic cells and RALDH⁺ dendritic cells traffic to the peripheral lymph nodes (pLN) in response to commensal Candida to induce lymphocyte homing molecules on pLN high endothelial venules (HEV). (D) Recognition of Candida by intestinal dendritic cells induces a tolerogenic phenotype characterized by IDO expression and induction of Candida-specific regulatory T cells. Bottom panel depicts situation where antibiotic treatment-induced dysbiosis combined with immunosuppression leads to invasive candidiasis. (E) Antibiotic-mediated disruption of commensal bacteria promotes intestinal overgrowth of commensal Candida. (F) Mucosal disruption (for example following chemotherapy-induced mucositis) allows for bloodstream invasion by intestinal commensal Candida and dissemination to peripheral organs. Candida activates complement in the bloodstream which promotes neutrophil and monocyte phagocytosis and activation. (G) DC-derived IL-23p19 activates NK cells to produce GM-CSF needed for neutrophil antimicrobial activity. Neutropenia as well as polymorphisms which impair PMN and monocyte function promote full development of invasive candidiasis.

Figure 3.. Interactions between fungi and the immune system of the skin.

(A) Malassezia species are associated with areas of the skin where sebaceous secretions are present. These fungi utilize long chain fatty acids such as sebum as required carbon sources. Malassezia yeasts have been associated with dermatologic conditions such as Malassezia folliculitis. Normally confined to the infundibulum region of the skin, Malassezia yeasts can invade into the hair follicle causing damage and inflammation. (B) Metabolic byproducts of Malassezia yeasts are important in skin homeostasis. Short chain fatty acids produced from the metabolic breakdown of sebum have dual anti-bacterial and anti-mycotic properties. Potent Ahr indolic ligands produced by Malassezia can inhibit phagocyte responses to TLR stimulation and contribute to cutaneous invariant γδ T cell homeostasis in the skin. (C) Immune responses to Candida albicans skin infection are compartmentalized. In the epidermis, Dectin-1 engagement on LC by C. albicans yeasts stimulates IL-6 production leading to the induction of Th17 CD4⁺ T cell differentiation and skin immunity. CD103⁺ dermal DCs detect hyphae C. albicans and produce IL-12 thus priming Th1 CD4⁺ T cell differentiation and providing systemic protection. Skin TRPV1⁺ nociceptive nerves are able to detect C. albicans and respond by secreting CGRP which acts on nearby CD301b⁺ dermal DCs to produce IL-23. γδ T cells respond to IL-23 stimulation by producing IL-17 which activates neutrophils and stimulates anti-microbial peptide production by keratinocytes.