Inborn errors of immunity underlying fungal diseases in otherwise healthy individuals

Abstract

It has been estimated that there are at least 1.5 million fungal species, mostly present in the environment, but only a few of these fungi cause human disease. Most fungal diseases are self-healing and benign, but some are chronic or life-threatening. Acquired and inherited defects of immunity, including breaches of mucocutaneous barriers and circulating leukocyte deficiencies, account for most severe modern-day mycoses. Other types of infection typically accompany these fungal infections. More rarely, severe fungal diseases can strike otherwise healthy individuals. Historical reports of fungi causing chronic peripheral infections (e.g. affecting the nails, skin, hair), and invasive diseases (e.g. brain, lungs, liver), in otherwise healthy patients, can be traced back to the mid-20^th century. These fungi typically cause endemic, but not epidemic diseases, are more likely to underlie sporadic than familial cases, and only threaten a small proportion of infected individuals. The basis of this 'idiosyncratic' susceptibility has long remained unexplained, but it has recently become apparent that 'idiopathic' fungal diseases, in children, teenagers, and even adults, may be caused by single-gene inborn errors of immunity. The study of these unusual primary immunodeficiencies (PIDs) has led to the identification of molecules and cells playing a crucial role in human host defenses against certain fungi at particular anatomic sites. A picture is emerging of inborn errors of IL-17 immunity selectively underlying chronic mucocutaneous candidiasis, with little inter-individual variability, and of inborn errors of CARD9 immunity underlying various life-threatening invasive fungal diseases, differing between patients.

Figure 1. CARD9- and IL-17-mediated immunity in fungal diseases

The recognition of fungal molecules, such as β-glucans, α-mannans, and glycoplipids, by C-type lectin receptors (Dectin-1, Dectin-2, Dectin-3, and MINCLE) induces the assembly of a CARD9-BCL10-MALT1 complex, which mediates the activation of NF-κB and MAPK signaling, leading to the translocation of NF-κB and AP-1 into the nucleus. Following the recognition of C. albicans by Dectin-1, CARD9 also links RASGRF1 to H-RAS and initiates ERK signaling. This pathway ultimately results in the production of pro-inflammatory cytokines, such as IL-6 and GM-CSF, by phagocytes and epithelial cells. Similarly, the binding of IL-17A and IL-17F to the IL-17RA/IL-17RC receptor facilitates the recruitment of ACT1 to the receptor, leading to the activation of NF-κB, MAPK, and C/EBP signaling, thereby inducing the production of pro-inflammatory cytokines and chemokines (e.g. IL-6, CXCL1), matrix metalloproteinases (e.g. MMP1), and antimicrobial peptides (e.g. β-defensin 3). In T cells, IL-6, IL-23, IL-27, and IFNs (IFN-α, IFN-β, and IFN-γ) bind to their receptors, leading to the recruitment of JAK family kinases to the receptor and the activation of downstream STAT1 and STAT3 signaling. STAT1 activation abolishes the expression of Th17 signature cytokines (e.g. IL-17A, IL-17F), whereas STAT3 activation induces the production of RORγT, which cooperates with STAT3 to promote Th17 cell differentiation. IKK, IκB kinase; NEMO, NF-κB essential modulator; IFNR, IFN receptor; JAK, Janus kinase; TYK2, tyrosine kinase 2; MMP1, matrix metalloproteinase 1; BD-3, β-defensin 3. Red stars indicate the genetic causes of invasive fungal diseases and of “isolated’”chronic mucocutaneous candidiasis.

Figure 2. Fungal taxonomy

The disease-causing fungi identified in CARD9-deficient patients are shown in red.