Human invasive mycoses: immunogenetics on the rise.

Exophiala species are ubiquitous dematiaceous yeast-like fungi of the order Chaetothyriales that bear melanin-like pigment in their cell wall that is responsible for their dark color and is thought to be a major fungal virulence factor [1–3]. Among the agents of phaeohyphomycosis (cutaneous, subcutaneous, and invasive infections caused by dark-walled fungi), most human Exophiala infections are subacute to chronic and confined to the skin, typically following traumatic inoculation [1–3]. Invasive Exophiala infections are rare and associated with high fatality rates [1–3].Exophiala dermatitidis accounts for most of these invasive infections and has a tropism for the central nervous system; Exophiala spinifera infection is less common, with no neurotropism but with a predilection for bone [1–3]. Until now, inherited susceptibility to invasive Exophiala infection was recognized only in patients with chronic granulomatous disease (CGD) [4], who have defects in phagocyte oxidative cytotoxicity [5, 6]. In this issue of The Journal of Infectious Diseases, Lanternier et al describe 2 patients with autosomal recessive CARD9 deficiency who developed disseminated Exophiala infections [7]: an Angolan girl who presented at 5 years of age with E. dermatitidis infection of the brain and liver and an Iranian woman who presented at 18 years of age with E. spinifera infection of the subcutaneous tissue, bone, and lung. These cases identify CARD9 deficiency as a critical genetic risk factor for invasive Exophiala infection in humans, further expanding the spectrum of human invasive fungal disease associated with CARD9 deficiency. Other CARD9-associated infections include those caused by Candida, Trichophyton, and Phialophora species [8–11]. Therefore, CARD9 mutations are likely to account for some of the invasive phaeohyphomycosis infections in putatively immunocompetent patients, particularly those caused by neurotropic fungi such as Cladophialophora, Fonsecaea, Rhinocladiella, Curvularia, Exserohilum, and Chaetomium species [1–3]. CARD9 is a key adaptor molecule that complexes with MALT1 and BCL-10 to relay syk-mediated fungal recognition signals [12, 13]. Fungal sensing occurs through several immunoreceptor tyrosine-based activation motif–associated C-type lectin receptors (CLRs), including dectin-1, dectin-2, dectin-3, mincle, and, likely, others yet undiscovered [14–17]. This central positioning of CARD9 downstream of multiple fungal sensors likely accounts for the diverse spectrum of invasive fungal infections in patients with loss-of-function CARD9 mutations. The occurrence of spontaneous invasive fungal infections in patients with CARD9 deficiency and the absence of similar infections in patients with MYD88 or IRAK4mutations underscore the critical differences between the human C-type lectin and Toll-like receptor pathways [7–11, 18]. Intriguingly, there is, so far, no correlation between specific CARD9 mutations and specific invasive fungal infections; also, all CARD9-deficient patients with invasive fungal infections have been infected by only a single fungal pathogen [7–11]. Further, no pulmonary invasive fungal infections have yet been reported in CARD9-deficient patients, despite the ubiquity of inhaled filamentous fungi. Presumably, CARD9 will have critical functional roles in the induction of fungus-, CLR-, anatomical site–, and cell type–specific protective immune responses [19]. In addition, it remains puzzling that some CARD9-deficient patients present with invasive fungal disease early in life, whereas others exhibit adultonset disease [7–11]. The mechanisms by which CARD9 deficiency predispose to invasive fungal infections remain elusive but are likely to be somewhat distinct from those that account for enhanced susceptibility to chronic mucocutaneous candidiasis (CMC), Received 16 July 2014; accepted 16 July 2014; electronically published 23 July 2014. Correspondence: Michail S. Lionakis, MD, ScD, Fungal Pathogenesis Unit, Laboratory of Clinical Infectious Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, 9000 Rockville Pike, Bldg 10, Rm 11C102, Bethesda, MD 20892 ([email protected]). The Journal of Infectious Diseases 2015;211:1205–7 Published by Oxford University Press on behalf of the Infectious Diseases Society of America 2014. Thiswork iswritten by (a) US Government employee(s) and is in the public domain in the US. DOI: 10.1093/infdis/jiu411