CARD9 mutations linked to subcutaneous phaeohyphomycosis and TH17 cell deficiencies

Black Yeasts and Their Filamentous Relatives: Principles of Pathogenesis and Host Defense

“…Similar to infections in humans, systemic phaeohyphomycoses frequently occur in otherwise apparently healthy hosts. However, susceptibility to these infections was recently found to be associated with mutations in the CARD9 gene, encoding a critical adaptor mediating C-type lectin receptors and impairing cytokine production of innate immune cells (89). In contrast to expectations, black yeasts are not observed as emerging opportunists in immunocompromised or otherwise debilitated vertebrates.…”

Mendelian Genetics of Human Susceptibility to Fungal Infection

“…However, the impact of CARD9 deficiency on specific antidermatophyte immune responses was not tested. More recently, four patients from China were reported to develop severe subcutaneous phaeohyphomycosis with Phialophora verrucosa as a result of novel point and frameshift CARD9 mutations, which abolished P. verrucosa-induced mononuclear cellular responses (Wang et al 2013b). No candidiasis was seen in these patients (Wang et al 2013b) nor in the majority of the patients with p.Q289X and p.R101C mutations (Lanternier et al 2013), implying that different CARD9 mutations may confer different fungal infection susceptibilities at different anatomical sites.…”

“…More recently, four patients from China were reported to develop severe subcutaneous phaeohyphomycosis with Phialophora verrucosa as a result of novel point and frameshift CARD9 mutations, which abolished P. verrucosa-induced mononuclear cellular responses (Wang et al 2013b). No candidiasis was seen in these patients (Wang et al 2013b) nor in the majority of the patients with p.Q289X and p.R101C mutations (Lanternier et al 2013), implying that different CARD9 mutations may confer different fungal infection susceptibilities at different anatomical sites. Remarkably, although Card9 is indispensable for control of IA, tuberculosis, and listeriosis in mice Dorhoi et al 2010;Jhingran et al 2012), no infections by molds, intracellular bacteria or mycobacteria have thus far been reported in CARD9-deficient humans.…”

“…Hence, patients with mutations in MYD88, the adaptor molecule downstream from TLRs do not develop fungal disease ; conversely, patients with mutations in CARD9, the adaptor molecule downstream from CLRs, which forms a complex with BCL-10 and MALT1 for optimal signaling, are susceptible to both mucosal and systemic mycoses (Fig. 2) (Glocker et al 2009;Drewniak et al 2013;Lanternier et al 2013;Wang et al 2013b). Specifically, an initial report described members of a consanguineous Iranian family with CMC, superficial dermatophytosis, and Candida meningitis caused by a homozygous CARD9 point mutation ( p.Q295X) associated with decreased proportions of circulating IL-17 þ T lymphocytes (Glocker et al 2009), implying a role for human CARD9 in Th17 differentiation, consonant with a similar role of CARD9 in mice (LeibundGut-Landmann et al 2007).…”

The Evolving View of IL-17-Mediated Immunity in Defense Against Mucocutaneous Candidiasis in Humans

“…However, two of the eight patients reported in this family also had invasive candidiasis and two of the patients had no proven candidal disease. More intriguingly, several patients with invasive infections caused by dermatophytes but not Candida have been reported recently [56][57][58]. Thus, the expanding spectrum of clinical phenotype in patients with CARD9 deficiency makes a direct relationship between CMC and this PID to be further elucidated.…”