Impaired Specific Antifungal Immunity in CARD9-Deficient Patients with Phaeohyphomycosis

Abstract

Phaeohyphomycosis is a group of severe infections caused by dematiaceous fungi. We previously identified CARD9 deficiencies in four Chinese patients with phaeohyphomycosis caused by Phialophora verrucosa. In this study, we sought to identify the genetic and immunological mechanisms underlying rare dematiaceous fungal infections in three otherwise healthy patients with phaeohyphomycosis caused by Exophiala spinifera, Ochroconis musae, and Corynespora cassiicola. CARD9 sequencing in these patients showed one mutation (p.S23X) that, to our knowledge, has not been characterized and two previously characterized mutations (p.D274fsX60 and p.L64fsX59) that led to lack of CARD9 protein expression. Patient-derived CARD9-deficient cells showed a selective impairment of proinflammatory cytokine and chemokine production, NF-κB activation, and T helper type 22- and T helper type 17-associated responses upon fungus-specific stimulation, whereas phagocytosis and reactive oxygen species production were intact. Consistently, Card9-knockout mice were highly susceptible to phaeohyphomycosis and exhibited immune deficiencies similar to those of patients, including diminished NF-κB and p38 MAPK activation in local and in vitro functional studies. This work clarifies the association between inherited CARD9 deficiencies and phaeohyphomycosis, and furthers current knowledge on the spectrum and pathophysiology of diseases resulting from CARD9 deficiencies.

Frequency and Geographic Distribution of CARD9 Mutations in Patients With Severe Fungal Infections

“…To analyze the role of CARD9 deficiency in fungal infection, we reviewed the literature and identified 60 cases until 2018. The total number of patients with severe fungal infection related to CARD9 deficiency has been summarized in Tables 1A , B ( Boudghène-Stambouli and Mérad-Boudia, 1989 , 1991 , 1998 ; Pruszkowski et al, 1995 ; Glocker et al, 2009 ; Drewniak et al, 2013 ; Gavino et al, 2014 ; Wang et al, 2014 ; Drummond et al, 2015 ; Grumach et al, 2015 ; Herbst et al, 2015 ; Jachiet et al, 2015 ; Lanternier et al, 2015a , b ; Alves de Medeiros et al, 2016 ; Gavino et al, 2016 ; Jones et al, 2016 ; Rieber et al, 2016 ; Yan et al, 2016 ; Boudghene-Stambouli et al, 2017 ; Gavino et al, 2018 ; Sari et al, 2018 ; Vaezi et al, 2018 ; Wang et al, 2018a , b ). The age at the time of diagnosis ranged from 4 to 91 years (mean 34.3 ± 17.9 years).…”

Human CARD9: A Critical Molecule of Fungal Immune Surveillance

“…CARD9-dependent production of neutrophil-attracting chemokines is also evident during pulmonary infection with A. fumigatus in mice ( 14 ), and we recently reported CARD9-deficient patients who developed extrapulmonary A. fumigatus infection that was associated with a lack of neutrophil accumulation at the infected site ( 21 ). Moreover, reduced production of CXC chemokines resulting in a lack of neutrophil recruitment has been described in chronically fungal-infected subcutaneous tissue in experimental phaeohyphomycosis models ( 22 ). Therefore, CARD9 appears to be a central regulator of neutrophil recruitment to specific organs during invasive fungal infection.…”

Phaeohyphomycosis caused by Phialophora americana with CARD9 mutation and 20‐year literature review in China

“…Dematiaceous fungi, also known as phaeohyphomycetes or melanized fungi, are so named owing to the dark pigmentation in the walls of their hyphae and/or spores . They are ubiquitous in soil, wood and rotting vegetation worldwide and are characterised by slow growth . According to the most recent literature, they are divided into 70 genera and approximately 150 species .…”