title: Impairment of Immune Response against Dematiaceous Fungi in Card9 Knockout Mice.
abstract: Dematiaceous fungi are a large group of pathogens that can cause a wide range of diseases in both immunocompetent and immunocompromised hosts. Based on our previous finding of caspase recruitment domain-containing protein 9 (CARD9) mutations in patients with subcutaneous phaeohyphomycosis caused by Phialophora verrucosa (P. verrucosa), we further investigated the exact role of CARD9 in the pathogenesis of phaeohyphomycosis using Card9 knockout (Card9 KO) mice. We showed that Card9 KO mice are profoundly susceptible to P. verrucosa infection compared with wild-type mice, reflected by significantly more severe footpad swelling, higher fungal burden, lower survival, and systemic dissemination. The inability of Card9 KO mice to control P. verrucosa infection was associated with lack of Th17 differentiation and reduction of tumor necrosis factor (TNF)-α, interleukin (IL)-1β, IL-6, and IL-17A levels in footpad homogenates. In vitro experiments showed a defect of fungal conidia killing and pro-inflammatory cytokine production in Card9 KO bone marrow-derived macrophages and dendritic cells. Furthermore, ex vivo coculture and in vitro T cell differentiation assay demonstrated that Card9 signaling pathway acts indispensably on differentiation of Th17 cells. In conclusion, our findings suggest that CARD9 mediate the innate immune and Th17-mediated adaptive immune responses against dematiaceous fungal infections at the early stage of infection.
authors.affiliation: Department of Dermatology, Peking University First Hospital, Beijing, China.|Research Center for Medical Mycology, Peking University, Beijing, China.|Beijing Key Laboratory of Molecular Diagnosis on Dermatoses, Beijing, China.
authors.forename: Weiwei
authors.initials: W
authors.lastname: Wu
authors.affiliation: Department of Dermatology, Peking University First Hospital, Beijing, China.|Research Center for Medical Mycology, Peking University, Beijing, China.|Beijing Key Laboratory of Molecular Diagnosis on Dermatoses, Beijing, China.
authors.forename: Ruijun
authors.initials: R
authors.lastname: Zhang
authors.affiliation: Department of Dermatology, Peking University First Hospital, Beijing, China.|Research Center for Medical Mycology, Peking University, Beijing, China.|Beijing Key Laboratory of Molecular Diagnosis on Dermatoses, Beijing, China.
authors.forename: Xiaowen
authors.initials: X
authors.lastname: Wang
authors.affiliation: Department of Dermatology, Peking University First Hospital, Beijing, China.|Research Center for Medical Mycology, Peking University, Beijing, China.|Beijing Key Laboratory of Molecular Diagnosis on Dermatoses, Beijing, China.
authors.forename: Yinggai
authors.initials: Y
authors.lastname: Song
authors.affiliation: Department of Immunology, School of Basic Medical Sciences, Peking University Health Science Center, Beijing, China.|Peking University Center for Human Disease Genomics, Beijing, China.|Key Laboratory of Medical Immunology, Ministry of Health, Beijing, China.
authors.forename: Zhengyang
authors.initials: Z
authors.lastname: Liu
authors.affiliation: Department of Immunology, School of Basic Medical Sciences, Peking University Health Science Center, Beijing, China.|Peking University Center for Human Disease Genomics, Beijing, China.|Key Laboratory of Medical Immunology, Ministry of Health, Beijing, China.
authors.forename: Wenling
authors.initials: W
authors.lastname: Han
authors.affiliation: Department of Dermatology, Peking University First Hospital, Beijing, China. mycolab@126.com.|Research Center for Medical Mycology, Peking University, Beijing, China. mycolab@126.com.|Beijing Key Laboratory of Molecular Diagnosis on Dermatoses, Beijing, China. mycolab@126.com.
authors.forename: Ruoyu
authors.initials: R
authors.lastname: Li
mesh_terms: D000818:Animals; D053468:CARD Signaling Adaptor Proteins / Q000172:deficiency*; D002478:Cells, Cultured; D015169:Colony Count, Microbial; D016207:Cytokines / Q000032:analysis; D004195:Disease Models, Animal; D004198:Disease Susceptibility; D008264:Macrophages / Q000276:immunology / Q000382:microbiology; D018345:Mice, Knockout; D060446:Phaeohyphomycosis / Q000276:immunology* / Q000382:microbiology / Q000473:pathology*; D010676:Phialophora / Q000276:immunology*; D016019:Survival Analysis
chemical_list: D053468:CARD Signaling Adaptor Proteins; C513280:Card9 protein, mouse; D016207:Cytokines
keywords: CARD9; Dendritic cells; Macrophages; Murine model; Phialophora verrucosa; Th17