Primary Cutaneous Aspergillosis in a Patient with CARD9 Deficiency and Aspergillus Susceptibility of Card9 Knockout Mice
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ORIGINAL ARTICLE
Primary Cutaneous Aspergillosis in a Patient with CARD9 Deficiency and Aspergillus Susceptibility of Card9 Knockout Mice Yi Zhang 1,2,3,4 & Chen Huang 1,2,3,4 & Yinggai Song 1,2,3,4 & Yubo Ma 1,2,3,4 & Zhe Wan 1,2,3,4 & Xuejun Zhu 1,2,3,4 & Xiaowen Wang 1,2,3,4 & Ruoyu Li 1,2,3,4 Received: 5 June 2020 / Accepted: 3 November 2020 # Springer Science+Business Media, LLC, part of Springer Nature 2020
Abstract Purpose We describe a case of primary cutaneous aspergillosis caused by Aspergillus fumigatus, and elucidate the underlying genetic and immunological mechanisms. Materials and Methods Routine clinical and laboratory investigations were performed. Whole-exome sequencing of the patient’s DNA suggested the presence of a CARD9 mutation, which was confirmed by Sanger sequencing. Innate and adaptive immunological responses of patient-derived CARD9-deficient cells were evaluated with ELISA and flow cytometry. Cutaneous and pulmonary aspergillosis models were established in Card9 knockout (KO) mice, which were compared with wild-type and immunosuppressed mice, to explore the pathogenesis and Aspergillus susceptibility. Results A 45-year-old man presented with a 37-year history of skin lesions on his face. A diagnosis of primary cutaneous aspergillosis was made through histopathology, immunohistochemistry, and tissue culture. Sanger sequencing of CARD9 showed a homozygous frame-shift mutation (c.819_820insG, p.D274fsX60), which led to the lack of CARD9 expression. Peripheral blood mononuclear cells from the patient showed selective impairment of proinflammatory cytokines, and Th1-, Th17-, and Th22-associated responses upon fungus-specific stimulation. The cutaneous aspergillosis model established in Card9 KO mice presented with persistent infection, with fungal germs and short hyphae in tissue, consistent with the patient’s lesions. Skin lesions in immunosuppressed mice were more severe, and led to death. Unlike our patient, Card9 KO mice were relatively susceptible to pulmonary aspergillosis, with reasons to be investigated. Conclusions This is, to our knowledge, the first report that links cutaneous aspergillosis to CARD9 mutation. This work enriches both the phenotypic spectrum of CARD9 deficiencies and the genetic background of cutaneous aspergillosis. Keywords Primary cutaneous aspergillosis . Aspergillus fumigatus . CARD9 . knockout mice
Introduction Xiaowen Wang and Ruoyu Li contributed equally to this work. * Xiaowen Wang [email protected] * Ruoyu Li [email protected] 1
Department of Dermatology and Venerology, Peking University First Hospital, No. 8 Xishiku Street, Xicheng District, Beijing 100034, China
2
Research Center for Medical Mycology, Peking University, Beijing, China
3
Beijing Key Laboratory of Molecular Diagnosis on Dermatoses, Beijing, China
4
National Clinical Research Center for Skin and Immune Diseases, Beijing, China
Primary cutaneous aspergillosis (PCA) is an uncommon infection caused by Aspergillus spp., in which an infected skin lesion is the initial source of disease
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