Xiaowen Wang1,2,3,4, Ruoyu Li5,6,7,8, Yi Zhang9,10,11,12, Chen Huang9,10,11,12, Yinggai Song9,10,11,12, Yubo Ma9,10,11,12, Zhe Wan9,10,11,12, Xuejun Zhu9,10,11,12. 1. Department of Dermatology and Venerology, Peking University First Hospital, No. 8 Xishiku Street, Xicheng District, Beijing, 100034, China. xiaowenpku@126.com. 2. Research Center for Medical Mycology, Peking University, Beijing, China. xiaowenpku@126.com. 3. Beijing Key Laboratory of Molecular Diagnosis on Dermatoses, Beijing, China. xiaowenpku@126.com. 4. National Clinical Research Center for Skin and Immune Diseases, Beijing, China. xiaowenpku@126.com. 5. Department of Dermatology and Venerology, Peking University First Hospital, No. 8 Xishiku Street, Xicheng District, Beijing, 100034, China. mycolab@126.com. 6. Research Center for Medical Mycology, Peking University, Beijing, China. mycolab@126.com. 7. Beijing Key Laboratory of Molecular Diagnosis on Dermatoses, Beijing, China. mycolab@126.com. 8. National Clinical Research Center for Skin and Immune Diseases, Beijing, China. mycolab@126.com. 9. Department of Dermatology and Venerology, Peking University First Hospital, No. 8 Xishiku Street, Xicheng District, Beijing, 100034, China. 10. Research Center for Medical Mycology, Peking University, Beijing, China. 11. Beijing Key Laboratory of Molecular Diagnosis on Dermatoses, Beijing, China. 12. National Clinical Research Center for Skin and Immune Diseases, Beijing, China.
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.
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.
Authors: Frank L van de Veerdonk; Mark S Gresnigt; Luigina Romani; Mihai G Netea; Jean-Paul Latgé Journal: Nat Rev Microbiol Date: 2017-09-18 Impact factor: 60.633
Authors: Ausana Mapook; Kevin D Hyde; Khadija Hassan; Blondelle Matio Kemkuignou; Adéla Čmoková; Frank Surup; Eric Kuhnert; Pathompong Paomephan; Tian Cheng; Sybren de Hoog; Yinggai Song; Ruvishika S Jayawardena; Abdullah M S Al-Hatmi; Tokameh Mahmoudi; Nadia Ponts; Lena Studt-Reinhold; Florence Richard-Forget; K W Thilini Chethana; Dulanjalee L Harishchandra; Peter E Mortimer; Huili Li; Saisamorm Lumyong; Worawoot Aiduang; Jaturong Kumla; Nakarin Suwannarach; Chitrabhanu S Bhunjun; Feng-Ming Yu; Qi Zhao; Doug Schaefer; Marc Stadler Journal: Fungal Divers Date: 2022-09-15 Impact factor: 24.902