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Primary Cutaneous Aspergillosis in a Patient with CARD9 Deficiency and Aspergillus Susceptibility of Card9 Knockout Mice

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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.

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Acknowledgments

We thank the patient, his family members, and healthy donors for their participation in this study. We also thank Huihui Liu for technical advice on the analysis of FACS results and Jin Shao for help with the immunohistochemistry of patient’s tissue sections.

Funding

This work was supported by the International Cooperation and Exchanges Project from National Natural Science Foundation of China (NSFC No. 81520108026) and the National Natural Science Foundation of China (NSFC No. 81872539).

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Author notes

  1. Xiaowen Wang and Ruoyu Li contributed equally to this work.

Authors and Affiliations

  1. Department of Dermatology and Venerology, Peking University First Hospital, No. 8 Xishiku Street, Xicheng District, Beijing, 100034, China

    Yi Zhang, Chen Huang, Yinggai Song, Yubo Ma, Zhe Wan, Xuejun Zhu, Xiaowen Wang & Ruoyu Li

  2. Research Center for Medical Mycology, Peking University, Beijing, China

    Yi Zhang, Chen Huang, Yinggai Song, Yubo Ma, Zhe Wan, Xuejun Zhu, Xiaowen Wang & Ruoyu Li

  3. Beijing Key Laboratory of Molecular Diagnosis on Dermatoses, Beijing, China

    Yi Zhang, Chen Huang, Yinggai Song, Yubo Ma, Zhe Wan, Xuejun Zhu, Xiaowen Wang & Ruoyu Li

  4. National Clinical Research Center for Skin and Immune Diseases, Beijing, China

    Yi Zhang, Chen Huang, Yinggai Song, Yubo Ma, Zhe Wan, Xuejun Zhu, Xiaowen Wang & Ruoyu Li

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  1. Yi Zhang
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  2. Chen Huang
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Contributions

X.W. and R.L. are the principal investigators who conceived this study. Y.Z. and C.H. conducted the research, and analyzed and interpreted the data. Z.W. and Y.S. contributed with the identification of the fungus. Y.M. participated in animal experiments. X.Z. provided the clinical oversight of the patient. Y.Z. drafted the manuscript and X.W. and R.L. critically revised the manuscript.

Corresponding authors

Correspondence to Xiaowen Wang or Ruoyu Li.

Ethics declarations

This study was approved by the Clinical Research Ethics Committee of the Peking University First Hospital. We obtained blood samples from the patient, his son, and three ethnically matched healthy volunteers, after obtaining informed consent. The patient gave permission to publish his images and medical information. Animal studies were approved by the Institutional Ethics Committee of Peking University First Hospital in accordance with the institutional guidelines.

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The authors declare that they have no conflicts of interest.

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Zhang, Y., Huang, C., Song, Y. et al. Primary Cutaneous Aspergillosis in a Patient with CARD9 Deficiency and Aspergillus Susceptibility of Card9 Knockout Mice. J Clin Immunol 41, 427–440 (2021). https://doi.org/10.1007/s10875-020-00909-0

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