Impairment of Immune Response against Dematiaceous Fungi in Card9 Knockout Mice
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- 作者：Weiwei Wu ; Ruijun Zhang ; Xiaowen Wang ; Yinggai Song ; Zhengyang Liu…
- 关键词：Phialophora verrucosa ; CARD9 ; Murine model ; Macrophages ; Dendritic cells ; Th17
- 刊名：Mycopathologia
- 出版年：2016
- 出版时间：October 2016
- 年：2016
- 卷：181
- 期：9-10
- 页码：631-642
- 全文大小：1,598 KB
- 刊物类别：Biomedical and Life Sciences
- 刊物主题：Life Sciences
Microbiology
Medical Microbiology
Plant Sciences
Microbial Ecology - 出版者：Springer Netherlands
- ISSN：1573-0832
- 卷排序：181
文摘
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.