Impairment of Immune Response against Dematiaceous Fungi in Card9 Knockout Mice
Impairment of Immune Response against Dematiaceous Fungi in Card9 Knockout Mice
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DOI：
10.1007/s11046-016-0029-0
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发表时间：
2016-07
期刊：
影响因子：
5.5
通讯作者：
Weiwei Wu;Ruijun Zhang;Xiaowen Wang;Yinggai Song;Zhengyang Liu;W. Han;Ruoyu Li
中科院分区：
文献类型：
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作者：
Weiwei Wu;Ruijun Zhang;Xiaowen Wang;Yinggai Song;Zhengyang Liu;W. Han;Ruoyu Li
真菌是一大类病原体，可在免疫功能正常和免疫功能低下的宿主中引起广泛的疾病。基于我们之前在疣状hialophora verrucosa（P.）引起的皮下褐丝菌病患者中发现的caspase募集结构域蛋白9 （CARD9）突变。我们利用card9敲除（Card9KO）小鼠进一步研究了CARD9在褐丝酵母菌病发病机制中的确切作用。我们发现card9ko小鼠对toP非常敏感。疣杆菌感染与野生型小鼠相比，表现为更严重的足垫肿胀，更高的真菌负担，更低的存活率和全身传播。card9ko小鼠无法控制p。疣状瘤感染与足垫匀浆中Th17分化缺乏和肿瘤坏死因子(TNF)-α、白细胞介素(IL)-1β、IL-6和IL- 17a水平降低有关。体外实验显示，card9ko骨髓源性巨噬细胞和树突状细胞在真菌分生孢子杀灭和促炎细胞因子产生方面存在缺陷。此外，体外共培养和体外T细胞分化实验表明，Card9信号通路对Th17细胞的分化起着不可或缺的作用。综上所述，我们的研究结果表明，CARD9介导先天性免疫和th17介导的适应性免疫反应，在感染的早期阶段对抗真菌感染。
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 byPhialophora verrucosa(P. verrucosa), we further investigated the exact role of CARD9 in the pathogenesis of phaeohyphomycosis usingCard9knockout (Card9KO) mice. We showed thatCard9KO mice are profoundly susceptible toP. verrucosainfection compared with wild-type mice, reflected by significantly more severe footpad swelling, higher fungal burden, lower survival, and systemic dissemination. The inability ofCard9KO mice to controlP. verrucosainfection 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 inCard9KO 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.