Inflammasome-mediated GSDMD activation facilitates escape of Candida albicans from macrophages.
Inflammasome-mediated GSDMD activation facilitates escape of Candida albicans from macrophages.
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DOI：
10.1038/s41467-021-27034-9
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发表时间：
2021-11-18
影响因子：
16.6
通讯作者：
Luo HR
中科院分区：
文献类型：
--
作者：
Ding X;Kambara H;Guo R;Kanneganti A;Acosta-Zaldívar M;Li J;Liu F;Bei T;Qi W;Xie X;Han W;Liu N;Zhang C;Zhang X;Yu H;Zhao L;Ma F;Köhler JR;Luo HR
白色念珠菌是真菌性败血症最常见的原因。抑制炎性体活性可抵抗多种微生物和LPS诱导的脓毒症;然而，炎性体信号似乎可保护免受C。白色念珠菌感染，因此炎性小体抑制剂在临床上对念珠菌病没有用。在这里，我们显示GSDMD，一个已知的炎性靶点和关键的pyroptotic细胞死亡介质，矛盾的破坏念珠菌病，改善结果和生存的念珠菌感染的小鼠。机械性地，C.白色念珠菌劫持了典型的炎性小体-GSDMD轴介导的焦亡，以促进它们从巨噬细胞逃逸，部署菌丝和念珠菌溶解素，一种由菌丝表达的成孔毒素。抑制GSDMD可通过抑制C.白色念珠菌从巨噬细胞逃逸，同时维持炎性小体依赖性但GSDMD非依赖性的IL-1β产生，用于抗真菌宿主防御。本研究证实了GSDMD在体内外念珠菌逃避宿主免疫中的关键作用，并提示GSDMD可能是念珠菌治疗的潜在靶点。白色念珠菌引起的败血症已经显示炎性体信号传导在感染期间保护白色念珠菌，并且因此在这种情况下限制炎性体抑制剂。在这里，作者暗示Gasdermin D参与了C.ablicans的免疫逃避，并提出了治疗靶向。
Candida albicans is the most common cause of fungal sepsis. Inhibition of inflammasome activity confers resistance to polymicrobial and LPS-induced sepsis; however, inflammasome signaling appears to protect against C. albicans infection, so inflammasome inhibitors are not clinically useful for candidiasis. Here we show disruption of GSDMD, a known inflammasome target and key pyroptotic cell death mediator, paradoxically alleviates candidiasis, improving outcomes and survival of Candida-infected mice. Mechanistically, C. albicans hijacked the canonical inflammasome-GSDMD axis-mediated pyroptosis to promote their escape from macrophages, deploying hyphae and candidalysin, a pore-forming toxin expressed by hyphae. GSDMD inhibition alleviated candidiasis by preventing C. albicans escape from macrophages while maintaining inflammasome-dependent but GSDMD-independent IL-1β production for anti-fungal host defenses. This study demonstrates key functions for GSDMD in Candida’s escape from host immunity in vitro and in vivo and suggests that GSDMD may be a potential therapeutic target in C. albicans-induced sepsis. Inflammasome signalling has been shown to protect Candida albicans during infection and as such limits inflammasome inhibitors in this context. Here the authors implicate Gasdermin D in C.ablicans immune evasion and suggests its targeting therapeutically.
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影响因子：
5.2
作者：
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通讯作者：
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通讯作者：
Netea MG