A human commensal-pathogenic fungus suppresses host immunity via targeting TBK1

IF 20.6 1区 医学 Q1 MICROBIOLOGY Cell host & microbe Pub Date : 2024-07-30 DOI:10.1016/j.chom.2024.07.003
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Abstract

Candida albicans stably colonizes humans but is the leading cause of hospital-acquired fungemia. Traditionally, masking immunogenic moieties has been viewed as a tactic for immune evasion. Here, we demonstrate that C. albicans blocks type I interferon (IFN-I) signaling via translocating an effector protein Cmi1 into host cells. Mechanistically, Cmi1 binds and inhibits TANK-binding kinase 1 (TBK1) to abrogate IFN-regulatory factor 3 (IRF3) phosphorylation, thereby suppressing the IFN-I cascade. Murine infection with a cmi1 mutant displays an exaggerated IFN-I response in both kidneys and bone-marrow-derived macrophages, leading to rapid fungal clearance and host survival. Remarkably, the lack of CMI1 compromises gut commensalism and increases IFN-I response in mouse colonic cells. These phenotypes of cmi1 are rescued by the depletion of IFN-I receptor. This work establishes the importance of TBK1 inhibition in fungal pathogenesis and reveals that a human commensal-pathogenic fungus significantly impacts host immunity during gut colonization and infection via delivering effector proteins into host cells.

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一种人类共生致病真菌通过靶向 TBK1 抑制宿主免疫力
白色念珠菌在人体内稳定定植,但却是医院获得性真菌病的主要病因。传统上,掩盖免疫原性分子被视为一种免疫逃避策略。在这里,我们证明白僵菌通过将效应蛋白 Cmi1 转运到宿主细胞中来阻断 I 型干扰素(IFN-I)信号传导。从机理上讲,Cmi1能结合并抑制TANK结合激酶1(TBK1),从而抑制IFN调节因子3(IRF3)的磷酸化,从而抑制IFN-I级联反应。小鼠感染 cmi1 突变体后,肾脏和骨髓衍生巨噬细胞中的 IFN-I 反应都会加剧,从而导致真菌快速清除和宿主存活。值得注意的是,缺乏 CMI1 会影响肠道共生,并增加小鼠结肠细胞中的 IFN-I 反应。IFN-I 受体的缺失可挽救 cmi1 的这些表型。这项研究确定了 TBK1 抑制在真菌致病过程中的重要性,并揭示了一种人类共生致病真菌在肠道定植和感染过程中通过向宿主细胞输送效应蛋白对宿主免疫产生了重大影响。
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来源期刊
Cell host & microbe
Cell host & microbe 生物-微生物学
CiteScore
45.10
自引率
1.70%
发文量
201
审稿时长
4-8 weeks
期刊介绍: Cell Host & Microbe is a scientific journal that was launched in March 2007. The journal aims to provide a platform for scientists to exchange ideas and concepts related to the study of microbes and their interaction with host organisms at a molecular, cellular, and immune level. It publishes novel findings on a wide range of microorganisms including bacteria, fungi, parasites, and viruses. The journal focuses on the interface between the microbe and its host, whether the host is a vertebrate, invertebrate, or plant, and whether the microbe is pathogenic, non-pathogenic, or commensal. The integrated study of microbes and their interactions with each other, their host, and the cellular environment they inhabit is a unifying theme of the journal. The published work in Cell Host & Microbe is expected to be of exceptional significance within its field and also of interest to researchers in other areas. In addition to primary research articles, the journal features expert analysis, commentary, and reviews on current topics of interest in the field.
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