High-Throughput Screening Identifies Genes Required for Candida albicans Induction of Macrophage Pyroptosis.
High-Throughput Screening Identifies Genes Required for Candida albicans Induction of Macrophage Pyroptosis.
复制标题
DOI：
10.1128/mbio.01581-18
复制
发表时间：
2018-08-21
期刊：
影响因子：
6.4
通讯作者：
Cowen LE
中科院分区：
文献类型：
--
作者：
O'Meara TR;Duah K;Guo CX;Maxson ME;Gaudet RG;Koselny K;Wellington M;Powers ME;MacAlpine J;O'Meara MJ;Veri AO;Grinstein S;Noble SM;Krysan D;Gray-Owen SD;Cowen LE
先天免疫系统是抵御侵袭性真菌感染的第一道防线。因此，许多成功的真菌病原体已经进化出与宿主免疫细胞相互作用的优雅策略。例如，白色念珠菌在被巨噬细胞吞噬后，经历了一个形态发生开关，与细胞壁重塑耦合，然后诱导巨噬细胞焦亡，这是一种炎症细胞死亡程序。为了阐明白色念珠菌协调宿主反应的遗传回路，我们首次对白色念珠菌与哺乳动物免疫细胞的相互作用进行了大规模分析。我们鉴定了98个白色念珠菌基因，这些基因能够在不影响巨噬细胞真菌细胞形态的情况下使巨噬细胞热亡，包括细胞壁生物发生和Hog1信号级联的特定决定因素。利用这些突变基因，我们发现在感染过程中焦亡激活缺陷影响免疫细胞募集。在检查白色念珠菌感染引起热亡所需的宿主电路时，我们发现炎性体的启动和激活可以解耦。最后，我们观察到含有CARD （ASC）寡聚化的凋亡相关斑点样蛋白可以在白色念珠菌菌丝吞噬溶酶体破裂之前发生，这表明吞噬溶酶体破裂不是炎性体的激活信号。综合这些数据，本研究确定了使真菌细胞壁重塑和巨噬细胞热亡激活独立于形态发生影响的基因，并确定了白色念珠菌感染时热亡所需的巨噬细胞信号成分。白色念珠菌是人类粘膜微生物群的天然成员，也可引起浅表感染和危及生命的全身感染，这两种感染都以炎症为特征。宿主防御主要依靠先天免疫细胞（如巨噬细胞和中性粒细胞）对白色念珠菌的摄取和破坏。虽然一些白色念珠菌细胞被巨噬细胞杀死，但大多数细胞会发生形态改变，并通过诱导巨噬细胞热亡而逃逸。在这里，我们研究了白色念珠菌基因和宿主因子在细胞内真菌的作用下促进巨噬细胞热亡。这项工作为了解宿主免疫细胞如何与白色念珠菌相互作用提供了基础，并可能导致调节真菌感染引起的炎症的有效策略。
The innate immune system is the first line of defense against invasive fungal infections. As a consequence, many successful fungal pathogens have evolved elegant strategies to interact with host immune cells. For example, Candida albicans undergoes a morphogenetic switch coupled to cell wall remodeling upon phagocytosis by macrophages and then induces macrophage pyroptosis, an inflammatory cell death program. To elucidate the genetic circuitry through which C. albicans orchestrates this host response, we performed the first large-scale analysis of C. albicans interactions with mammalian immune cells. We identified 98 C. albicans genes that enable macrophage pyroptosis without influencing fungal cell morphology in the macrophage, including specific determinants of cell wall biogenesis and the Hog1 signaling cascade. Using these mutated genes, we discovered that defects in the activation of pyroptosis affect immune cell recruitment during infection. Examining host circuitry required for pyroptosis in response to C. albicans infection, we discovered that inflammasome priming and activation can be decoupled. Finally, we observed that apoptosis-associated speck-like protein containing a CARD (ASC) oligomerization can occur prior to phagolysosomal rupture by C. albicans hyphae, demonstrating that phagolysosomal rupture is not the inflammasome activating signal. Taking the data together, this work defines genes that enable fungal cell wall remodeling and activation of macrophage pyroptosis independently of effects on morphogenesis and identifies macrophage signaling components that are required for pyroptosis in response to C. albicans infection. Candida albicans is a natural member of the human mucosal microbiota that can also cause superficial infections and life-threatening systemic infections, both of which are characterized by inflammation. Host defense relies mainly on the ingestion and destruction of C. albicans by innate immune cells, such as macrophages and neutrophils. Although some C. albicans cells are killed by macrophages, most undergo a morphological change and escape by inducing macrophage pyroptosis. Here, we investigated the C. albicans genes and host factors that promote macrophage pyroptosis in response to intracellular fungi. This work provides a foundation for understanding how host immune cells interact with C. albicans and may lead to effective strategies to modulate inflammation induced by fungal infections.