N-Acetylglucosamine Metabolism Promotes Survival of Candida albicans in the Phagosome.
N-Acetylglucosamine Metabolism Promotes Survival of Candida albicans in the Phagosome.
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DOI：
10.1128/msphere.00357-17
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发表时间：
2017-09
期刊：
影响因子：
4.8
通讯作者：
Lorenz MC
中科院分区：
文献类型：
--
作者：
Vesely EM;Williams RB;Konopka JB;Lorenz MC
白色念珠菌是最重要的医学相关真菌病原体，播散性念珠菌病是第四大常见的医院相关血流感染。巨噬细胞和中性粒细胞是先天性免疫细胞，通过吞噬和破坏白色念珠菌细胞在宿主防御中发挥关键作用。为了在巨噬细胞的攻击中存活下来，白色念珠菌通过利用吞噬体中可用的替代碳源来产生能量。有趣的是，白色念珠菌对氨基酸和羧酸的代谢提高了吞噬体的pH值，从而阻断了吞噬体的酸化，这是启动抗微生物攻击所必需的。在这项工作中，我们证明，代谢的第三种类型的碳源，氨基糖GlcNAc，也诱导pH值中和和生存的白色念珠菌吞噬。这种机制在遗传和生理上不同于先前描述的pH中和机制，表明白色念珠菌的强大代谢可塑性确保了巨噬细胞吞噬作用后的存活。先天性免疫细胞的吞噬作用是哺乳动物宿主内抵抗微生物增殖和传播的最有效屏障之一。白色念珠菌是一种致病酵母，具有强大的机制，可以在巨噬细胞吞噬作用下存活。白色念珠菌存活的部分原因是它可以利用吞噬体中可用的替代碳源，包括羧酸和氨基酸。此外，这些化合物的代谢提高了细胞外环境的pH，这对抗了吞噬溶酶体的酸化和成熟。在这项研究中，我们证明了白色念珠菌的代谢的额外的碳源，N-乙酰葡糖胺（GlcNAc），有利于中和的吞噬体的一种新的机制。GlcNAc的催化作用通过释放氨而升高环境pH，这与羧酸上的生长不同，但与氨基酸上的生长相似。然而，GlcNAc代谢对pH的影响在遗传上不同于氨基酸催化剂诱导的中和，因为STP 2或ATO 5的突变不损害GlcNAc的作用。与此相反，突变体缺乏专用的GlcNAc转运基因NGT 1或负责catenylation的GlcNAc的酶是有缺陷的，在改变吞噬体的pH值。这与吞噬作用后存活率降低和损伤巨噬细胞的能力降低相关。因此，GlcNAc代谢代表白色念珠菌用于对抗吞噬溶酶体的快速酸化的第三种遗传独立机制，从而允许细胞逃逸并传播感染。重要性白色念珠菌是最重要的医学相关的真菌病原体，与播散性念珠菌病是第四个最常见的医院相关的血流感染。巨噬细胞和中性粒细胞是先天性免疫细胞，通过吞噬和破坏白色念珠菌细胞在宿主防御中发挥关键作用。为了在巨噬细胞的攻击中存活下来，白色念珠菌通过利用吞噬体中可用的替代碳源来产生能量。有趣的是，白色念珠菌对氨基酸和羧酸的代谢提高了吞噬体的pH值，从而阻断了吞噬体的酸化，这是启动抗微生物攻击所必需的。在这项工作中，我们证明，代谢的第三种类型的碳源，氨基糖GlcNAc，也诱导pH值中和和生存的白色念珠菌吞噬。这种机制在遗传和生理上不同于先前描述的pH中和机制，表明白色念珠菌的强大代谢可塑性确保了巨噬细胞吞噬作用后的存活。
Candida albicans is the most important medically relevant fungal pathogen, with disseminated candidiasis being the fourth most common hospital-associated bloodstream infection. Macrophages and neutrophils are innate immune cells that play a key role in host defense by phagocytosing and destroying C. albicans cells. To survive this attack by macrophages, C. albicans generates energy by utilizing alternative carbon sources that are available in the phagosome. Interestingly, metabolism of amino acids and carboxylic acids by C. albicans raises the pH of the phagosome and thereby blocks the acidification of the phagosome, which is needed to initiate antimicrobial attack. In this work, we demonstrate that metabolism of a third type of carbon source, the amino sugar GlcNAc, also induces pH neutralization and survival of C. albicans upon phagocytosis. This mechanism is genetically and physiologically distinct from the previously described mechanisms of pH neutralization, indicating that the robust metabolic plasticity of C. albicans ensures survival upon macrophage phagocytosis. Phagocytosis by innate immune cells is one of the most effective barriers against the multiplication and dissemination of microbes within the mammalian host. Candida albicans, a pathogenic yeast, has robust mechanisms that allow survival upon macrophage phagocytosis. C. albicans survives in part because it can utilize the alternative carbon sources available in the phagosome, including carboxylic acids and amino acids. Furthermore, metabolism of these compounds raises the pH of the extracellular environment, which combats the acidification and maturation of the phagolysosome. In this study, we demonstrate that metabolism by C. albicans of an additional carbon source, N-acetylglucosamine (GlcNAc), facilitates neutralization of the phagosome by a novel mechanism. Catabolism of GlcNAc raised the ambient pH through release of ammonia, which is distinct from growth on carboxylic acids but similar to growth on amino acids. However, the effect of GlcNAc metabolism on pH was genetically distinct from the neutralization induced by catabolism of amino acids, as mutation of STP2 or ATO5 did not impair the effects of GlcNAc. In contrast, mutants lacking the dedicated GlcNAc transporter gene NGT1 or the enzymes responsible for catabolism of GlcNAc were defective in altering the pH of the phagosome. This correlated with reduced survival following phagocytosis and decreased ability to damage macrophages. Thus, GlcNAc metabolism represents the third genetically independent mechanism that C. albicans utilizes to combat the rapid acidification of the phagolysosome, allowing for cells to escape and propagate infection. IMPORTANCE Candida albicans is the most important medically relevant fungal pathogen, with disseminated candidiasis being the fourth most common hospital-associated bloodstream infection. Macrophages and neutrophils are innate immune cells that play a key role in host defense by phagocytosing and destroying C. albicans cells. To survive this attack by macrophages, C. albicans generates energy by utilizing alternative carbon sources that are available in the phagosome. Interestingly, metabolism of amino acids and carboxylic acids by C. albicans raises the pH of the phagosome and thereby blocks the acidification of the phagosome, which is needed to initiate antimicrobial attack. In this work, we demonstrate that metabolism of a third type of carbon source, the amino sugar GlcNAc, also induces pH neutralization and survival of C. albicans upon phagocytosis. This mechanism is genetically and physiologically distinct from the previously described mechanisms of pH neutralization, indicating that the robust metabolic plasticity of C. albicans ensures survival upon macrophage phagocytosis.