Survival in macrophages induces enhanced virulence in Cryptococcus.
Survival in macrophages induces enhanced virulence in Cryptococcus.
复制标题
巨噬细胞中的存活诱导隐球菌中增强的毒力。
作者：
隐球菌是一种普遍存在的环境真菌，经常在人体肺部定植。定植可导致多种结果，从清除到长期定植到危及生命的脑膜脑炎。不管结果如何，这个过程始于与吞噬细胞的相遇。使用斑马鱼感染模型，我们注意到隐球菌细胞在具有致病性复制和传播能力之前首先在巨噬细胞内度过一段时间。在初次接触中发生了什么“许可”过程？获得许可的隐球菌细胞有何不同？为了解决这一问题，我们分离了被培养的巨噬细胞吞噬后的隐球菌细胞，发现这些巨噬细胞在斑马鱼和小鼠模型中都具有更强的毒性。尽管产生了较厚的多糖胶囊，但它们仍然受到斑马鱼巨噬细胞的吞噬。对这些获得许可的细胞中抗原细胞壁成分的分析表明，甘露糖和几丁质成分比在培养细胞或体外诱导的胶囊生产细胞中更容易用于染色。隐球菌在体外能够在巨噬细胞之间存在或转移，这增加了这种真菌在肺部生长过程中在细胞内和细胞外生活之间交替的可能性。我们的研究结果提高了细胞内生命随着时间的推移有其优势的可能性，并且吞噬诱导的甘露糖和几丁质暴露的改变是使后续几轮吞噬对真菌更有益的一种方式。隐球菌病始于肺部，最终可以通过血液传播，导致中枢神经系统的毁灭性感染。在斑马鱼模型中，少量接种到血液中的隐球菌最初被吞噬，在它们离开巨噬细胞后变得更有能力传播。同样，小鼠肺中的存活产生隐球菌细胞类型，传播增强。在这项研究中，我们评估了吞噬作用如何改变隐球菌在发病过程中的性质。巨噬细胞（MECs）获得增强毒力的“许可”。它们在鱼体内的传播速度超过了培养的细胞，在小鼠肺部的竞争也超过了非mec细胞。对其细胞表面的分析表明，mec具有增加细胞壁成分甘露糖和几丁质物质的可用性，这些物质参与引发吞噬作用。这些发现提示隐球菌如何调整其细胞表面诱导并存活于肺早期发病过程中的反复吞噬。
Cryptococcus is a ubiquitous environmental fungus and frequent colonizer of human lungs. Colonization can lead to diverse outcomes, from clearance to long-term colonization to life-threatening meningoencephalitis. Regardless of the outcome, the process starts with an encounter with phagocytes. Using the zebrafish model of this infection, we have noted that cryptococcal cells first spend time inside macrophages before they become capable of pathogenic replication and dissemination. What “licensing” process takes place during this initial encounter, and how are licensed cryptococcal cells different? To address this, we isolated cryptococcal cells after phagocytosis by cultured macrophages and found these macrophage-experienced cells to be markedly more virulent in both zebrafish and mouse models. Despite producing a thick polysaccharide capsule, they were still subject to phagocytosis by macrophages in the zebrafish. Analysis of antigenic cell wall components in these licensed cells demonstrated that components of mannose and chitin are more available for staining than they are in culture-grown cells or cells with capsule production induced in vitro. Cryptococcus is capable of exiting or transferring between macrophages in vitro, raising the likelihood that this fungus alternates between intracellular and extracellular life during growth in the lungs. Our results raise the possibility that intracellular life has its advantages over time, and phagocytosis-induced alteration in mannose and chitin exposure is one way that makes subsequent rounds of phagocytosis more beneficial to the fungus. Cryptococcosis begins in the lungs and can ultimately travel through the bloodstream to cause devastating infection in the central nervous system. In the zebrafish model, small amounts of cryptococcus inoculated into the bloodstream are initially phagocytosed and become far more capable of dissemination after they exit macrophages. Similarly, survival in the mouse lung produces cryptococcal cell types with enhanced dissemination. In this study, we have evaluated how phagocytosis changes the properties of Cryptococcus during pathogenesis. Macrophage-experienced cells (MECs) become “licensed” for enhanced virulence. They out-disseminate culture-grown cells in the fish and out-compete non-MECs in the mouse lung. Analysis of their cell surface demonstrates that MECs have increased availability of cell wall components mannose and chitin substances involved in provoking phagocytosis. These findings suggest how Cryptococcus might tune its cell surface to induce but survive repeated phagocytosis during early pathogenesis in the lung.
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影响因子：
4.6
作者：
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通讯作者：
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影响因子：
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DOI：
10.1084/jem.20100793
发表时间：
2011-03-14
期刊：
The Journal of experimental medicine
影响因子：
--
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影响因子：
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作者：
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影响因子：
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