Microglia protect fungi against copper starvation and promote brain infection
Microglia protect fungi against copper starvation and promote brain infection
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DOI：
10.1101/2022.09.07.506901
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发表时间：
2022-09
期刊：
影响因子：
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通讯作者：
Sally H. Mohamed;M. Fu;Sofia Hain;Alanoud Alselami;E. Vanhoffelen;Yanjian Li;E. Bojang;R. Lukande-R.
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文献类型：
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作者：
Sally H. Mohamed;M. Fu;Sofia Hain;Alanoud Alselami;E. Vanhoffelen;Yanjian Li;E. Bojang;R. Lukande-R.
小胶质细胞提供了对一系列脑感染的保护，但这些胶质细胞如何对真菌做出反应却知之甚少。我们研究了小胶质细胞在隐球菌脑膜炎中的作用，隐球菌脑膜炎是人类真菌性脑感染的最常见原因。使用一系列基于转基因和化学的小胶质细胞耗竭方法，我们发现，与其他感染期间的保护作用相反，小胶质细胞支持隐球菌真菌脑感染。我们表明，小胶质细胞成为细胞内真菌生长的宿主，并且是真菌获得限制性微量营养素铜的位点。我们开发了一种报告真菌菌株来跟踪真菌的铜饥饿反应，发现酵母在小胶质细胞内受到铜饥饿的保护。最后，我们表明，用IFNγ刺激小胶质细胞会导致吞噬体铜对细胞内真菌的限制。这些数据为为什么小胶质细胞耗竭在这种危及生命的真菌感染的背景下具有治疗效果提供了机制解释，并且是小胶质细胞促进感染的少数例子之一。我们的数据表明，组织驻留的吞噬细胞可以支持隐球菌感染作为细胞内水库和微生物营养获取的网站，以及这些机制可能被IFNγ免疫治疗阻断。
Microglia provide protection against a range of brain infections, but how these glial cells respond to fungi is poorly understood. We investigated the role of microglia in the context of cryptococcal meningitis, the most common cause of fungal brain infections in humans. Using a series of transgenic- and chemical-based microglia depletion methods we found that, contrary to their protective role during other infections, microglia supported cryptococcal fungal brain infection. We show that microglia become hosts for intracellular fungal growth and are a site in which the fungus accesses the restricted micronutrient copper. We developed a reporter fungal strain to track copper starvation responses by the fungus and found that yeast were protected from copper starvation within microglia. Lastly, we show that stimulation of microglia with IFNγ causes restriction of phagosomal copper to intracellular fungi. These data provide a mechanistic explanation for why microglia depletion has a therapeutic effect in the context of this life-threatening fungal infection and is one of the few examples of microglia acting to promote infection. Our data demonstrate how tissue-resident phagocytes can support cryptococcal infections by acting as intracellular reservoirs and sites of microbial nutrient acquisition, and how these mechanisms may be blocked by IFNγ immunotherapy.