Roles for Microglia in Cryptococcal Brain Dissemination in the Zebrafish Larva.
Roles for Microglia in Cryptococcal Brain Dissemination in the Zebrafish Larva.
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DOI：
10.1128/spectrum.04315-22
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发表时间：
2023-01-31
影响因子：
3.7
通讯作者：
中科院分区：
文献类型：
--
作者：
隐球菌感染始于肺部，但酵母细胞随后进入血液，从血液进入中枢神经系统。由此产生的脑膜脑炎是最常见的表现，而且很难治疗。这种真菌如何与血脑屏障（BBB）相互作用并在脑实质中建立生长仍然是真菌发病机制的核心问题。我们和其他人已经开发了斑马鱼幼虫作为隐球菌病的模型宿主，并证明在该模型中可以复制血行性中枢神经系统感染。在这里，我们使用这个模型来检查血脑屏障交叉的细节以及前后立即发生的事件。我们观察了血脑屏障穿越的多种机制，发现小胶质细胞作为大脑的常驻吞噬细胞，可能具有多种作用。首先，小胶质细胞要么积极地将酵母细胞转移过血脑屏障，要么在跨越血脑屏障后立即占据相当大的比例。其次，在适应性免疫细胞出现之前，小胶质细胞能够在发育阶段清除单个隐球菌细胞。第三，小胶质细胞的作用是维持内皮细胞的完整性，防止其他不依赖吞噬细胞的交叉形式。这些提出的小胶质细胞在斑马鱼幼虫感染期间的功能产生了关于隐球菌性脑膜脑炎的建立和控制的新假设。隐球菌性脑膜炎是一种脑部真菌感染，是HIV感染者死亡的主要原因。感染始于肺部，但可以进入血液并传播到大脑。真菌必须穿过一种叫做血脑屏障的结构才能进入并引起脑膜炎。了解隐球菌如何穿过血脑屏障对于理解和预防脑部感染至关重要。使用斑马鱼幼虫作为模型宿主，我们发现小胶质细胞，大脑的常驻吞噬细胞，可能在大脑隐球菌感染中发挥多种先前未被认识到的作用。这些作用包括加强血脑屏障的完整性，在隐球菌细胞交叉后清除隐球菌细胞，并可能通过一种以前未知的机制直接参与交叉。
Cryptococcal infection begins in the lungs, but yeast cells subsequently access the bloodstream, from which they can reach the central nervous system (CNS). The resulting meningoencephalitis is the most common presentation and is very difficult to treat. How this fungus interacts with the blood-brain barrier (BBB) and establishes growth in the brain parenchyma remains a central question in fungal pathogenesis. We and others have developed the zebrafish larva as a model host for cryptococcosis and demonstrated that hematogenous CNS infection is replicated in this model. Here, we have used this model to examine the details of BBB crossing and the events immediately before and after. We have observed multiple mechanisms of BBB crossing and found that microglia, the resident phagocytes of the brain, likely have multiple roles. First, microglia either actively transfer yeast cells across the BBB or take up a significant proportion of them immediately after crossing. Second, microglia are capable of clearing individual cryptococcal cells at a developmental stage before adaptive immune cells have emerged. Third, microglia serve to maintain endothelial integrity, preventing other, phagocyte-independent forms of crossing. These proposed microglial functions during infection in the zebrafish larva generate new hypotheses concerning the establishment and control of cryptococcal meningoencephalitis. IMPORTANCE Cryptococcal meningitis is a fungal infection of the brain and a major cause of death in people with uncontrolled HIV. Infection begins in the lungs but can enter the bloodstream and disseminate to the brain. A structure called the blood-brain barrier must be crossed for the fungus to enter and cause meningitis. Learning how Cryptococcus crosses the blood-brain barrier will be crucial to understanding and possibly preventing brain infection. Using the zebrafish larva as a model host, we show that microglia, the resident phagocytes of the brain, potentially play multiple previously unappreciated roles in cryptococcal infection of the brain. These roles include reinforcing the integrity of the blood-brain barrier, clearing cryptococcal cells after they have crossed, and possibly participating directly in crossing via a previously unknown mechanism.
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