Evidence of a Role for Monocytes in Dissemination and Brain Invasion by Cryptococcus neoformans
Evidence of a Role for Monocytes in Dissemination and Brain Invasion by Cryptococcus neoformans
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DOI：
10.1128/iai.01065-08
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发表时间：
2009-01-01
影响因子：
3.1
通讯作者：
Dromer, Francoise
中科院分区：
文献类型：
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作者：
Charlier, Caroline;Nielsen, Kirsten;Dromer, Francoise
隐球菌病的发病机制，包括导致脑膜脑炎的事件，在很大程度上仍然是未知的。存在新生隐球菌跨细胞通过血脑屏障（BBB）和随后的BBB破坏的证据，但游离酵母的细胞旁通过和单核细胞在酵母传播和脑侵袭（特洛伊木马方法）中的作用仍然不确定。我们使用我们的模型播散性隐球菌病，其中跨越血脑屏障开始6小时后静脉接种，研究血脑屏障的细胞旁通道。我们制备了体外感染C.新生酵母（BMDM酵母）和游离酵母，并测量组织中的真菌负荷。(i)BMDM酵母菌处理1和24 h后，小鼠脾和肺的CFU比游离酵母菌处理组高2倍以上（P < 0.05），而脑的CFU仅在24 h时增加了3.9倍（P < 0.05）。(ii)通过比较幼稚小鼠和预先建立的隐球菌病小鼠的脑侵袭动力学，我们发现，在后一种情况下，CFU较低，除了在6小时，当CFU从接种BMDM酵母菌的小鼠与幼稚小鼠和2.5倍高于预先建立的隐球菌病的小鼠接种游离酵母菌。(iii)通过氯膦酸盐注射获得的晚期吞噬细胞耗竭降低了疾病的严重程度，并在所有研究器官中降低了40%的真菌负荷。这些结果为C.新生菌，以及涉及游离酵母菌的机制，以及吞噬细胞在真菌传播中的作用。
The pathogenesis of cryptococcosis, including the events leading to the production of meningoencephalitis, is still largely unknown. Evidence of a transcellular passage of Cryptococcus neoformans across the blood-brain barrier (BBB) and subsequent BBB disruption exists, but the paracellular passage of free yeasts and the role of monocytes in yeast dissemination and brain invasion (Trojan horse method) remain uncertain. We used our model of disseminated cryptococcosis, in which crossing of the BBB starts 6 h after intravenous inoculation, to study paracellular passage of the BBB. We prepared bone marrow-derived monocytes (BMDM) infected in vitro with C. neoformans (BMDM yeasts) and free yeasts and measured fungal loads in tissues. (i) Spleen and lung CFU were > 2-fold higher in mice treated with BMDM yeasts than in those treated with free yeasts for 1 and 24 h (P < 0.05), while brain CFU were increased (3.9 times) only at 24 h (P < 0.05). (ii) By comparing the kinetics of brain invasion in naive mice and in mice with preestablished cryptococcosis, we found that CFU were lower in the latter case, except at 6 h, when CFU from mice inoculated with BMDM yeasts were comparable to those measured in naive mice and 2.5-fold higher than those in mice with preestablished cryptococcosis who were inoculated with free yeasts. (iii) Late phagocyte depletion obtained by clodronate injection reduced disease severity and lowered the fungal burden by 40% in all organs studied. These results provide evidence for Trojan horse crossing of the BBB by C. neoformans, together with mechanisms involving free yeasts, and overall for a role of phagocytes in fungal dissemination.