The blood-brain barrier internalises Cryptococcus neoformans via the EphA2-tyrosine kinase receptor.
The blood-brain barrier internalises Cryptococcus neoformans via the EphA2-tyrosine kinase receptor.
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DOI：
10.1111/cmi.12811
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发表时间：
2018-03
影响因子：
3.4
通讯作者：
Gelli A
中科院分区：
文献类型：
--
作者：
Aaron PA;Jamklang M;Uhrig JP;Gelli A
新型隐球菌是一种机会性真菌病原体，在免疫力受损的人群中最常见，可导致危及生命的脑膜炎。在这里，我们解析了用C. neoformans以确定C.新生儿通过选择特定的信号传导途径作为促进其自身进入的手段来侵入CNS。在C.为了进一步研究EPH-EphrinA 1（EphA 2）酪氨酸激酶受体信号传导途径，在人脑内皮细胞系中沉默EphA 2受体转录物或用抗体或化学抑制剂阻断EphA 2活性可阻止C.在BBB的体外模型中的新生儿。相比之下，用EphA 2化学激动剂或EphA 2配体处理脑内皮细胞促进真菌细胞更大程度地迁移穿过BBB。C.新生儿通过EphA 2的CD 44依赖性磷酸化激活了EPH-酪氨酸激酶途径，促进了EphA 2受体的聚集和内化。此外，表达EphA 2的HEK 293 T细胞揭示了EphA 2与C. neoformans，促进了C.新人类这些结果表明，C.新生儿通过CD 44促进EphA 2活性，这又产生了促进C.新生儿穿过血脑屏障
Cryptococcus neoformans is an opportunistic fungal pathogen that causes life-threatening meningitis most commonly in populations with impaired immunity. Here we resolved the transcriptome of the human brain endothelium challenged with C. neoformans to establish whether C. neoformans invades the CNS by co-opting particular signaling pathways as a means to promote its own entry. Among the 5 major pathways targeted by C. neoformans, the EPH-EphrinA1 (EphA2) tyrosine kinase receptor-signaling pathway was examined further. Silencing the EphA2 receptor transcript in a human brain endothelial cell line or blocking EphA2 activity with an antibody or chemical inhibitor prevented transmigration of C. neoformans in an in vitro model of the BBB. In contrast, treating brain endothelial cells with an EphA2 chemical agonist or an EphA2 ligand promoted greater migration of fungal cells across the BBB. C. neoformans activated the EPH-tyrosine kinase pathway through a CD44-dependent phosphorylation of EphA2, promoting clustering and internalization of EphA2 receptors. Moreover, HEK293T cells expressing EphA2 revealed an association between EphA2 and C. neoformans that boosted internalization of C. neoformans. Collectively the results suggest that C. neoformans promotes EphA2 activity via CD44 and this in turn creates a permeable barrier that facilitates the migration of C. neoformans across the BBB.
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影响因子：
3.4
作者：
Jong, Ambrose;Wu, Chun-Hua;Huang, Sheng-He
通讯作者：
Huang, Sheng-He
影响因子：
4.8
作者：
Lennon, Frances E.;Mirzapoiazova, Tamara;Singleton, Patrick A.
通讯作者：
Singleton, Patrick A.
影响因子：
21.3
作者：
Carter, N;Nakamoto, T;Hunter, T
通讯作者：
Hunter, T
影响因子：
3.4
作者：
Jong, Ambrose;Wu, Chun-Hua;Huang, Sheng-He
通讯作者：
Huang, Sheng-He
影响因子：
3.1
作者：
Charlier, Caroline;Nielsen, Kirsten;Dromer, Francoise
通讯作者：
Dromer, Francoise