He Xiaolong, Shi Xiaolu, Puthiyakunnon Santhosh, Zhang Like, Zeng Qing, Li Yan, Boddu Swapna, Qiu Jiawen, Lai Zhihao, Ma Chao, Xie Yulong, Long Min, Du Lei, Huang Sheng-He, Cao Hong
Department of Microbiology, Guangdong Provincial Key Laboratory of Tropical Disease Research, School of Public Health and Tropical Medicine, Southern Medical University, Guangzhou, 510515, China.
The Second School of Clinical Medicine, Southern Medical University, Guangzhou, 510515, China.
J Biomed Sci. 2016 Feb 20;23:28. doi: 10.1186/s12929-016-0247-2.
Cryptococcus neoformans (Cn) is an important opportunistic pathogen in the immunocompromised people, including AIDS patients, which leads to fatal cryptococcal meningitis with high mortality rate. Previous researches have shown that HIV-1 gp41-I90 ectodomain can enhance Cn adhesion to and invasion of brain microvascular endothelial cell (BMEC), which constitutes the blood brain barrier (BBB). However, little is known about the role of HIV-1 gp41-I90 in the monocyte transmigration across Cn-infected BBB. In the present study, we provide evidence that HIV-1 gp41-I90 and Cn synergistically enhance monocytes transmigration across the BBB in vitro and in vivo. The underlying mechanisms for this phenomenon require further study.
In this study, the enhancing role of HIV-1 gp41-I90 in monocyte transmigration across Cn-infected BBB was demonstrated by performed transmigration assays in vitro and in vivo.
Our results showed that the transmigration rate of monocytes are positively associated with Cn and/or HIV-1 gp41-I90, the co-exposure (HIV-1 gp41-I90 + Cn) group showed a higher THP-1 transmigration rate (P < 0.01). Using CD44 knock-down HBMEC or CD44 inhibitor Bikunin in the assay, the facilitation of transmigration rates of monocyte enhanced by HIV-1 gp41-I90 was significantly suppressed. Western blotting analysis and biotin/avidin enzyme-linked immunosorbent assays (BA-ELISAs) showed that Cn and HIV-1 gp41-I90 could increase the expression of CD44 and ICAM-1 on the HBMEC. Moreover, Cn and/or HIV-1 gp41-I90 could also induce CD44 redistribution to the membrane lipid rafts. By establishing the mouse cryptococcal meningitis model, we found that HIV-1 gp41-I90 and Cn could synergistically enhance the monocytes transmigration, increase the BBB permeability and injury in vivo.
Collectively, our findings suggested that HIV-1 gp41-I90 ectodomain can enhance the transmigration of THP-1 through Cn-infected BBB, which may be mediated by CD44. This novel study enlightens the future prospects to elaborate the inflammatory responses induced by HIV-1 gp41-I90 ectodomain and to effectively eliminate the opportunistic infections in AIDS patients.
新型隐球菌（Cn）是免疫功能低下人群（包括艾滋病患者）中的一种重要机会性病原体，可导致致命的隐球菌性脑膜炎，死亡率很高。先前的研究表明，HIV-1 gp41-I90胞外域可增强Cn对脑微血管内皮细胞（BMEC）的黏附和侵袭，而BMEC构成了血脑屏障（BBB）。然而，关于HIV-1 gp41-I90在单核细胞穿越受Cn感染的BBB迁移中的作用知之甚少。在本研究中，我们提供证据表明，HIV-1 gp41-I90和Cn在体外和体内协同增强单核细胞穿越BBB的迁移。这种现象的潜在机制需要进一步研究。
在本研究中，通过体外和体内迁移试验证明了HIV-1 gp41-I90在单核细胞穿越受Cn感染的BBB迁移中的增强作用。
我们的结果表明，单核细胞的迁移率与Cn和/或HIV-1 gp41-I90呈正相关，共同暴露（HIV-1 gp41-I90 + Cn）组显示THP-1迁移率更高（P < 0.01）。在试验中使用CD44敲低的HBMEC或CD44抑制剂比库宁，HIV-1 gp41-I90增强的单核细胞迁移率的促进作用被显著抑制。蛋白质印迹分析和生物素/抗生物素蛋白酶联免疫吸附测定（BA-ELISA）表明，Cn和HIV-1 gp41-I90可增加HBMEC上CD44和ICAM-1的表达。此外，Cn和/或HIV-1 gp41-I90还可诱导CD44重新分布到膜脂筏。通过建立小鼠隐球菌性脑膜炎模型，我们发现HIV-1 gp41-I90和Cn可协同增强单核细胞迁移，增加体内BBB通透性和损伤。
总体而言，我们的研究结果表明，HIV-1 gp41-I90胞外域可增强THP-1通过受Cn感染的BBB的迁移，这可能由CD44介导。这项新研究为阐明HIV-1 gp41-I90胞外域诱导的炎症反应以及有效消除艾滋病患者的机会性感染开辟了未来前景。
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