Integrin-mediated signal transduction in brain endothelial cells during infection with N. meningitidis: mechanisms of crossing the blood-brain barrier

脑膜炎奈瑟氏菌在鼻咽定植，在穿过血脑屏障引起脑膜炎之前，可以从鼻咽播撒血液。我们发现脑膜炎奈瑟氏菌可诱导基质金属蛋白酶-8的释放，而基质金属蛋白酶-8在紧密连接(TJ)组分封闭蛋白的分解和细胞黏附的丧失中起着至关重要的作用。本研究旨在探讨脑膜炎奈瑟氏菌感染对脑血管内皮细胞基质金属蛋白酶-8表达及调控的影响。将分析细菌因素对细胞黏附和封闭切割丧失的具体影响，以及不同处理(地塞米松、化学修饰的四环素)对细胞单层的调节/保护。此外，在黏附的早期阶段观察到了表皮生长因子受体(EGFR)的激活，这是一种跨膜受体激酶。项目的第二部分旨在分析EGFR在脑膜炎奈瑟菌黏附/侵袭过程中的作用。应确定与EGFR结合的细菌因子以及EGFR介导的细胞信号事件，并特别关注EGFR/整合素串扰。

Neisseria meningitidis colonizes the nasopharynx, from which it can seed the bloodstream before crossing the blood-brain barrier to cause meningitis. We showed that N. meningitidis induces the release of the matrix metalloproteinase (MMP)-8, that plays a crucial role in disassembly of the tight junction (TJ) component occludin and loss of cell adhesion. The proposed project aims to investigate the expression and regulation of MMP-8 in brain endothelial cells in response to N. meningitidis infection. The specific effect of bacterial factors on loss of cell adhesion and occludin cleavage will be analysed as well as the regulation/protection of cell monolayers by different treatments (dexamethason, chemically modified tetracyclines). Furthermore, activation of the epidermal growth factor receptor (EGFR), a transmembrane receptor kinase, during the early step of adhesion was observed. The second part of the projects aims to analyse the role of EGFR in adhesion/invasion process of N. meningitidis. Bacterial factors that bind to EGFR shall be identified as well as EGFR-mediated cell signalling events with specific focus on the EGFR/integrin crosstalk.