State Key Laboratory of Agricultural Microbiology, College of Veterinary Medicine, Huazhong Agricultural University, Wuhan, China.
Key Laboratory of Preventive Veterinary Medicine in Hubei Province, The Cooperative Innovation Center for Sustainable Pig Production, Wuhan, China.
Front Cell Infect Microbiol. 2019 Jan 9;8:448. doi: 10.3389/fcimb.2018.00448. eCollection 2018.
Bacterial penetration of the blood-brain barrier requires its successful invasion of brain microvascular endothelial cells (BMECs), and host actin cytoskeleton rearrangement in these cells is a key prerequisite for this process. We have reported previously that meningitic can induce the activation of host's epidermal growth factor receptor (EGFR) to facilitate its invasion of BMECs. However, it is unknown how EGFR specifically functions during this invasion process. Here, we identified an important EGFR-interacting protein, α-actinin-4 (ACTN4), which is involved in maintaining and regulating the actin cytoskeleton. We observed that transactivated-EGFR competitively recruited ACTN4 from intracellular F-actin fibers to disrupt the cytoskeleton, thus facilitating bacterial invasion of BMECs. Strikingly, this mechanism operated not only for meningitic , but also for infections with , a Gram-positive meningitis-causing bacterial pathogen, thus revealing a common mechanism hijacked by these meningitic pathogens where EGFR competitively recruits ACTN4. Ever rising levels of antibiotic-resistant bacteria and the emergence of their extended-spectrum antimicrobial-resistant counterparts remind us that EGFR could act as an alternative non-antibiotic target to better prevent and control bacterial meningitis.
细菌穿透血脑屏障需要成功入侵脑微血管内皮细胞（BMEC），而宿主细胞中的肌动蛋白细胞骨架重排是这一过程的关键前提。我们之前曾报道过，脑膜炎奈瑟菌可以激活宿主的表皮生长因子受体（EGFR），从而促进其入侵 BMEC。然而，EGFR 在这一入侵过程中是如何特异性发挥作用的尚不清楚。在这里，我们鉴定了一个重要的 EGFR 相互作用蛋白，α-辅肌动蛋白-4（ACTN4），它参与维持和调节肌动蛋白细胞骨架。我们观察到，转激活的 EGFR 从细胞内 F-肌动蛋白纤维中竞争募集 ACTN4，破坏细胞骨架，从而促进细菌入侵 BMEC。引人注目的是，这种机制不仅对脑膜炎奈瑟菌有效，而且对革兰氏阳性脑膜炎致病菌 也有效，从而揭示了这些脑膜炎病原体劫持的一种共同机制，即 EGFR 竞争性募集 ACTN4。不断上升的抗生素耐药菌水平以及它们的广谱抗菌耐药性对应物的出现提醒我们，EGFR 可以作为一种替代非抗生素靶点，以更好地预防和控制细菌性脑膜炎。
