人循环单核细胞是寨卡病毒(ZIKV)感染的确立靶标。由于它们向任何组织的重要迁移特性,包括中枢神经系统(CNS),需要更好地了解ZIKV感染后单核细胞迁移的潜在机制.这里,我们监测了粘合力,暴露于ZIKV的单核细胞的迁移和迁移特性。我们发现,与模拟暴露的样本相比,ZIKV增强了单核细胞对胶原蛋白的粘附,并且对mDia和Cdc42功能的药理学抑制诱导了暴露于模拟和ZIKV的单核细胞中粘附的显着降低。相比之下,大多数测试的小分子靶向肌动蛋白聚合调节剂都抑制了单核细胞通过胶原蛋白的迁移,包括Rac1,ROCK,Cdc42,mDia,Arp2/3、肌球蛋白-II和LFA-1。ZIKV暴露的单核细胞迁移显示出与模拟暴露的单核细胞非常相似的特征。最后,通过人脑微血管内皮细胞(hCMEC/D3)的单核细胞迁移评估显示对Rac1,ROCK,和Cdc42,与它们的感染状态无关。相比之下,我们发现LFA-1的拮抗剂BIRT377显著抑制ZIKV暴露的单核细胞的迁移,但不抑制模拟暴露的单核细胞的迁移.随着BIRT377增加ZIKV暴露的单核细胞的粘附,我们认为LFA-1可能参与粘附后步骤以增强病毒诱导的迁移。这些数据表明ZIKV暴露会触发在生理条件下未被利用的单核细胞的特定迁移特性。这项工作提供了对病毒神经侵袭重要的病毒-宿主相互作用的进一步见解,并提供了新的靶标来特异性抑制感染细胞向CNS的浸润。总结句子:单核细胞的迁移涉及由小RhoGTP酶和整合素调节的大量肌动蛋白细胞骨架重组,可以被病毒颠覆。
Human circulating monocytes are established targets for Zika virus (ZIKV) infection. Because of their important migratory properties toward any tissues, including the central nervous system (CNS), a better understanding of the mechanisms underlying monocyte transmigration upon ZIKV infection is required. Here, we monitored adhesion, migration and transmigration properties of monocytes exposed to ZIKV. We found that ZIKV enhanced monocyte adhesion on collagen compared to mock-exposed samples, and that pharmacological inhibition of mDia and Cdc42 function induced a significant decrease of adhesion in both mock- and ZIKV-exposed monocytes. In contrast, monocyte migration through collagen was inhibited by most of the tested small molecules targeting regulators of actin polymerization, including Rac1, ROCK, Cdc42, mDia, Arp2/3, Myosin-II and LFA-1. ZIKV-exposed monocyte migration showed a very similar profile to that of their mock-exposed counterparts. Finally, assessment of monocyte transmigration through human cerebral microvascular endothelial cells (hCMEC/D3) showed dependency on Rac1, ROCK, and Cdc42, independently of their infection status. In contrast, we identified that BIRT377, an antagonist of LFA-1, significantly inhibited transmigration of ZIKV-exposed but not mock-exposed monocytes. As BIRT377 increased adhesion of ZIKV-exposed monocytes, we propose that LFA-1 might be involved in a post-adhesion step to enhance viro-induced transmigration. These data suggest that ZIKV exposure triggers specific migratory properties of monocytes that are not exploited under physiological conditions. This work provides further insights on virus-host interactions important for viral neuroinvasion and offers novel targets to specifically inhibit the infiltration of infected cells to the CNS. SUMMARY SENTENCE: Monocyte transmigration involves massive actin cytoskeleton reorganization regulated by small Rho GTPases and integrins, which can be subverted by viruses.