Molecular Food Microbiology Laboratory, Department of Food Science, Purdue University, West Lafayette, IN 47907, USA.
Department of Comparative Pathobiology, Purdue University, West Lafayette, IN 47907, USA.
Cell Host Microbe. 2018 Apr 11;23(4):470-484.e7. doi: 10.1016/j.chom.2018.03.004. Epub 2018 Apr 5.
Intestinal epithelial cells are the first line of defense against enteric pathogens, yet bacterial pathogens, such as Listeria monocytogenes, can breach this barrier. We show that Listeria adhesion protein (LAP) induces intestinal epithelial barrier dysfunction to promote bacterial translocation. These disruptions are attributed to the production of pro-inflammatory cytokines TNF-α and IL-6, which is observed in mice challenged with WT and isogenic strains lacking the surface invasion protein Internalin A (ΔinlA), but not a lap mutant. Additionally, upon engagement of its surface receptor Hsp60, LAP activates canonical NF-κB signaling, facilitating myosin light-chain kinase (MLCK)-mediated opening of the epithelial barrier via cellular redistribution of the epithelial junctional proteins claudin-1, occludin, and E-cadherin. Pharmacological inhibition of MLCK or NF-κB in cells or genetic ablation of MLCK in mice prevents mislocalization of junctional proteins and L. monocytogenes translocation. Thus, L. monocytogenes uses LAP to exploit epithelial defenses and cross the intestinal epithelial barrier.
肠上皮细胞是抵御肠道病原体的第一道防线，但细菌病原体，如李斯特菌，可以突破这道屏障。我们发现李斯特菌黏附蛋白（LAP）诱导肠上皮屏障功能障碍，促进细菌易位。这些破坏归因于促炎细胞因子 TNF-α 和 IL-6 的产生，在受到 WT 及缺乏表面入侵蛋白 Internalin A（ΔinlA）的同基因株挑战的小鼠中观察到这种现象，但 lap 突变体没有。此外，LAP 通过与表面受体 Hsp60 结合，激活经典 NF-κB 信号通路，通过上皮连接蛋白 claudin-1、occludin 和 E-钙黏蛋白的细胞内重新分布，促进肌球蛋白轻链激酶（MLCK）介导的上皮屏障开放。在细胞中抑制 MLCK 或 NF-κB 的药理学或在小鼠中遗传消融 MLCK 可防止连接蛋白的定位错误和李斯特菌的易位。因此，李斯特菌利用 LAP 来利用上皮防御并穿过肠上皮屏障。
