College of Veterinary Medicine, Nanjing Agricultural University, Nanjing, China.
OIE Reference Laboratory for Swine Streptococcosis, Nanjing, China.
PLoS Pathog. 2022 Jul 19;18(7):e1010710. doi: 10.1371/journal.ppat.1010710. eCollection 2022 Jul.
Streptococcus suis (S. suis) is one of the important pathogens that cause bacterial meningitis in pigs and humans. Evading host immune defences and penetrating the blood-brain barrier (BBB) are the preconditions for S. suis to cause meningitis, while the underlying mechanisms during these pathogenic processes are not fully understood. By detecting the red blood and white blood cells counts, IL-8 expression, and the pathological injury of brain in a mouse infection model, a serine-rich repeat (SRR) glycoprotein, designated as SssP1, was identified as a critical facilitator in the process of causing meningitis in this study. SssP1 was exported to assemble a fimbria-like component, thus contributed to the bacterial adhesion to and invasion into human brain microvascular endothelial cells (HBMECs), and activates the host inflammatory response during meningitis but is not involved in the actin cytoskeleton rearrangement and the disruption of tight junctions. Furthermore, the deletion of sssP1 significantly attenuates the ability of S. suis to traverse the BBB in vivo and in vitro. A pull-down analysis identified vimentin as the potential receptors of SssP1 during meningitis and following Far-Western blot results confirmed this ligand-receptor binding mediated by the NR2 (the second nonrepeat region) region of SssP1. The co-localisation of vimentin and S. suis observed by laser scanning confocal microscopy with multiplex fluorescence indicated that vimentin significantly enhances the interaction between SssP1 and BBB. Further study identified that the NR216-781 and NR1711-2214 fragments of SssP1 play critical roles to bind to the BBB depending on the sialylation of vimentin, and this binding is significantly attenuated when the antiserum of NR216-781 or NR1711-2214 blocked the bacterial cells, or the vimentin antibody blocked the BBB. Similar binding attenuations are observed when the bacterial cells were preincubated with the vimentin, or the BBB was preincubated with the recombinant protein NR216-781, NR1711-2214 or sialidase. In conclusion, these results reveal a novel receptor-ligand interaction that enhances adhesion to and penetration of the BBB to cause bacterial meningitis in the S. suis infection and highlight the importance of vimentin in host-pathogen interactions.
猪链球菌（S. suis）是引起猪和人类细菌性脑膜炎的重要病原体之一。逃避宿主免疫防御和穿透血脑屏障（BBB）是 S. suis 引起脑膜炎的前提条件，而这些致病过程中的潜在机制尚不完全清楚。本研究通过检测小鼠感染模型中的红细胞和白细胞计数、IL-8 表达和脑的病理损伤，鉴定出一种富含丝氨酸的重复（SRR）糖蛋白，命名为 SssP1，它是导致脑膜炎过程中的关键促进因子。SssP1 被输出组装成一种类似于菌毛的成分，从而有助于细菌黏附和侵袭人脑微血管内皮细胞（HBMEC），并在脑膜炎过程中激活宿主炎症反应，但不参与肌动蛋白细胞骨架重排和紧密连接的破坏。此外，sssP1 的缺失显著降低了 S. suis 在体内和体外穿透 BBB 的能力。下拉分析鉴定出波形蛋白是 SssP1 在脑膜炎期间的潜在受体，随后的 Far-Western blot 结果证实了这种配体-受体结合是由 SssP1 的 NR2（第二个非重复区）区介导的。激光共聚焦显微镜的多重荧光共定位观察到 S. suis 和波形蛋白的共定位表明，波形蛋白显著增强了 SssP1 与 BBB 的相互作用。进一步的研究表明，SssP1 的 NR216-781 和 NR1711-2214 片段在依赖于波形蛋白唾液酸化的情况下，对于与 BBB 结合至关重要，当用 NR216-781 或 NR1711-2214 的抗血清阻断细菌细胞，或用波形蛋白抗体阻断 BBB 时，这种结合显著减弱。当细菌细胞预先用波形蛋白孵育，或 BBB 预先用重组蛋白 NR216-781、NR1711-2214 或唾液酸酶孵育时，也观察到类似的结合减弱。总之，这些结果揭示了一种新的受体-配体相互作用，增强了对 BBB 的黏附和穿透，导致 S. suis 感染引起的细菌性脑膜炎，并强调了波形蛋白在宿主-病原体相互作用中的重要性。
