Department of Immunology and Microbiology, University of Colorado Anschutz Medical Campus, Aurora, Colorado, USA.
Infect Immun. 2021 Nov 16;89(12):e0034021. doi: 10.1128/IAI.00340-21. Epub 2021 Sep 7.
Streptococcus agalactiae (group B Streptococcus, or GBS) is an opportunistic pathogen capable of causing invasive disease in susceptible individuals, including the newborn. Currently, GBS is the leading cause of meningitis in the neonatal period. We have recently shown that GBS interacts directly with host type III intermediate filament vimentin to gain access to the central nervous system. This results in characteristic meningeal inflammation and disease progression; however, the specific role of vimentin in the inflammatory process is unknown. Here, we investigate the contribution of vimentin to the pathogenesis of GBS meningitis. We show that a CRISPR-targeted deletion of vimentin in human cerebral microvascular endothelial cells (hCMEC) reduced GBS induction of neutrophil attractants interleukin-8 (IL-8) and CXCL-1 as well as NF-κB activation. We further show that inhibition of vimentin localization also prevented similar chemokine activation by GBS. One known chemokine regulator is the nucleotide-binding oligomerization domain containing protein 2 (NOD2), which is known to interact directly with vimentin. Thus, we hypothesized that NOD2 would also promote GBS chemokine induction. We show that GBS infection induced NOD2 transcription in hCMEC comparably to the muramyl dipeptide (MDP) NOD2 agonist, and the chemokine induction was reduced in the presence of a NOD2 inhibitor. Using a mouse model of GBS meningitis, we also observed increased NOD2 transcript and NOD2 activation in brain tissue of infected mice. Lastly, we show that NOD2-mediated and induction required vimentin, further indicating the importance of vimentin in mediating inflammatory responses in brain endothelium.
无乳链球菌（B 群链球菌，或 GBS）是一种机会性病原体，能够使包括新生儿在内的易感个体发生侵袭性疾病。目前，GBS 是新生儿期脑膜炎的主要病因。我们最近发现，GBS 可直接与宿主 III 型中间丝波形蛋白相互作用，从而进入中枢神经系统。这会导致特征性的脑膜炎症和疾病进展；然而，波形蛋白在炎症过程中的具体作用尚不清楚。在这里，我们研究了波形蛋白在 GBS 脑膜炎发病机制中的作用。我们发现，CRISPR 靶向敲除人脑微血管内皮细胞（hCMEC）中的波形蛋白可减少 GBS 诱导的中性粒细胞趋化因子白细胞介素-8（IL-8）和 CXCL-1 的产生，并减少 NF-κB 的激活。我们进一步表明，抑制波形蛋白定位也可防止 GBS 引起类似趋化因子的激活。已知的一种趋化因子调节剂是核苷酸结合寡聚化结构域富含蛋白 2（NOD2），它已知可与波形蛋白直接相互作用。因此，我们假设 NOD2 也会促进 GBS 趋化因子的诱导。我们发现，GBS 感染可诱导 hCMEC 中 NOD2 的转录，与 NOD2 激动剂 muramyl dipeptide（MDP）相当，并且在存在 NOD2 抑制剂的情况下，趋化因子的诱导减少。在 GBS 脑膜炎的小鼠模型中，我们还观察到感染小鼠脑组织中 NOD2 转录物和 NOD2 激活增加。最后，我们发现 NOD2 介导的 和 诱导需要波形蛋白，这进一步表明波形蛋白在介导脑内皮细胞炎症反应中的重要性。
