Vimentin regulates chemokine expression and NOD2 activation in brain endothelium during Group B streptococcal infection.
Abstract: Streptococcus agalactiae (Group B Streptococcus , 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 IL-8 and CXCL-1, as well as NFκB 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 comparable 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 IL8 and CXCL1 induction required vimentin, further indicating the importance of vimentin in mediating inflammatory responses in brain endothelium.
Keywords: vimentin / NOD2 activation / activation in brain / interacts directly / chemokine regulator / GBS meningitis
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