The Group B Streptococcal surface antigen I/II protein, BspC, interacts with host vimentin to promote adherence to brain endothelium and inflammation during the pathogenesis of meningitis

Abstract

Streptococcus agalactiae (Group B Streptococcus, GBS) normally colonizes healthy adults but can cause invasive disease, such as meningitis, in the newborn. To gain access to the central nervous system, GBS must interact with and penetrate brain or meningeal blood vessels; however, the exact mechanisms are still being elucidated. Here, we investigate the contribution of BspC, an antigen I/II family adhesin, to the pathogenesis of GBS meningitis. Disruption of the bspC gene reduced GBS adherence to human cerebral microvascular endothelial cells (hCMEC), while heterologous expression of BspC in non-adherent Lactococcus lactis conferred bacterial attachment. In a murine model of hematogenous meningitis, mice infected with ΔbspC mutants exhibited lower mortality as well as decreased brain bacterial counts and inflammatory infiltrate compared with mice infected with WT GBS strains. Further, BspC was both necessary and sufficient to induce neutrophil chemokine expression. We determined that BspC interacts with the host cytoskeleton component vimentin, and confirmed this interaction using a bacterial two-hybrid assay, immunofluorescent staining, and imaging flow cytometry. Vimentin null mice were protected from WT GBS infection and also exhibited less inflammatory cytokine production in brain tissue. These results suggest that BspC and the vimentin interaction is critical for the pathogenesis of GBS meningitis.AUTHOR SUMMARYGroup B Streptococcus (GBS) typically colonizes healthy adults but can cause severe disease in immune compromised individuals, including newborns. Despite wide-spread intrapartum antibiotic prophylaxis given to pregnant women, GBS remains a leading cause of neonatal meningitis. To cause meningitis, GBS must interact with and penetrate the blood-brain barrier (BBB), which separates bacteria and immune cells in the blood from the brain. In order to develop targeted therapies to treat GBS meningitis, it is important to understand the mechanisms of BBB crossing. Here, we describe the role of the GBS surface factor, BspC, in promoting meningitis and discover the host ligand for BspC, vimentin, which is an intermediate filament protein that is constitutively expressed by endothelial cells. We determined that BspC interacts with the C-terminal domain of cell-surface vimentin to promote bacterial attachment to brain endothelial cells and that purified BspC protein can induce immune signaling pathways. In a mouse model of hematogenous meningitis, we observed that a GBS mutant lacking BspC was less virulent compared to WT GBS and resulted in less inflammatory disease. We also observed that mice lacking vimentin were protected from GBS infection. These results reveal the importance of the BspC-vimentin interaction in the progression of GBS meningitis disease.

Dynamic monitoring of CD45-/CD31+/DAPI+ circulating endothelial cells aneuploid for chromosome 8 during neoadjuvant chemotherapy in locally advanced breast cancer

“…21 Notably, a strong expression of Vim in endothelial cells may favor transendothelial migration. 22 Vim+ aneuploid CECs significantly increased after NCT. High expression of Vim in endothelial cells may increase the probability of transendothelial migration of primary tumor cells and of their conversion to CTCs.…”

Vimentin as a Multifaceted Player and Potential Therapeutic Target in Viral Infections

“…Indeed, the structural organization of extracellular vimentin and/or the concurrent PTMs could potentially influence its actions. Based on epitope recognition by a variety of antibodies, it has been reported that the tail domain is accessible in activated platelets [ 45 ] and on the surface of human cerebral microvascular endothelial cells [ 58 ]. Nevertheless, evidence from deletion analysis indicated that the head domain of vimentin could be involved in protein–protein interactions in the extracellular medium [ 44 ].…”

Identification of zinc-dependent mechanisms used by Group B Streptococcus to overcome calprotectin-mediated stress

“…During acute bacterial meningitis, neutrophils predominate in the cerebral spinal fluid, which is often used as a diagnostic marker. Following interaction with human cerebral microvascular endothelial cells (hCMEC) in vitro, GBS induces a characteristic neutrophilic inflammatory response, including expression of chemoattractants interleukin-8 (IL-8), C-X-C motif chemokine ligand 1 (CXCL-1), and CXCL-2 (33)(34)(35). Similar results are observed in animal models of experimental GBS meningitis, as brain tissue of GBS infected mice shows increased neutrophil and monocyte infiltration compared to naïve controls (35) indicating a close interaction between GBS and granulocytic cells during active infection.…”

“…Following interaction with human cerebral microvascular endothelial cells (hCMEC) in vitro, GBS induces a characteristic neutrophilic inflammatory response, including expression of chemoattractants interleukin-8 (IL-8), C-X-C motif chemokine ligand 1 (CXCL-1), and CXCL-2 (33)(34)(35). Similar results are observed in animal models of experimental GBS meningitis, as brain tissue of GBS infected mice shows increased neutrophil and monocyte infiltration compared to naïve controls (35) indicating a close interaction between GBS and granulocytic cells during active infection. Additional studies have shown that, in response to GBS, neutrophils elaborate extracellular traps decorated with lactoferrin (36) and that S100A9, a calprotectin subunit, is present in the blood and amniotic fluid during intrauterine GBS infection (37).…”