| First Author | Gilpin TE | Year | 2021 |
| Journal | J Immunol | Volume | 207 |
| Issue | 4 | Pages | 1065-1077 |
| PubMed ID | 34321229 | Mgi Jnum | J:318701 |
| Mgi Id | MGI:6845010 | Doi | 10.4049/jimmunol.2001094 |
| Citation | Gilpin TE, et al. (2021) Mycobacterium bovis Bacillus Calmette-Guerin-Infected Dendritic Cells Induce TNF-alpha-Dependent Cell Cluster Formation That Promotes Bacterial Dissemination through an In Vitro Model of the Blood-Brain Barrier. J Immunol 207(4):1065-1077 |
| abstractText | CNS tuberculosis (CNSTB) is the most severe manifestation of extrapulmonary tuberculosis infection, but the mechanism of how mycobacteria cross the blood-brain barrier (BBB) is not well understood. In this study, we report a novel murine in vitro BBB model combining primary brain endothelial cells, Mycobacterium bovis bacillus Calmette-Guerin-infected dendritic cells (DCs), PBMCs, and bacterial Ag-specific CD4(+) T cells. We show that mycobacterial infection limits DC mobility and also induces cellular cluster formation that has a similar composition to pulmonary mycobacterial granulomas. Within the clusters, infection from DCs disseminates to the recruited monocytes, promoting bacterial expansion. Mycobacterium-induced in vitro granulomas have been described previously, but this report shows that they can form on brain endothelial cell monolayers. Cellular cluster formation leads to cluster-associated damage of the endothelial cell monolayer defined by mitochondrial stress, disorganization of the tight junction proteins ZO-1 and claudin-5, upregulation of the adhesion molecules VCAM-1 and ICAM-1, and increased transmigration of bacteria-infected cells across the BBB. TNF-alpha inhibition reduces cluster formation on brain endothelial cells and mitigates cluster-associated damage. These data describe a model of bacterial dissemination across the BBB shedding light on a mechanism that might contribute to CNS tuberculosis infection and facilitate treatments. |
