Mycobacterium bovis bacillus calmette-guerin-infected dendritic cells induce tnf-α-dependent cell cluster formation that promotes bacterial dissemination through an in vitro model of the blood-brain barrier

Gilpin, Trey E. and Walter, Fruzsina and Herbáth, Melinda and Sándor, Mátyás and Fabry, Zsuzsanna (2021) Mycobacterium bovis bacillus calmette-guerin-infected dendritic cells induce tnf-α-dependent cell cluster formation that promotes bacterial dissemination through an in vitro model of the blood-brain barrier. JOURNAL OF IMMUNOLOGY, 207 (4). pp. 1065-1077. ISSN 0022-1767

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Abstract

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-a 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. © 2021 American Association of Immunologists. All rights reserved.

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