M. tuberculosis invades and disrupts the blood-brain barrier directly to initiate meningitis

Tuberculous meningitis (TBM) is the most severe form of tuberculosis and HIV-1 co-infection worsens the already poor prognosis. How Mycobacterium tuberculosis (Mtb) crosses the blood brain barrier (BBB) and the influence of HIV-1 on pathogenesis remains unclear. Using human pericytes, astrocytes, endothelial cells, and microglia alone; and combined in an in vitro BBB we investigated Mtb +/- HIV-1 co-infection on central nervous system cell entry and function. Mtb infected and multiplied in all cell types with HIV-1 increasing entry to astrocytes and pericytes, and growth in HIV-1 positive pericytes and endothelial cells. The permeability of the BBB increased resulting in translocation of bacilli across it. Cytopathic effects included increased markers of cellular stress, ROS release, the induction of neurotoxic astrocytes, and increased secretion of neuroexcitotoxic glutamate. Distinct cell-type specific production of inflammatory and effector mediators were observed. These data indicate Mtb can translocate the BBB directly to initiate meningitis.