Mycobacteria trehalose dimycolate interactions with host Mincle remodel blood-brain barrier junctions for brain invasion

Tuberculous meningitis is unique among bacterial meningitides because it occurs in two temporally separated steps: mycobacteria first invade the brain, then form infected macrophage aggregates called Rich foci, which later erode the meninges. Here, using transparent zebrafish larvae, we detail the first step-brain invasion. We find that whereas elsewhere in the body mycobacteria disseminate within phagocytes, only extracellular mycobacteria reach the brain microvasculature. There, they adhere to the microvascular endothelium and grow into microcolonies. These microcolonies induce endothelial tight junction reorganization, creating transient gaps through which bacteria enter the brain and infect microglia to initiate Rich foci. This reorganization is induced by mycobacterial surface glycolipid trehalose dimycolate interacting with its receptor, Mincle. Strikingly, the pathogens Mycobacterium tuberculosis and Mycobacterium marinum and the saprophyte Mycobacterium smegmatis can all invade the brain via this pathway. Thus, M. tuberculosis initiates meningitis, the deadliest form of tuberculosis, using an ancestral determinant important for environmental fitness.