UC San Diego

Bacterial infections of the brain affect approximately 3 million people every year. Only certain bacterial pathogens are able to breach the tightly regulated blood-brain barrier (BBB) to cause meningitis, including group B Streptococcus (GBS) and Mycobacterium tuberculosis. GBS is the leading cause of bacterial meningitis in neonates and M. tuberculosis is the causative agent of tuberculosis (TB), with TB meningitis being the deadliest form of TB. Bacteria are believed to move from the bloodstream to the brain, likely by crossing the endothelial cells of the blood-brain barrier (BBB). Historically, there has been a lack of models to visualize bacterial invasion into the brain in vivo. To elucidate how GBS and Mycobacteria cross the BBB, we utilized the optically transparent zebrafish larva. Through time-lapse confocal imaging, we observed the formation of extracellular GBS microcolonies attached to brain blood vessels, causing the formation of perforations in the vessels. This leads to GBS-induced endothelial cell death which facilitates GBS entry into the brain. Alternatively, mycobacteria utilize a different method to enter the brain. We find that extracellular mycobacteria grow into microcolonies in the brain microvasculature and use the mycobacterial serine threonine kinase PknD and the cell surface glycolipid trehalose dimycolate (TDM) to adhere to these vessels. TDM further reorganizes endothelial tight junctions to produce transient gaps through which mycobacteria paracellularly enter the brain without killing endothelial cells.