Blood-Brain Barrier Traversal By African Trypanosomes
Glasgow, United Kingdom
The neurological complications of Human African trypanosomiasis, or sleeping sickness, caused by Trypanosoma brucei gambiense and T. b. rhodesiense are attributed to the penetration of the central nervous system by trypanosomes. Yet, how the single-cell trypanosome protozoan parasites spread from the blood to brain over the blood-brain barrier (BBB) remains an unresolved issue. This barrier is comprised of brain microvascular endothelial cells (BMEC) especially designed to keep pathogens out. Safe drugs for treating sleeping sickness are lacking and alternative treatments are urgently required. Using our human BMEC BBB model, we previously found that a parasite protease, brucipain, induced calcium activation signals that allowed this barrier to open-up to parasite crossing. Because human BMEC express Protease-Activated Receptors (PARs) that trigger calcium signals in BMEC, we hypothesized a functional link between parasite brucipain and BMEC PARs. Utilizing RNA interference to block the production of one type of PAR called PAR-2, we hindered the ability of trypanosomes to both open-up and cross human BMEC. Using gene-profiling methods to interrogate candidate BMEC pathways specifically triggered by brucipain, several pathways that potentially link brain inflammatory processes were identified, a finding congruent with the known role of PAR-2 as a mediator of inflammation. Overall, our data support a role for brucipain and BMEC PAR in trypanosome BBB transmigration, and as potential triggers for brain inflammation associated with the disease. We have also recently also demonstrated that transmigration of the Lyme disease spirochete B. burgdorferi across the BBB also depends on the bacterium’s ability to influence Ca2+ responses in human BMEC. Careful examination of these processes could identify other pathways amenable to further investigation, even pharmacological prevention of disseminated disease in humans using advanced agonists or antagonists currently in clinical trials for other purposes.
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