ICAM-1/CD18-mediated sequestration of parasitized phagocytes in cortical capillaries promotes neuronal colonization by Toxoplasma gondii

Abstract Microbial translocation across the blood-brain barrier (BBB) is a prerequisite for colonization of the central nervous system. The obligate intracellular parasite Toxoplasma gondii chronically infects the brain parenchyma of humans and animals, in a remarkably stealthy fashion. Here, we addressed the mechanisms of BBB crossing by intracarotid delivery of parasites and parasite-infected leukocytes into the cerebral circulation of mice. Unexpectedly, parasitized dendritic cells (DCs) and other peripheral blood mononuclear cells persistently sequestered in cortical capillaries. Post-replicative egress of T. gondii from sequestered DCs was followed by rapid parasite localization within cortical neurons. Infection-induced microvascular inflammation dramatically elevated the sequestration of parasitized DCs while treatments targeting the ICAM-1/CD18 leukocyte adhesion axis with blocking antibodies strongly reverted sequestration. Secreted parasite effectors TgWIP and GRA15, implicated in leukocyte hypermigration and inflammatory activation, strain genotype-dependently elevated numbers of sequestered parasitized DCs in capillaries and cerebral parasite loads. The data unveil that sequestration of parasitized leukocytes in cortical capillaries, with posterior parasite transmigration across the BBB upon egress, constitutes a mechanism for the rapid reach of T. gondii to cortical neurons during primary infection.