Passage of parasites across the blood-brain barrier

Abstract

The blood-brain barrier (BBB) is a structural and functional barrier that protects the central nervous system (CNS) from invasion by blood-borne pathogens including parasites. However, some intracellular and extracellular parasites can traverse the BBB during the course of infection and cause neurological disturbances and/or damage which are at times fatal. The means by which parasites cross the BBB and how the immune system controls the parasites within the brain are still unclear. In this review we present the current understanding of the processes utilized by two human neuropathogenic parasites, Trypanosoma brucei spp and Toxoplasma gondii, to go across the BBB and consequences of CNS invasion. We also describe briefly other parasites that can invade the brain and how they interact with or circumvent the BBB. The roles played by parasite-derived and host-derived molecules during parasitic and white blood cell invasion of the brain are discussed.

Figure 1. Crossing of the blood-brain barrier (BBB) by parasites associated with WBCs. (A) Illustration of a cerebral post-capillary vessel showing the BBB, consisting of a complex of cerebral endothelial cells and their tight junctions, basement membranes and pericytes as well as astrocytic end-feet. Note the perivascular space that is noticeable during inflammation. (B) Toxoplasma gondii crossing the BBB. (1) Induction of vascular cell adhesion molecule 1 (VCAM-1) and adhesion molecules activated leukocyte cell adhesion molecule (ALCAM) in the brain during infection might aid the monocytes infected Toxoplasma gondii tachyzoites to cross the BBB. The infection cause an increased motility of the monocytes which may facilitate their migration into the brain. Toxoplasma gondii can invade endothelial cells, however, its ability to cross the BBB as extracellular parasites in vivo is not clear. (C) The extracellular parasite Trypanosoma brucei spp and T cells cross the endothelial cell layer, the endothelial basement membrane and the parenchymal to invade the brain parenchyma. (1) TNFα and IFNα/β are released upon TLR9/MyD88-mediated activation of the innate immune response. (2) TNFα induces ICAM/VCAM on cerebral endothelial cells which allow attachment of T cells. IFNα/β induces a limited release of CXCL10 by endothelial cells and/or astrocytes, which is enough for penetration of T cells accompanied by some trypanosomes into the perivascular space. (3) Trypanosome-derived antigens taken up and expressed by macrophages could then be recognized by sensitized T cells to induce IFNγ, which augment the process through (4) induction of CXCL10 production by astrocytes and (5) molecules that open the parenchymal basement membrane for spread of both T cells and trypanosomes into the brain parenchyma. (6) Once inside the brain the parasites are most likely controlled by macrophages or microglia which produce trypanotoxic or static molecules.

Figure 2. Large accumulation of T. b. brucei (red) in the choroid plexus following intra-peritoneal injection in a rodent model. Choroid plexus loaded with trypanosomes is seen already one week after the infection and before trypanosome crossing of the BBB, of which timing and prevalence is dependent on the rodent strain.