Intracellular transport of Toxoplasma gondii through the blood–brain barrier

Abstract

Toxoplasma gondii establishes latent infection in the central nervous system of immunocompentent hosts. Toxoplasmic encephalitis is a life threatening reactivation of latent infection in the brain of immunocompromised patients. To further understand the mechanisms of entry into the brain of T. gondii we investigated host molecules and cells involved in the passage of the parasite through the blood-brain barrier. First, using microarrays brain endothelial cells were found to upregulate, among others, chemokines and adhesion molecules following infection with tachyzoites. Using flow cytometry we observed upregulated ICAM-1 expression on the surface of brain endothelial cells following infection; ICAM-1 expression was further increased after pre-incubation with IFN-γ. Compared to RH tachyzoites, ME49 tachyzoites induced a stronger upregulation of ICAM-1 and an earlier and stronger IL-6 and MCP-1 secretion by brain endothelial cells. Using an in vitro coculture model of the BBB (primary glia cells and brain endothelial cells) we found a stronger migration of infected antigen-presenting cells compared to lymphocytes (4.63% vs. 0.6% of all cells) across the BBB. Among all antigen-presenting cells CD11b + /CD11c + cells showed the highest infection rate, whereas the majority of infected cells that migrated through the blood-brain barrier were CD11b + /CD11c − cells. Infection of PBMCs with type I or type II Toxoplasma strains resulted in similar patterns of cell migration across the in vitro BBB model.In conclusion, these results suggest that T. gondii modulates gene expression of brain endothelial cells to promote its own migration through the blood-brain barrier in a 'Trojan horse' manner. Cells expressing CD11b either with or without CD11c are likely candidate cells for the intracellular transport of T. gondii across the BBB. T. gondii type I and type II strains induced similar migration patterns of antigen-presenting cells across the in vitro BBB.

CD40 Induces Anti-Toxoplasma gondii Activity in Nonhematopoietic Cells Dependent on Autophagy Proteins

“…These studies were conducted using human brain microvascular endothelial cells (HBMVEC) and human umbilical vein endothelial cells (HUVEC). These cells are likely involved in the invasion of the brain and fetus, respectively, during parasite dissemination via the bloodstream (42,43). Primary HBMVEC and HUVEC express CD40 (3,44).…”

Concepts and Mechanisms: Crossing Host Barriers

“…According to this scenario, a pathogen first infects a bone-marrow-derived cell, such as a macrophage, monocyte, or dendritic cell, which may then penetrate the BBB, acting as a shuttle for the microbe. For example, CD11b expressing cells are infected and used by T. gondii to breach the BBB (Lachenmaier et al 2011). Similarly, monocytes or macrophages may be used by C. neoformans, L. monocytogenes, M. tuberculosis, and Brucella and Salmonella spp for entry into the CNS (Greiffenberg et al 1998;Drevets et al 2004;JoinLambert et al 2005;Charlier et al 2009).…”

Motile invaded neutrophils in the small intestine ofToxoplasma gondii-infected mice reveal a potential mechanism for parasite spread

“…Consequently, recent studies have focused on the role of immune cells in transporting parasites between tissues (4,(16)(17)(18)(19)(20)(21)(22)(23). For example, cluster of differentiation 11b-positive (CD11b + ) cells have been implicated in the dissemination of T. gondii through the blood and across the blood-brain barrier (4,19). Following oral infection, it is thought that the initial invasion or traversal of intestinal epithelial cells by ingested parasites is followed by parasite replication in tissue and the transport by host cells to other tissues.…”