Toxoplasma Gondii strategies to bypass the blood-brain barrier restrictiveness

Toxoplasmosis is a pathological condition linked to the intracellular infection by the coccidian parasite Toxoplasma Gondii. The disease remains asymptomatic in most cases, with the parasite establishing latent infections residing undetected in tissue cysts. Nevertheless, the reactivation of the dormant cysts in immunocompromised individuals may have severe effects. In particular, parasites located at cerebral level can potentially lead to lethal encephalitis in case of acute tissue infection. To enter the brain parenchyma, Toxoplasma Gondii must first evade the blood-brain barrier control. Indeed, the wall of brain vessels is a non-permissive endothelial layer protecting the underlying tissue from blood-carried pathogens, self-immune system, and potentially toxic molecules. Many researchers are concordant in proposing three main strategies allowing Toxoplasma Gondii to cross the brain endothelial barrier: transcellular, paracellular, and intracellular. However, the mechanisms and modalities of parasite transmigration are still largely undissected. Konradt and colleagues documented the transcellular passage of Toxoplasma Gondii using live imaging of infected mouse brain in vivo. The parasites manage to overcome the restrictions of the endothelial layer in the form of tachyzoites: in this stage of its life cycle, Toxoplasma Gondii invades the host cells to set up intracellular replication until causing cell lysis and the dissemination of the freshly egressed tachyzoites. This work confirmed the invasion of brain parenchyma after parasite egression from endothelial cells, which were proved to be a replicative niche for Toxoplasma Gondii. The intracellular infection of brain endothelial cells has been linked to dysregulation of focal adhesion kinase (FAK) signaling in an in vitro study by Ross et al. The reduction of FAK autophosphorylation observed in Toxoplasma Gondii infected endothelial cells impacted the intercellular tight junction organization, increasing the parasite transmigration frequency across the BBB model by paracellular route. The impact of Toxoplasma Gondii infection on adhesion molecules also influences the parasite intracellular migration across the brain endothelium. Ross and collaborators demonstrated that the regulation of integrins and other cell adhesion molecules (CAMs) induced by intracellular Toxoplasma Gondii potentiates infected dendritic cells adhesion to murine brain endothelium monolayers and transendothelial migration (TEM). The transmigration of tachyzoites into brain parenchyma by means of carrier dendritic cells is known as “Trojan horse” strategy. Overall, these studies provide a global view on the main strategies adopted by Toxoplasma Gondii to elude the blood-brain barrier and set latent brain infection, with a particular attention on the critical role of adhesion molecules and tight junctions regulation in the process.