Role of GR-1+ monocytes in dissemination and invasion of the brain by T. gondii, and defense against toxoplasmosis

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The intracellular protozoan parasite Toxoplasma gondii traverses biological barriers such as the blood-brain-barrier (BBB) to reach the CNS. In immunocompromised patients (AIDS- and transplant patients), reactivation of the latent infection results in severe pathology. It is unknown whether Toxoplasma disseminates as free, extracellular parasites or if it resides inside infected leukocytes, which are permissive hosts that can cross many biological barriers (Trojan horse theory). GR-1+ monocytes are recruited to the site of infection during the early stage of infection, produce pro-inflammatory cytokines including IL-12, and contribute to control of parasite replication. However, the role of these cells in transmigration across the BBB and in reactivation of latent infection is unknown. In this study, I will investigate the mechanism(s) of T. gondii dissemination and transmigration across the BBB. Using an in-vitro co-culture model of the BBB as well as in-vivo studies it is the aim to determine whether Toxoplasma uses extracellular and/or intracellular pathways to establish itself in the brain. In addition the role of tight junction proteins and adhesion molecules in the process of transmigration will be explored. Finally, I will investigate the importance of GR-1+ monocytes in the control of parasite replication in the acute phase of infection and after reactivation, using the murine model.