Toxoplasma entry receptors in the CNS

Abstract: Toxoplasma gondii is an obligate intracellular parasite that establishes chronic infection by establishing latent infection in the brain, eyes and in other tissue sites. Reactivation of latent infection poses a significant threat to the health of humans when the immune response becomes suppressed. Exactly how T. gondii disseminates throughout the body and enters the brain is not clear. The Trojan horse hypothesis posits that instead of entering tissues as free parasites, T. gondii tachyzoites are ferried to the brain by migratory myeloid cells. A recent multiphoton imaging report documented that parasites instead directly invaded brain microvascular endothelial cells and colonized the brain by lytic breaching of the blood brain barrier. Thus, knowledge about the adhesion and invasion receptors used by the parasite to gain entry into host cells comprising the blood brain barrier will be critical for interrupting CNS infection and disease. The objective of this exploratory project is to identify the CNS entry receptor(s) ofT. gondii. Aim 1 will use a ligand receptor capture chemoproteomic approach to identify surface glyproteins engaged by the parasite on brain microvascular endothelial cells, microglia and astrocytes. Aim 2 will interrogate the role of the candidate receptors identified in Aim 1 in the adhesion and invasion of these CNS-localized cells that serve as a portal of entry for parasite colonization.