title: CD40 induces anti-Toxoplasma gondii activity in nonhematopoietic cells dependent on autophagy proteins.
abstract: Toxoplasma gondii infects both hematopoietic and nonhematopoietic cells and can cause cerebral and ocular toxoplasmosis, as a result of either congenital or postnatally acquired infections. Host protection likely acts at both cellular levels to control the parasite. CD40 is a key factor for protection against cerebral and ocular toxoplasmosis. We determined if CD40 induces anti-T. gondii activity at the level of nonhematopoietic cells. Engagement of CD40 on various endothelial cells including human microvascular brain endothelial cells, human umbilical vein endothelial cells, and a mouse endothelial cell line as well as human and mouse retinal pigment epithelial cells resulted in killing of T. gondii. CD40 stimulation increased expression of the autophagy proteins Beclin 1 and LC3 II, enhanced autophagy flux, and led to recruitment of LC3 around the parasite. The late endosomal/lysosomal marker LAMP-1 accumulated around the parasite in CD40-stimulated cells. This was accompanied by killing of T. gondii dependent on lysosomal enzymes. Accumulation of LAMP-1 and killing of T. gondii were dependent on the autophagy proteins Beclin 1 and Atg7. Together, these studies revealed that CD40 induces toxoplasmacidal activity in various nonhematopoietic cells dependent on proteins of the autophagy machinery.
authors.affiliation: Department of Pathology, Case Western Reserve University School of Medicine, Cleveland, Ohio, USA.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Van Grol
authors.forename: Luis
authors.initials: L
authors.lastname: Muniz-Feliciano
authors.forename: Jose-Andres C
authors.initials: JA
authors.lastname: Portillo
authors.forename: Vera L
authors.initials: VL
authors.lastname: Bonilha
authors.forename: Carlos S
authors.initials: CS
authors.lastname: Subauste
mesh_terms: D000818:Animals; D001343:Autophagy / Q000502:physiology*; D019013:CD40 Antigens / Q000235:genetics / Q000378:metabolism*; D002460:Cell Line; D042783:Endothelial Cells / Q000378:metabolism / Q000469:parasitology*; D004847:Epithelial Cells / Q000378:metabolism / Q000469:parasitology*; D005786:Gene Expression Regulation / Q000276:immunology; D006801:Humans; D051379:Mice; D055213:Retinal Pigment Epithelium / Q000166:cytology / Q000378:metabolism; D014122:Toxoplasma / Q000276:immunology*
chemical_list: D019013:CD40 Antigens