UC Irvine

Toxoplasma gondii is a foodborne parasite that infects virtually all warm-blooded animals and can cause severe disease in individuals with compromised or weakened immune systems. During dissemination in its infected hosts, T. gondii traverses endothelial barriers to enter tissues and establish chronic infections that underlie the most severe manifestations of toxoplasmosis. Despite a growing appreciation for the importance of endothelial infection in T. gondii pathogenesis, the molecular interactions occurring at this host-pathogen interface remain poorly defined. The research presented here examines T. gondii infection in the context of human primary endothelial cells in static conditions and, for the first time, under the physiological conditions of shear stress found in the bloodstream. We demonstrate that T. gondii infection of primary human umbilical vein endothelial cells (HUVEC) altered cell morphology and dysregulated barrier function, increasing permeability to low molecular weight polymers. Altered cell morphology coincided with parasite-induced remodeling of the three main components of the cytoskeleton: actin microfilaments, intermediate filaments, and microtubules. By conducting a global transcriptome analysis of infected endothelial cells, we identified gene expression changes associated with mechanotransduction and show that T. gondii infection activated Hippo signaling. Infected endothelial cells exposed to shear forces exhibit disrupted planar cell polarity and fragmented Golgi. RNA-Seq analysis on infected endothelial cells exposed to shear suggests that infection alters expression of genes associated with cell proliferation and lipid metabolism. Collectively, this work reveals novel interactions occurring at the interface between endothelial cells and T. gondii to provide insights into processes linked to parasite dissemination and pathogenesis.