Toxoplasma gondii Co-opts the Unfolded Protein Response To Enhance Migration and Dissemination of Infected Host Cells

Abstract

<i>Toxoplasma gondii</i> is an intracellular parasite that reconfigures its host cell to promote pathogenesis. One consequence of <i>Toxoplasma</i> parasitism is increased migratory activity of host cells, which facilitates dissemination. Here, we show that <i>Toxoplasma</i> triggers the unfolded protein response (UPR) in host cells through calcium release from the endoplasmic reticulum (ER). We further identify a novel role for the host ER stress sensor protein IRE1 in <i>Toxoplasma</i> pathogenesis. Upon infection, <i>Toxoplasma</i> activates IRE1, engaging its noncanonical role in actin remodeling through the binding of filamin A. By inducing cytoskeletal remodeling via IRE1 oligomerization in host cells, <i>Toxoplasma</i> enhances host cell migration <i>in vitro</i> and dissemination of the parasite to host organs <i>in vivo</i> Our study has identified novel mechanisms used by <i>Toxoplasma</i> to induce dissemination of infected cells, providing new insights into strategies for treatment of toxoplasmosis.<b>IMPORTANCE</b> Cells that are infected with the parasite <i>Toxoplasma gondii</i> exhibit heightened migratory activity, which facilitates dissemination of the infection throughout the body. In this report, we identify a new mechanism used by <i>Toxoplasma</i> to hijack its host cell and increase its mobility. We further show that the ability of <i>Toxoplasma</i> to increase host cell migration involves not the enzymatic activity of IRE1 but rather IRE1 engagement with actin cytoskeletal remodeling. Depletion of IRE1 from infected host cells reduces their migration <i>in vitro</i> and significantly hinders dissemination of <i>Toxoplasma in vivo</i> Our findings reveal a new mechanism underlying host-pathogen interactions, demonstrating how host cells are co-opted to spread a persistent infection around the body.