PT - JOURNAL ARTICLE AU - Leonardo Augusto AU - Jennifer Martynowicz AU - Parth H. Amin AU - Nada S. Alakhras AU - Mark H. Kaplan AU - Ronald C. Wek AU - William J. Sullivan, Jr TI - <em>Toxoplasma gondii</em> co-opts the unfolded protein response to enhance migration and dissemination of infected host cells AID - 10.1101/2020.04.14.042069 DP - 2020 Jan 01 TA - bioRxiv PG - 2020.04.14.042069 4099 - http://biorxiv.org/content/early/2020/04/16/2020.04.14.042069.short 4100 - http://biorxiv.org/content/early/2020/04/16/2020.04.14.042069.full AB - Toxoplasma gondii is an intracellular parasite that reconfigures its host cell to promote pathogenesis. One consequence of Toxoplasma parasitism is increased migratory activity of host cells, which facilitates dissemination. Here we show that Toxoplasma triggers the unfolded protein response (UPR) in host cells through calcium release from the endoplasmic reticulum (ER). We further found that host IRE1, an ER stress sensor protein activated during Toxoplasma infection, also plays a noncanonical role in actin remodeling by binding filamin A in infected cells. By inducing cytoskeletal remodeling via IRE1 oligomerization in host cells, Toxoplasma enhances host cell migration in vitro and dissemination of the parasite to host organs in vivo. Our study identifies novel mechanisms used by Toxoplasma to induce dissemination of infected cells, providing new insights into strategies for treatment of toxoplasmosis.Importance Cells that are infected with the parasite Toxoplasma gondii exhibit heightened migratory activity, which facilitates dissemination of the infection throughout the body. In this study, we identify a new mechanism used by Toxoplasma to hijack its host cell and increase its mobility. We further show that the ability of Toxoplasma to increase host cell migration does not involve the enzymatic activity of IRE1, but rather IRE1 engagement with actin cytoskeletal remodeling. Depletion of IRE1 from infected host cells reduces their migration in vitro and significantly hinders dissemination of Toxoplasma in vivo. 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.Competing Interest Statement