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

Abstract

<jats:title>ABSTRACT</jats:title> <jats:p><jats:named-content content-type="genus-species">Toxoplasma gondii</jats:named-content> is an intracellular parasite that reconfigures its host cell to promote pathogenesis. One consequence of <jats:italic>Toxoplasma</jats:italic> parasitism is increased migratory activity of host cells, which facilitates dissemination. Here, we show that <jats:italic>Toxoplasma</jats:italic> 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 <jats:italic>Toxoplasma</jats:italic> pathogenesis. Upon infection, <jats:italic>Toxoplasma</jats:italic> 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, <jats:italic>Toxoplasma</jats:italic> enhances host cell migration <jats:italic>in vitro</jats:italic> and dissemination of the parasite to host organs <jats:italic>in vivo</jats:italic>. Our study has identified novel mechanisms used by <jats:italic>Toxoplasma</jats:italic> to induce dissemination of infected cells, providing new insights into strategies for treatment of toxoplasmosis.</jats:p> <jats:p><jats:bold>IMPORTANCE</jats:bold> Cells that are infected with the parasite <jats:named-content content-type="genus-species">Toxoplasma gondii</jats:named-content> exhibit heightened migratory activity, which facilitates dissemination of the infection throughout the body. In this report, we identify a new mechanism used by <jats:italic>Toxoplasma</jats:italic> to hijack its host cell and increase its mobility. We further show that the ability of <jats:italic>Toxoplasma</jats:italic> 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 <jats:italic>in vitro</jats:italic> and significantly hinders dissemination of <jats:italic>Toxoplasma in vivo</jats:italic>. 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.</jats:p>

Lessons from Toxoplasma: Host responses that mediate parasite control and the microbial effectors that subvert them

“…In infected cells, reduced β1 integrin activity and suppressed focal adhesion kinase phosphorylation decrease adhesion and increase migration (Cook et al, 2018). Other studies have provided evidence that the infection-induced unfolded protein response also contributes to increased migration and parasite spread (Augusto et al, 2020). These observations have now been complemented by the identification of parasite effectors that promote migration and trafficking.…”

Manipulation of Host Cell Organelles by Intracellular Pathogens

“…Similar to a variety of bacterial pathogens, T. gondii forms parasitophorous vacuoles (PV), subcellular compartments that function as barrier against host cell immune factors, as well as niche for replication through nutrition obtained from the host cell [ 67 , 68 ]. In contrast to the LCV of L. pneumophila , the PV of T. gondii does not fuse with vesicles but rather forms narrow contacts with host organelles that might contribute to manipulation of cellular pathways [ 69 ]. Experiments showed associations of two organelles with the parasitophorous vacuole membrane (PVM) including the ER.…”

“…Interactions of proteins secreted by T. gondii (GRA3/GRA5) residing in the PVM with the ER-anchoring protein calcium-modulating ligand (CAMLG) might induce association between PVM and organelles, though further studies have to test this hypothesis ( Figure 4 ) [ 70 , 71 ]. It was also shown that the UPR was impaired during T. gondii pathogenesis through manipulation of Ca 2+ efflux from ER, leading to activation of the cytoskeleton-rearranging stress sensor IRE1, promoting host cell migration and parasite dissemination [ 69 ].…”

Endoplasmic Reticulum Stress, a Target for Drug Design and Drug Resistance in Parasitosis

“…In addition, Leishmania infection induced ER stress of the host to facilitate infection through the PERK-eIF2α-ATF4 and IRE1-XBP1 pathways ( Dias-Teixeira et al, 2016 , 2017 ; Galluzzi et al, 2016 ; Abhishek et al, 2018 ). And Toxoplasma triggered the UPR in host cells, which affected calcium release from ER, can enhance host cell migration and dissemination of the parasite to host organs ( Augusto et al, 2020 ). However, Poncet et al (2021) have showed that the IRE1a/XBP1s branch of the UPR was a key regulator of host defense upon Toxoplasma gondii infection, that mice deficient for IRE1a and XBP1 in DCs displayed a severe susceptibility to T. gondii infection, which indicates that the UPR induced by parasites also plays an important role in host immune defense.…”