Toxoplasma gondii Co-opts the Unfolded Protein Response To Enhance Migration and Dissemination of Infected Host Cells
Toxoplasma gondii Co-opts the Unfolded Protein Response To Enhance Migration and Dissemination of Infected Host Cells
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DOI：
10.1128/mbio.00915-20
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发表时间：
2020-07-01
期刊：
影响因子：
6.4
通讯作者：
Sullivan, William J., Jr.
中科院分区：
文献类型：
--
作者：
Augusto, Leonardo;Martynowicz, Jennifer;Sullivan, William J., Jr.
刚地弓形虫是一种细胞内寄生虫，其重组宿主细胞以促进致病。弓形虫寄生的一个后果是宿主细胞的迁移活动增加，这有利于传播。在这里，我们表明，弓形虫触发未折叠的蛋白质反应（UPR）在宿主细胞通过钙释放内质网（ER）。我们进一步确定了一个新的作用，宿主ER应激传感器蛋白IRE 1在弓形虫发病机制。感染后，弓形虫激活IRE 1，通过与细丝蛋白A的结合在肌动蛋白重塑中发挥非经典作用。通过诱导宿主细胞中IRE 1寡聚化的细胞骨架重塑，弓形虫增强了体外宿主细胞迁移和体内寄生虫向宿主器官的传播。我们的研究已经确定了新的机制，弓形虫感染细胞的传播诱导，提供了新的见解的战略治疗toxoplasmois.IMPORTANCE感染弓形虫的细胞表现出高度的迁移活动，这有利于整个身体的感染传播。在这份报告中，我们确定了一个新的机制，弓形虫劫持其宿主细胞，并增加其流动性。我们进一步表明，弓形虫增加宿主细胞迁移的能力不涉及IRE 1的酶活性，而是IRE 1参与肌动蛋白细胞骨架重塑。从感染的宿主细胞中消耗IRE 1减少了它们的体外迁移，并显著阻碍了弓形虫在体内的传播。我们的研究结果揭示了宿主-病原体相互作用的新机制，展示了宿主细胞如何被选择在身体周围传播持续感染。
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 identify a novel role for the host ER stress sensor protein IRE1 in Toxoplasma pathogenesis. Upon infection, Toxoplasma 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, Toxoplasma enhances host cell migration in vitro and dissemination of the parasite to host organs in vivo. Our study has identified 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 report, 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 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 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.