Toxoplasma MIC2 is a major determinant of invasion and virulence.
Toxoplasma MIC2 is a major determinant of invasion and virulence.
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DOI：
10.1371/journal.ppat.0020084
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发表时间：
2006-08
期刊：
影响因子：
6.7
通讯作者：
Carruthers VB
中科院分区：
文献类型：
--
作者：
Huynh MH;Carruthers VB
像它的顶复门亲戚一样，专性细胞内原生动物刚地弓形虫积极侵入哺乳动物细胞，并使用独特的滑动运动形式。最近发现的几个跨膜粘附复合物，可能能够抓住外部受体和膜下放线菌球蛋白电机，表明寄生虫有多种选择宿主细胞的识别和入侵。为了测试跨膜粘附素MIC 2与其伴侣蛋白M2 AP一起是否参与主要的侵袭途径，我们利用条件表达系统引入脱水四环素响应mic 2构建体，使我们能够敲除内源性mic 2基因。MIC 2的条件性抑制提供了第一次直接确定这种蛋白在感染中的作用的机会。在急性弓形虫病小鼠模型中，MIC 2表达降低导致M2 AP的误作用、宿主细胞附着和侵袭明显缺陷、螺旋滑动运动丧失以及不能支持致死性感染。MIC 2缺陷型寄生虫感染小鼠的存活率与感染组织中较低的寄生虫负荷、减弱的炎症免疫应答和诱导长期保护性免疫相关。我们的研究结果表明，MIC 2蛋白复合物是弓形虫感染的主要毒力决定因素，MIC 2缺陷型寄生虫构成了实验性弓形虫病的有效减毒活疫苗。 刚地弓形虫是一种原生动物寄生虫，可感染包括人类在内的多种宿主。在因HIV/AIDS或器官移植后免疫抑制治疗而导致免疫力减弱的人群中，慢性T。弓形虫感染是一种严重的威胁，可能导致大脑、心脏或肺部的致命疾病。作为细胞内寄生虫，侵入宿主细胞是确保寄生虫在感染期间存活的关键第一步。通过使用可调控的表达系统，这项研究表明，一种称为MIC 2的粘附蛋白是寄生虫入侵系统的限制性组成部分，并且它是寄生虫螺旋状运动所必需的。此外，用缺乏MIC 2的寄生虫感染小鼠不再导致导致死亡的急性感染。小鼠不仅能在感染后存活，还能免受致死剂量野生型寄生虫的感染，这表明诱导了保护性免疫。除了对减毒活疫苗的开发有影响外，这项工作还表明，针对MIC 2的新治疗策略可能会限制弓形虫感染的严重程度。
Like its apicomplexan kin, the obligate intracellular protozoan Toxoplasma gondii actively invades mammalian cells and uses a unique form of gliding motility. The recent identification of several transmembrane adhesive complexes, potentially capable of gripping external receptors and the sub-membrane actinomyosin motor, suggests that the parasite has multiple options for host-cell recognition and invasion. To test whether the transmembrane adhesin MIC2, together with its partner protein M2AP, participates in a major invasion pathway, we utilized a conditional expression system to introduce an anhydrotetracycline-responsive mic2 construct, allowing us to then knockout the endogenous mic2 gene. Conditional suppression of MIC2 provided the first opportunity to directly determine the role of this protein in infection. Reduced MIC2 expression resulted in mistrafficking of M2AP, markedly defective host-cell attachment and invasion, the loss of helical gliding motility, and the inability to support lethal infection in a murine model of acute toxoplasmosis. Survival of mice infected with MIC2-deficient parasites correlated with lower parasite burden in infected tissues, an attenuated inflammatory immune response, and induction of long-term protective immunity. Our findings demonstrate that the MIC2 protein complex is a major virulence determinant for Toxoplasma infection and that MIC2-deficient parasites constitute an effective live-attenuated vaccine for experimental toxoplasmosis. Toxoplasma gondii is a protozoan parasite that infects a broad range of hosts including humans. In people with weakened immunity resulting from HIV/AIDS or immune-suppressive treatment following organ transplantation, reactivation of a chronic T. gondii infection represents a serious threat, potentially leading to lethal disease within the brain, heart, or lungs. As an intracellular parasite, invasion into a host cell is a critical first step in ensuring parasite survival during infection. By using a regulatable expression system, this study shows that an adhesive protein called MIC2 is a limiting component of the parasite's invasion system and that it is required for the corkscrew-like movement of the parasite. Moreover, infection of mice with parasites lacking MIC2 no longer resulted in an acute infection leading to death. Not only do mice survive infection, they are protected from infection with a lethal dose of wild-type parasites, indicating an induction of protective immunity. In addition to having implications for the development of live-attenuated vaccines, this work suggests that novel treatment strategies directed at MIC2 may limit the severity of Toxoplasma infections.