Toxoplasma gondii ingests and digests host cytosolic proteins.
Toxoplasma gondii ingests and digests host cytosolic proteins.
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DOI：
10.1128/mbio.01188-14
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发表时间：
2014-07-15
期刊：
影响因子：
6.4
通讯作者：
Carruthers VB
中科院分区：
文献类型：
--
作者：
Dou Z;McGovern OL;Di Cristina M;Carruthers VB
弓形虫寄生虫在细胞内复制时存在于非融合空泡内。虽然这种液泡的界膜提供了一个保护屏障，以防止溶酶体水解酶的酸化和降解，但它也将寄生虫与宿主胞质溶胶物理隔离。因此，已经表明弓形虫通过膜通道或转运蛋白从宿主获得物质。寄生虫在细胞内复制期间通过内吞作用内化大分子的能力尚未被测试。在这里，我们表明，弓形虫摄取宿主胞质蛋白质，并利用其内溶酶体系统内的组织蛋白酶L和其他蛋白酶将其消化。摄入量减少突变型寄生虫缺乏一个intravacuolar网络的管状膜，暗示这一装置作为一个可能的管道贩运到寄生虫。参与该途径的蛋白质的遗传消融与寄生虫复制减少和毒力减弱有关。我们发现，有毒的I型和无毒的II型菌株寄生虫摄取和消化宿主来源的蛋白质，这表明该途径并不局限于高毒力菌株。这些发现提供了第一个明确的证据，表明弓形虫在细胞内驻留期间内化宿主的蛋白质，并表明寄生虫内溶酶体系统内的蛋白质消化有助于弓形虫病。弓形虫在免疫系统较弱的个体中引起重大疾病。这种感染的治疗方案有缺点，需要了解这种寄生虫如何在它感染的细胞内生存，作为中断其生存策略的前奏。这项研究表明，弓形虫从它感染的细胞的细胞质中内化蛋白质，并在寄生虫的消化区室中降解这些蛋白质。参与该途径的蛋白质的破坏减少了寄生虫的复制，减轻了疾病的严重程度。一种新的寄生虫摄取途径的鉴定为干扰这一过程和改善感染结果提供了机会。
The protozoan parasite Toxoplasma gondii resides within a nonfusogenic vacuole during intracellular replication. Although the limiting membrane of this vacuole provides a protective barrier to acidification and degradation by lysosomal hydrolases, it also physically segregates the parasite from the host cytosol. Accordingly, it has been suggested that T. gondii acquires material from the host via membrane channels or transporters. The ability of the parasite to internalize macromolecules via endocytosis during intracellular replication has not been tested. Here, we show that Toxoplasma ingests host cytosolic proteins and digests them using cathepsin L and other proteases within its endolysosomal system. Ingestion was reduced in mutant parasites lacking an intravacuolar network of tubular membranes, implicating this apparatus as a possible conduit for trafficking to the parasite. Genetic ablation of proteins involved in the pathway is associated with diminished parasite replication and virulence attenuation. We show that both virulent type I and avirulent type II strain parasites ingest and digest host-derived protein, indicating that the pathway is not restricted to highly virulent strains. The findings provide the first definitive evidence that T. gondii internalizes proteins from the host during intracellular residence and suggest that protein digestion within the endolysosomal system of the parasite contributes to toxoplasmosis. Toxoplasma gondii causes significant disease in individuals with weak immune systems. Treatment options for this infection have drawbacks, creating a need to understand how this parasite survives within the cells it infects as a prelude to interrupting its survival strategies. This study reveals that T. gondii internalizes proteins from the cytoplasm of the cells it infects and degrades such proteins within a digestive compartment within the parasite. Disruption of proteins involved in the pathway reduced parasite replication and lessened disease severity. The identification of a novel parasite ingestion pathway opens opportunities to interfere with this process and improve the outcome of infection.