Toxoplasma depends on lysosomal consumption of autophagosomes for persistent infection.
Toxoplasma depends on lysosomal consumption of autophagosomes for persistent infection.
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DOI：
10.1038/nmicrobiol.2017.96
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发表时间：
2017-06-19
影响因子：
28.3
通讯作者：
Carruthers VB
中科院分区：
文献类型：
--
作者：
Di Cristina M;Dou Z;Lunghi M;Kannan G;Huynh MH;McGovern OL;Schultz TL;Schultz AJ;Miller AJ;Hayes BM;van der Linden W;Emiliani C;Bogyo M;Besteiro S;Coppens I;Carruthers VB
在全球范围内，近20亿人感染了细胞内的弓形虫。这种持续感染可导致免疫功能低下的人患上严重疾病，并在流行病学上与主要精神疾病和认知障碍有关。目前没有治疗这种感染的方法。缺乏有效的治疗方法，部分原因是对维持这种长期感染的基本途径缺乏了解。虽然已知弓形虫在以囊壁为界的胞内囊内缓慢复制，但它如何在这个小生境中维持自身并重塑细胞器尚不清楚。在这里，我们确定了一个关键的作用，蛋白水解内寄生虫溶酶体细胞器（空泡室或VAC）在营业额的自噬体和持久性在神经感染。我们发现，破坏VAC定位的半胱氨酸蛋白酶损害VAC消化功能，并显着减少慢性感染。缺乏VAC蛋白酶的寄生虫死亡之前，寄生虫细胞质中未消化的自噬体的积累。这些发现表明寄生虫溶酶体降解在慢性感染中具有意想不到的功能，并确定了自噬在T。弓形虫及其近亲。这项工作还确定了弓形虫持久性的一个关键因素，并表明VAC蛋白水解是药理学发展的一个有前景的目标。
Globally, nearly 2 billion people are infected with the intracellular protozoan Toxoplasma gondii. This persistent infection can cause severe disease in immunocompromised people and is epidemiologically linked to major mental illnesses and cognitive impairment. There are currently no options for curing this infection. The lack of effective therapeutics is due partly to a poor understanding of essential pathways that maintain this long-term infection. Although it is known that Toxoplasma replicates slowly within intracellular cysts demarcated with a cyst wall, precisely how it sustains itself and remodels organelles in this niche is unknown. Here we identify a key role for proteolysis within the parasite lysosomal organelle (the vacuolar compartment or VAC) in turnover of autophagosomes and persistence during neural infection. We found that disrupting a VAC-localized cysteine protease compromised VAC digestive function and markedly reduced chronic infection. Death of parasites lacking the VAC protease was preceded by accumulation of undigested autophagosomes in the parasite cytoplasm. These findings suggest an unanticipated function for parasite lysosomal degradation in chronic infection and identify an intrinsic role for autophagy in the T. gondii parasite and its close relatives. This work also identifies a key element of Toxoplasma persistence and suggests that VAC proteolysis is a prospective target for pharmacologic development.
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影响因子：
7.4
作者：
Barclay, Jane;Clark, Anna K.;Malcangio, Marzia
通讯作者：
Malcangio, Marzia
影响因子：
1.5
作者：
Galizi, Roberto;Spano, Furio;Di Cristina, Manlio
通讯作者：
Di Cristina, Manlio
影响因子：
3.6
作者：
Lunghi, Matteo;Galizi, Roberto;Di Cristina, Manlio
通讯作者：
Di Cristina, Manlio
影响因子：
6.4
作者：
Dou Z;McGovern OL;Di Cristina M;Carruthers VB
通讯作者：
Carruthers VB
影响因子：
6.7
作者：
Besteiro S;Brooks CF;Striepen B;Dubremetz JF
通讯作者：
Dubremetz JF