Globally, nearly 2 billion people are infected with the intracellular protozoan Toxoplasma gondii¹. This persistent infection can cause severe disease in immunocompromised people and is epidemiologically linked to major mental illnesses² and cognitive impairment³. There are currently no options for curing this infection. The lack of effective therapeutics is due partly to a poor understanding of the essential pathways that maintain 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 pharmacological development.

中文翻译：

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弓形体依赖自噬体的溶酶体消耗来持续感染。

在全球范围内，近20亿人感染了细胞内的原生动物弓形虫¹。这种持续性感染可在免疫力低下的人中引起严重疾病，并且在流行病学上与重大精神疾病²和认知障碍^3相关。。当前没有治愈这种感染的选择。缺乏有效的治疗方法部分是由于对维持长期感染的基本途径了解不足。尽管已知弓形虫在用囊肿壁划定的细胞内囊肿中缓慢复制，但在这种环境中精确地维持自身和重塑细胞器的方式尚不清楚。在这里，我们确定了自噬体周转率和神经感染过程中持久性的寄生虫溶酶体细胞器（液泡隔室或VAC）中蛋白水解的关键作用。我们发现破坏VAC本地化的半胱氨酸蛋白酶会损害VAC的消化功能，并显着减少慢性感染。缺乏VAC蛋白酶的寄生虫死亡之前，未消化的自噬小体在寄生虫细胞质中积聚。这些发现表明在慢性感染中寄生虫溶酶体降解具有意想不到的功能，并确定了弓形虫寄生虫及其近亲中自噬的内在作用。这项工作还确定了弓形虫持久性的关键因素，并提示VAC蛋白水解是药理学发展的预期目标。