Laboratory of Pathogens and Host Immunity, CNRS, University of Montpellier, 34095 Montpellier, France.
Toulouse Institute for Infectious and Inflammatory Diseases, Infinity, University of Toulouse, CNRS, Inserm, Université Paul Sabatier, 31059 Toulouse, France.
Proc Natl Acad Sci U S A. 2023 Aug 22;120(34):e2309043120. doi: 10.1073/pnas.2309043120. Epub 2023 Aug 17.
is responsible for toxoplasmosis, a disease that can be serious when contracted during pregnancy, but can also be a threat for immunocompromised individuals. Acute infection is associated with the tachyzoite form that spreads rapidly within the host. However, under stress conditions, some parasites can differentiate into cyst-forming bradyzoites, residing mainly in the central nervous system, retina and muscle. Because this latent form of the parasite is resistant to all currently available treatments, and is central to persistence and transmission of the parasite, specific therapeutic strategies targeting this developmental stage need to be found. contains a plastid of endosymbiotic origin called the apicoplast, which is an appealing drug target because it is essential for tachyzoite viability and contains several key metabolic pathways that are largely absent from the mammalian host. Its function in bradyzoites, however, is unknown. Our objective was thus to study the contribution of the apicoplast to the viability and persistence of bradyzoites during chronic toxoplasmosis. We have used complementary strategies based on stage-specific promoters to generate conditional bradyzoite mutants of essential apicoplast genes. Our results show that specifically targeting the apicoplast in both in vitro or in vivo-differentiated bradyzoites leads to a loss of long-term bradyzoite viability, highlighting the importance of this organelle for this developmental stage. This validates the apicoplast as a potential area to look for therapeutic targets in bradyzoites, with the aim to interfere with this currently incurable parasite stage.
弓形虫负责一种疾病，这种疾病在怀孕期间感染可能很严重，但也可能对免疫功能低下的个体构成威胁。急性感染与速殖子形式有关，速殖子在宿主内迅速传播。然而，在应激条件下，一些寄生虫可以分化为形成包囊的缓殖子，主要存在于中枢神经系统、视网膜和肌肉中。由于寄生虫的这种潜伏形式对所有现有的治疗方法都有抗性，并且是寄生虫持续存在和传播的核心，因此需要找到针对这种发育阶段的特定治疗策略。
含有一个内共生起源的质体，称为顶质体，这是一个有吸引力的药物靶点，因为它对速殖子的存活至关重要，并且包含几个关键的代谢途径，而这些途径在哺乳动物宿主中基本上不存在。然而，它在缓殖子中的功能尚不清楚。因此，我们的目标是研究顶质体在慢性弓形虫病期间对缓殖子存活和持久性的贡献。我们使用基于阶段特异性启动子的互补策略，生成必需的顶质体基因的条件性缓殖子突变体。我们的结果表明，在体外或体内分化的缓殖子中特异性靶向顶质体，会导致长期缓殖子活力丧失，这突出了该细胞器对这一发育阶段的重要性。这验证了顶质体作为缓殖子中寻找治疗靶点的潜在区域，目的是干扰这种目前无法治愈的寄生虫阶段。
