Host autophagy is exploited by the intracellular parasite Toxoplasma gondii to enhance amino acids levels.
Host autophagy is exploited by the intracellular parasite Toxoplasma gondii to enhance amino acids levels.
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细胞内寄生虫弓形虫利用宿主自噬来提高氨基酸水平。
DOI：
10.1101/2023.12.08.570852
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发表时间：
2023
期刊：
影响因子：
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通讯作者：
Augusto,Leonardo
中科院分区：
文献类型：
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作者：
White,MatthewD;Angara,RajendraK;Dias,LeticiaTorres;Shinde,DhananjayD;Thomas,VinaiC;Augusto,Leonardo
弓形虫是一种分布广泛的寄生虫，几乎可以感染温血脊椎动物的任何有核细胞。据估计，全球约有20亿人感染了这种病原体。尽管大多数健康的人可以有效地控制寄生虫的复制，但某些寄生虫可能会逃避免疫反应，在大脑中建立对免疫系统难以抵抗的囊肿，并对可用的药物产生抗药性。由于它在大脑中的长期存在，这种寄生虫依赖于宿主细胞的营养，特别是氨基酸和脂质。因此，了解潜伏的寄生虫是如何在大脑中持续存在的，对于确定针对慢性形式的潜在药物靶点至关重要。虽然弓形虫被寄生的空泡(PV)或包囊屏蔽，但它利用宿主内质网(ER)的新陈代谢来维持其在大脑中的持久性，导致宿主神经变化。在这项研究中，我们证明了。生殖细胞破坏宿主内质网的动态平衡，导致未折叠蛋白与宿主内质网积累。宿主通过启动被称为内质网吞噬的自噬途径来对抗这种压力，该途径将未折叠的蛋白质分解成氨基酸，促进它们的循环。值得注意的是，通过限制细胞培养过程中各种氨基酸的供应，可以成功地逆转潜伏感染引起的小鼠行为改变和细胞培养潜伏状态的持续。淋病。我们的发现揭示了T。Gondiito利用宿主内质网和溶酶体途径，在感染期间提高营养水平。这些见解为弓形虫病的治疗提供了新的策略。重要意义细胞内寄生虫使用多种机制来操纵细胞环境，使它们能够在宿主体内存活。弓形虫是一种单细胞寄生虫，几乎能够感染任何温血脊椎动物的有核细胞，包括全球近20亿人。不幸的是，现有的治疗方法和免疫反应并不能完全有效地消除这种寄生虫的慢性持久性形式。这项研究表明。性激素诱导宿主的自噬途径，以提高感染细胞中的氨基酸水平。氨基酸的枯竭反过来会影响寄生虫的慢性形式的持久性，从而减少由慢性感染引起的小鼠神经变化。值得注意的是，我们的研究确定了宿主ER吞噬在寄生虫潜伏感染期间在宿主内持续存在的关键作用。
Toxoplasma gondii,a widespread parasite, has the ability to infect nearly any nucleated cell in warm-blooded vertebrates. It is estimated that around 2 billion people globally have been infected by this pathogen. Although most healthy individuals can effectively control parasite replication, certain parasites may evade the immune response, establishing cysts in the brain that are refractory to the immune system and resistance to available drugs. For its chronic persistence in the brain, the parasite relies on host cells’ nutrients, particularly amino acids and lipids. Therefore, understanding how latent parasites persist in the brain is crucial for identifying potential drug targets against chronic forms. While shielded within parasitophorous vacuoles (PVs) or cysts,Toxoplasmaexploits the host endoplasmic reticulum (ER) metabolism to sustains its persistence in the brain, resulting in host neurological alterations. In this study, we demonstrate thatT. gondiidisrupts the host ER homeostasis, resulting in accumulation of unfolded protein with the host ER. The host counters this stress by initiating an autophagic pathway known as ER-phagy, which breaks down unfolded proteins into amino acids, promoting their recycling. Remarkably, the persistence of latent forms in cell culture as well as behavioral changes in mice caused by the latent infection could be successfully reversed by restricting the availability of various amino acids duringT. gondiinfection. Our findings unveil the underlying mechanisms employed byT. gondiito exploit host ER and lysosomal pathways, enhancing nutrient levels during infection. These insights provide new strategies for the treatment of toxoplasmosis.ImportanceIntracellular parasites employ several mechanisms to manipulate the cellular environment, enabling them to persist in the host.Toxoplasma gondii, a single-celled parasite, possesses the ability to infect virtually any nucleated cell of warm-blooded vertebrates, including nearly 2 billion people worldwide. Unfortunately, existing treatments and immune responses are not entirely effective in eliminating the chronic persisting forms of the parasite. This study reveals thatT. gondiiinduces the host’s autophagic pathway to boost amino acid levels in infected cells. The depletion of amino acids, in turn, influences the persistence of the parasite’s chronic forms, resulting in a reduction of neurological alterations caused by chronic infection in mice. Significantly, our investigation establishes the crucial role of host ER-phagy in the parasite’s persistence within the host during latent infection.