PDF(Pubmed)
Abstract：
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 resistant 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, Toxoplasma exploits the host endoplasmic reticulum (ER) metabolism to sustain its persistence in the brain, resulting in host neurological alterations. In this study, we demonstrate that T. gondii disrupts the host ER homeostasis, resulting in the accumulation of unfolded protein within 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. Our findings unveil the underlying mechanisms employed by T. gondii to exploit host ER and lysosomal pathways, enhancing nutrient levels during infection. These insights provide new strategies for the treatment of toxoplasmosis.
OBJECTIVE: Intracellular 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 that T. gondii induces 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. Significantly, our investigation establishes the crucial role of host endoplasmic reticulum (ER)-phagy in the parasite\'s persistence within the host during latent infection.
OBJECTIVE: Intracellular 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 that T. gondii induces 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. Significantly, our investigation establishes the crucial role of host endoplasmic reticulum (ER)-phagy in the parasite\'s persistence within the host during latent infection.
摘要：
弓形虫,一种广泛存在的寄生虫,有能力感染温血脊椎动物中几乎任何有核细胞。据估计，全球约有20亿人感染了这种病原体。虽然大多数健康个体能有效控制寄生虫的复制，某些寄生虫可能逃避免疫反应，在大脑中建立囊肿，这些囊肿对免疫系统是难治性的，并且对现有药物具有抗性。因为它在大脑中的慢性持久性，寄生虫依赖于宿主细胞的营养,特别是氨基酸和脂类。因此,了解潜在的寄生虫如何在大脑中持续存在对于识别针对慢性形式的潜在药物靶标至关重要。当屏蔽在寄生虫液泡（PV）或囊肿中时，弓形虫利用宿主内质网（ER）代谢来维持其在大脑中的持久性，导致宿主神经改变。在这项研究中,我们证明弓形虫破坏宿主的内质网稳态，导致未折叠蛋白质在宿主ER内的积累。宿主通过启动称为ER-phagy的自噬途径来对抗这种压力，将未折叠的蛋白质分解成氨基酸，促进其回收利用。我们的发现揭示了弓形虫利用宿主ER和溶酶体途径的潜在机制，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。
目的：细胞内寄生虫利用多种机制来操纵细胞环境，使他们能够坚持在主机。弓形虫,单细胞寄生虫,具有感染温血脊椎动物几乎任何有核细胞的能力，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寄生虫的慢性持续形式。这项研究表明，弓形虫诱导宿主的自噬途径，以提高感染细胞中的氨基酸水平。氨基酸的消耗，反过来,影响寄生虫慢性形式的持久性。重要的是,我们的研究确定了宿主内质网(ER)-吞噬在潜伏感染期间寄生虫在宿主体内的持续存在中的关键作用。
目的：细胞内寄生虫利用多种机制来操纵细胞环境，使他们能够坚持在主机。弓形虫,单细胞寄生虫,具有感染温血脊椎动物几乎任何有核细胞的能力，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寄生虫的慢性持续形式。这项研究表明，弓形虫诱导宿主的自噬途径，以提高感染细胞中的氨基酸水平。氨基酸的消耗，反过来,影响寄生虫慢性形式的持久性。重要的是,我们的研究确定了宿主内质网(ER)-吞噬在潜伏感染期间寄生虫在宿主体内的持续存在中的关键作用。
