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内源性 DAF-12 配体的鉴定及其作为驱虫剂在. 中的应用

Characterization of the endogenous DAF-12 ligand and its use as an anthelmintic agent in .

机构信息

Department of Pharmacology, University of Texas Southwestern Medical Center, Dallas, United States.

Department of Biochemistry, University of Texas Southwestern Medical Center, Dallas, United States.

出版信息

Elife. 2021 Dec 7;10:e73535. doi: 10.7554/eLife.73535.

DOI:10.7554/eLife.73535
PMID:34874004
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC8651287/
Abstract

A prevalent feature of is a life-long and potentially lethal infection that is due to the nematode parasite's ability to autoinfect and, thereby, self-replicate within its host. Here, we investigated the role of the parasite's nuclear receptor, DAF-12, in governing infection. We identified Δ7-DA as the endogenous DAF-12 ligand and elucidated the hormone's biosynthetic pathway. Genetic loss of function of the ligand's rate-limiting enzyme demonstrated that Δ7-DA synthesis is necessary for parasite reproduction, whereas its absence is required for the development of infectious larvae. Availability of the ligand permits DAF-12 to function as an on/off switch governing autoinfection, making it vulnerable to therapeutic intervention. In a preclinical model of hyperinfection, pharmacologic activation of DAF-12 suppressed autoinfection and markedly reduced lethality. Moreover, when Δ7-DA was administered with ivermectin, the current but limited drug of choice for treating strongyloidiasis, the combinatorial effects of the two drugs resulted in a near cure of the disease.

摘要

一种普遍的特征是一种终身的、潜在致命的感染，这是由于线虫寄生虫能够自动感染，并在其宿主内自我复制。在这里，我们研究了寄生虫核受体 DAF-12 在控制感染中的作用。我们确定 Δ7-DA 是内源性 DAF-12 配体，并阐明了激素的生物合成途径。配体限速酶的遗传功能丧失表明，Δ7-DA 的合成对于寄生虫的繁殖是必要的，而其缺失对于传染性幼虫的发育是必需的。配体的可用性允许 DAF-12 作为一个开/关开关来控制自动感染，使其容易受到治疗干预。在一种过度感染的临床前模型中，DAF-12 的药理学激活抑制了自动感染，并显著降低了死亡率。此外，当 Δ7-DA 与伊维菌素联合使用时，伊维菌素是目前治疗类圆线虫病的有限选择药物，这两种药物的联合作用导致该疾病几乎被治愈。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0120/8651287/3f15ced814fb/elife-73535-fig8.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0120/8651287/805a9c8d7c0c/elife-73535-fig1.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0120/8651287/df3ec7eefa31/elife-73535-fig5-figsupp1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0120/8651287/a7fa2f96b745/elife-73535-fig6.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0120/8651287/a4ddf05717c2/elife-73535-fig6-figsupp1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0120/8651287/94234d0258cb/elife-73535-fig7.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0120/8651287/1af4fd5504ae/elife-73535-fig7-figsupp1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0120/8651287/3f15ced814fb/elife-73535-fig8.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0120/8651287/805a9c8d7c0c/elife-73535-fig1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0120/8651287/49823182e2f9/elife-73535-fig2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0120/8651287/f11719eb5af4/elife-73535-fig2-figsupp1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0120/8651287/11374594b0b7/elife-73535-fig2-figsupp2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0120/8651287/bceabdba8d8f/elife-73535-fig3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0120/8651287/022d1eecb4dd/elife-73535-fig4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0120/8651287/b9e153bc7b62/elife-73535-fig4-figsupp1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0120/8651287/974cebc55800/elife-73535-fig5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0120/8651287/df3ec7eefa31/elife-73535-fig5-figsupp1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0120/8651287/a7fa2f96b745/elife-73535-fig6.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0120/8651287/a4ddf05717c2/elife-73535-fig6-figsupp1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0120/8651287/94234d0258cb/elife-73535-fig7.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0120/8651287/1af4fd5504ae/elife-73535-fig7-figsupp1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0120/8651287/3f15ced814fb/elife-73535-fig8.jpg

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