TY - JOUR
T1 - Characterization of the endogenous DAF-12 ligand and its use as an anthelmintic agent in Strongyloides stercoralis
AU - Wang, Zhu
AU - Cheong, Mi Cheong
AU - Tsien, Jet
AU - Deng, Heping
AU - Qin, Tian
AU - Stoltzfus, Jonathan D.C.
AU - Jaleta, Tegegn G.
AU - Li, Xinshe
AU - Lok, James B.
AU - Kliewer, Steven A.
AU - Mangelsdorf, David J.
N1 - Funding Information:
Funder Grant reference number Author National Institutes of Health National Institutes of Health National Institutes of Health AI105856 GM141088 AI050886 James B Lok Steven A Kliewer David J Mangelsdorf Tian Qin James B Lok Welch Foundation I-1275 David J Mangelsdorf Welch Foundation I-1558 Steven A Kliewer Welch Foundation I-2010-20190330 Tian Qin Howard Hughes Medical Institute David J Mangelsdorf The funders had no role in study design, data collection, and interpretation, or the decision to submit the work for publication.
Funding Information:
We thank members of the Mango/Kliewer lab and Dr. Jeffrey McDonald (UT Southwestern) for fruitful discussions; Dr. Elissa Hallem (UCLA) for providing CRISPR plasmids; Adeiye Pilgrim (Emory) for assistance with cloning. This work was supported by the National Institutes of Health (grant AI105856 to JBL, DJM, and SAK, GM141088 to TQ, and AI050886 to JBL), the Robert A Welch Foundation (grants I-1275 to DJM, I-1558 to SAK, and I-2010-20190330 to TQ), UT Southwestern Eugene McDermott Scholarship (TQ), and the Howard Hughes Medical Institute (DJM).
Publisher Copyright:
© 2021, eLife Sciences Publications Ltd. All rights reserved.
PY - 2021/12
Y1 - 2021/12
N2 - A prevalent feature of Strongyloides stercoralis 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, Ss-DAF-12, in governing infection. We identified Δ7-DA as the endogenous Ss-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 Ss-DAF-12 to function as an on/ off switch governing autoinfection, making it vulnerable to therapeutic intervention. In a preclin-ical 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.
AB - A prevalent feature of Strongyloides stercoralis 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, Ss-DAF-12, in governing infection. We identified Δ7-DA as the endogenous Ss-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 Ss-DAF-12 to function as an on/ off switch governing autoinfection, making it vulnerable to therapeutic intervention. In a preclin-ical 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.
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U2 - 10.7554/eLife.73535
DO - 10.7554/eLife.73535
M3 - Article
C2 - 34874004
AN - SCOPUS:85122001259
VL - 10
JO - eLife
JF - eLife
SN - 2050-084X
M1 - e73535
ER -