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 - 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
SN - 2050-084X
VL - 10
JO - eLife
JF - eLife
M1 - e73535
ER -