Characterization of the endogenous DAF-12 ligand and its use as an anthelmintic agent in Strongyloides stercoralis
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 infec...
| Main Authors: | , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
eLife Sciences Publications Ltd
2021-12-01
|
| Series: | eLife |
| Subjects: | |
| Online Access: | https://elifesciences.org/articles/73535 |
| _version_ | 1828203257788366848 |
|---|---|
| author | Zhu Wang Mi Cheong Cheong Jet Tsien Heping Deng Tian Qin Jonathan DC Stoltzfus Tegegn G Jaleta Xinshe Li James B Lok Steven A Kliewer David J Mangelsdorf |
| author_facet | Zhu Wang Mi Cheong Cheong Jet Tsien Heping Deng Tian Qin Jonathan DC Stoltzfus Tegegn G Jaleta Xinshe Li James B Lok Steven A Kliewer David J Mangelsdorf |
| author_sort | Zhu Wang |
| collection | DOAJ |
| description | 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 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. |
| first_indexed | 2024-04-12T12:02:35Z |
| format | Article |
| id | doaj.art-6f5f66e5684e47abbcc6fddb9b866e23 |
| institution | Directory Open Access Journal |
| issn | 2050-084X |
| language | English |
| last_indexed | 2024-04-12T12:02:35Z |
| publishDate | 2021-12-01 |
| publisher | eLife Sciences Publications Ltd |
| record_format | Article |
| series | eLife |
| spelling | doaj.art-6f5f66e5684e47abbcc6fddb9b866e232022-12-22T03:33:49ZengeLife Sciences Publications LtdeLife2050-084X2021-12-011010.7554/eLife.73535Characterization of the endogenous DAF-12 ligand and its use as an anthelmintic agent in Strongyloides stercoralisZhu Wang0https://orcid.org/0000-0003-0768-0988Mi Cheong Cheong1Jet Tsien2https://orcid.org/0000-0002-2052-8051Heping Deng3Tian Qin4Jonathan DC Stoltzfus5https://orcid.org/0000-0002-4006-5306Tegegn G Jaleta6Xinshe Li7James B Lok8Steven A Kliewer9https://orcid.org/0000-0001-5161-641XDavid J Mangelsdorf10https://orcid.org/0000-0002-4355-0796Department of Pharmacology, University of Texas Southwestern Medical Center, Dallas, United StatesDepartment of Pharmacology, University of Texas Southwestern Medical Center, Dallas, United StatesDepartment of Biochemistry, University of Texas Southwestern Medical Center, Dallas, United StatesDepartment of Biochemistry, University of Texas Southwestern Medical Center, Dallas, United StatesDepartment of Biochemistry, University of Texas Southwestern Medical Center, Dallas, United StatesDepartment of Biology, Millersville University of Pennsylvania, Millersville, United StatesDepartment of Pathobiology, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, United StatesDepartment of Pathobiology, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, United StatesDepartment of Pathobiology, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, United StatesDepartment of Pharmacology, University of Texas Southwestern Medical Center, Dallas, United States; Department of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, United StatesDepartment of Pharmacology, University of Texas Southwestern Medical Center, Dallas, United States; Howard Hughes Medical Institute, University of Texas Southwestern Medical Center, Dallas, United StatesA 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 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.https://elifesciences.org/articles/73535nematode parasitismStrongyloides stercoralisDAF-12nuclear receptorivermectingerbil |
| spellingShingle | Zhu Wang Mi Cheong Cheong Jet Tsien Heping Deng Tian Qin Jonathan DC Stoltzfus Tegegn G Jaleta Xinshe Li James B Lok Steven A Kliewer David J Mangelsdorf Characterization of the endogenous DAF-12 ligand and its use as an anthelmintic agent in Strongyloides stercoralis eLife nematode parasitism Strongyloides stercoralis DAF-12 nuclear receptor ivermectin gerbil |
| title | Characterization of the endogenous DAF-12 ligand and its use as an anthelmintic agent in Strongyloides stercoralis |
| title_full | Characterization of the endogenous DAF-12 ligand and its use as an anthelmintic agent in Strongyloides stercoralis |
| title_fullStr | Characterization of the endogenous DAF-12 ligand and its use as an anthelmintic agent in Strongyloides stercoralis |
| title_full_unstemmed | Characterization of the endogenous DAF-12 ligand and its use as an anthelmintic agent in Strongyloides stercoralis |
| title_short | Characterization of the endogenous DAF-12 ligand and its use as an anthelmintic agent in Strongyloides stercoralis |
| title_sort | characterization of the endogenous daf 12 ligand and its use as an anthelmintic agent in strongyloides stercoralis |
| topic | nematode parasitism Strongyloides stercoralis DAF-12 nuclear receptor ivermectin gerbil |
| url | https://elifesciences.org/articles/73535 |
| work_keys_str_mv | AT zhuwang characterizationoftheendogenousdaf12ligandanditsuseasananthelminticagentinstrongyloidesstercoralis AT micheongcheong characterizationoftheendogenousdaf12ligandanditsuseasananthelminticagentinstrongyloidesstercoralis AT jettsien characterizationoftheendogenousdaf12ligandanditsuseasananthelminticagentinstrongyloidesstercoralis AT hepingdeng characterizationoftheendogenousdaf12ligandanditsuseasananthelminticagentinstrongyloidesstercoralis AT tianqin characterizationoftheendogenousdaf12ligandanditsuseasananthelminticagentinstrongyloidesstercoralis AT jonathandcstoltzfus characterizationoftheendogenousdaf12ligandanditsuseasananthelminticagentinstrongyloidesstercoralis AT tegegngjaleta characterizationoftheendogenousdaf12ligandanditsuseasananthelminticagentinstrongyloidesstercoralis AT xinsheli characterizationoftheendogenousdaf12ligandanditsuseasananthelminticagentinstrongyloidesstercoralis AT jamesblok characterizationoftheendogenousdaf12ligandanditsuseasananthelminticagentinstrongyloidesstercoralis AT stevenakliewer characterizationoftheendogenousdaf12ligandanditsuseasananthelminticagentinstrongyloidesstercoralis AT davidjmangelsdorf characterizationoftheendogenousdaf12ligandanditsuseasananthelminticagentinstrongyloidesstercoralis |