Characterization of the Endogenous DAF-12 Ligand and Its Use as an Anthelmintic Agent in Strongyloides stercoralis

Wang, Z.; Cheong, M. C.; Tsien, J.; Deng, H.; Qin, T.; Stoltzfus, J. D. C.; Jaleta, T. G.; Li, X.; Lok, J. B.; Kliewer, S. A.; Mangelsdorf, D. J.

doi:10.1101/2021.09.07.459359

bioRxiv · 10.1101/2021.09.07.459359

Characterization of the Endogenous DAF-12 Ligand and Its Use as an Anthelmintic Agent in Strongyloides stercoralis

Wang, Z.·Cheong, M. C.·Tsien, J.·Deng, H.·Qin, T.·Stoltzfus, J. D. C.·Jaleta, T. G.·Li, X.·Lok, J. B.·Kliewer, S. A.·Mangelsdorf, D. J.

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Abstract

A prevalent feature of Strongyloides stercoralis is a life-long and potentially lethal infection that is due to the nematode parasites ability to autoinfect and, thereby, self-replicate within its host. Here, we investigated the role of the parasites nuclear receptor, Ss-DAF-12, in governing infection. We identified {Delta}7-DA as the endogenous Ss-DAF-12 ligand and elucidated the hormones biosynthetic pathway. Genetic loss of function of the ligands rate-limiting enzyme demonstrated that {Delta}7-DA synthesis is necessary for parasite reproduction, whereas its absence is required for 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 {Delta}7-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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Wang, Z., Cheong, M. C., Tsien, J., Deng, H., Qin, T., Stoltzfus, J. D. C., Jaleta, T. G., Li, X., Lok, J. B., Kliewer, S. A., Mangelsdorf, D. J.. 2021-09-08. Characterization of the Endogenous DAF-12 Ligand and Its Use as an Anthelmintic Agent in Strongyloides stercoralis. https://doi.org/10.1101/2021.09.07.459359

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