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

Zhu Wang, Mi Cheong Cheong, Jet Tsien, Heping Deng, Tian Qin, Jonathan D.C. Stoltzfus, Tegegn G. Jaleta, Xinshe Li, James B. Lok, Steven A. Kliewer, David J. Mangelsdorf

Research output: Contribution to journalArticlepeer-review

2 Scopus citations

Abstract

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.

Original languageEnglish (US)
Article numbere73535
JournaleLife
Volume10
DOIs
StatePublished - Dec 2021

ASJC Scopus subject areas

  • Neuroscience(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Immunology and Microbiology(all)

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