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 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.
Highlights
Strongyloidiasis is a neglected tropical disease caused by the nematode parasite, Strongyloides stercoralis
The endogenous Ss-DAF-1 2 ligand was unknown, we demonstrated that pharmacologic administration of Δ7-DA to postparasitic L1 (PP-L1) or post- free-living (PFL)-L1 larvae commits them to FL reproductive development, even under conditions that would normally commit them to become L3i (Albarqi et al, 2016; Wang et al, 2009), and institutes a transcriptomic profile in L3i similar to L3+ (Stoltzfus et al, 2014)
The finding that the ligand binding pocket of Ss-DAF-1 2 is divergent from that of C. elegans (Ce)-DAF-12 (Wang et al, 2009) and the observation that S. stercoralis lacks an obvious ortholog of DAF-9 suggested that the Ss-DAF-12 ligand would likewise be divergent
Summary
Strongyloidiasis is a neglected tropical disease caused by the nematode parasite, Strongyloides stercoralis. Because of the unique nature of its lifecycle, S. stercoralis infections are often life-long and. Microbiology and Infectious Disease up to 2.5% of these infections will progress to a hyperinfection syndrome that has a 90% mortality rate if untreated (Milder et al, 1981). Such hyperinfections are often caused by administering glucocorticoids to otherwise asymptomatic patients (Milder et al, 1981).
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