<em>Strongyloides stercoralis</em> <em>age-1</em>: A Potential Regulator of Infective Larval Development in a Parasitic Nematode

<div><p>Infective third-stage larvae (L3i) of the human parasite <em>Strongyloides stercoralis</em> share many morphological, developmental, and behavioral attributes with <em>Caenorhabditis elegans</em> dauer larvae. The ‘dauer hypothesis’ predicts that the same molecular genetic mechanisms control both dauer larval development in <em>C. elegans</em> and L3i morphogenesis in <em>S. stercoralis</em>. In <em>C. elegans</em>, the phosphatidylinositol-3 (PI3) kinase catalytic subunit AGE-1 functions in the insulin/IGF-1 signaling (IIS) pathway to regulate formation of dauer larvae. Here we identify and characterize <em>Ss-age-1</em>, the <em>S. stercoralis</em> homolog of the gene encoding <em>C. elegans</em> AGE-1. Our analysis of the <em>Ss-age-1</em> genomic region revealed three exons encoding a predicted protein of 1,209 amino acids, which clustered with <em>C. elegans</em> AGE-1 in phylogenetic analysis. We examined temporal patterns of expression in the <em>S. stercoralis</em> life cycle by reverse transcription quantitative PCR and observed low levels of <em>Ss-age-1</em> transcripts in all stages. To compare anatomical patterns of expression between the two species, we used <em>Ss-age-1</em> or <em>Ce-age-1</em> promoter<em>::enhanced green fluorescent protein</em> reporter constructs expressed in transgenic animals for each species. We observed conservation of expression in amphidial neurons, which play a critical role in developmental regulation of both dauer larvae and L3i. Application of the PI3 kinase inhibitor LY294002 suppressed L3i <em>in vitro</em> activation in a dose-dependent fashion, with 100 µM resulting in a 90% decrease (odds ratio: 0.10, 95% confidence interval: 0.08–0.13) in the odds of resumption of feeding for treated L3i in comparison to the control. Together, these data support the hypothesis that <em>Ss-age-1</em> regulates the development of <em>S. stercoralis</em> L3i via an IIS pathway in a manner similar to that observed in <em>C. elegans</em> dauer larvae. Understanding the mechanisms by which infective larvae are formed and activated may lead to novel control measures and treatments for strongyloidiasis and other soil-transmitted helminthiases.</p>