Abstract
The infectious form of many parasitic nematodes, which afflict over one billion people globally, is a developmentally arrested third-stage larva (L3i). The parasitic nematode Strongyloides stercoralis differs from other nematode species that infect humans, in that its life cycle includes both parasitic and free-living forms, which can be leveraged to investigate the mechanisms of L3i arrest and activation. The free-living nematode Caenorhabditis elegans has a similar developmentally arrested larval form, the dauer, whose formation is controlled by four pathways: cyclic GMP (cGMP) signaling, insulin/IGF-1-like signaling (IIS), transforming growth factor β (TGFβ) signaling, and biosynthesis of dafachronic acid (DA) ligands that regulate a nuclear hormone receptor. We hypothesized that homologous pathways are present in S. stercoralis, have similar developmental regulation, and are involved in L3i arrest and activation. To test this, we undertook a deep-sequencing study of the polyadenylated transcriptome, generating over 2.3 billion paired-end reads from seven developmental stages. We constructed developmental expression profiles for S. stercoralis homologs of C. elegans dauer genes identified by BLAST searches of the S. stercoralis genome as well as de novo assembled transcripts. Intriguingly, genes encoding cGMP pathway components were coordinately up-regulated in L3i. In comparison to C. elegans, S. stercoralis has a paucity of genes encoding IIS ligands, several of which have abundance profiles suggesting involvement in L3i development. We also identified seven S. stercoralis genes encoding homologs of the single C. elegans dauer regulatory TGFβ ligand, three of which are only expressed in L3i. Putative DA biosynthetic genes did not appear to be coordinately regulated in L3i development. Our data suggest that while dauer pathway genes are present in S. stercoralis and may play a role in L3i development, there are significant differences between the two species. Understanding the mechanisms governing L3i development may lead to novel treatment and control strategies.
Highlights
Parasitic nematodes infect over one billion people worldwide, resulting in vast morbidity [1], as well as causing significant agricultural losses from infections of both animals and plants [2]
Understanding L3i development may lead to novel control strategies as well as new treatments for strongyloidiasis and other diseases caused by parasitic nematodes
While we have demonstrated that S. stercoralis IGF-1like signaling (IIS) plays a crucial role in post-free-living L3i arrest and activation [10,22], we have shown that an S. stercoralis transforming growth factor b (TGFb) ligand encoding gene, Ss-tgh-1, is transcriptionally regulated in a manner opposite to that of the C. elegans TGFb ligand encoding gene Ce-daf-7 [20,23]
Summary
Parasitic nematodes infect over one billion people worldwide, resulting in vast morbidity [1], as well as causing significant agricultural losses from infections of both animals and plants [2]. The infectious form of many parasitic nematodes, including those causing hookworm disease, filariasis, and strongyloidiasis, is a developmentally arrested third-stage larva (L3i), which is both stress-resistant and long-lived [3,4,5]. Our lab uses the parasitic nematode Strongyloides stercoralis, which infects 30–100 million people globally [1], to study mechanisms controlling L3i arrest and activation [6]. Post-free-living larvae constitutively form L3i [7] This life cycle allows us to investigate the mechanisms underlying different developmental fates for similar larval forms. We have developed molecular tools in S. stercoralis, which are unavailable in other parasitic nematodes, to investigate molecular mechanisms involved in L3i regulation [8,9,10]
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