Parasitic nematodes infect a significant proportion of the world's population and exact an enormous toll of human illness. These parasites infect their hosts as developmentally arrested infective larvae (usually third-stage larvae, (L3i) that resume development once they enter the host. Drawing upon extensive relevant findings in Caenorhabditis elegans, we have uncovered definitive evidence that insulin-like (ILS) and steroid-nuclear hormone receptor (NHR) signaling regulate L3i development before and during the infective process in the parasitic nematode Strongyloides stercoralis. In this renewal application, we propose to complete our studies on regulation of L3i development by ILS in S. stercoralis and initiate new research on the potential of a conserved steroid NHR signaling pathway as a therapeutic target in this parasite. The first of our two Specific Aims asks whether insulin signaling regulates formation and maintenance of L3i by S. stercoralis. Specifically we will determine whether the insulin-like receptor kinase Ss-DAF-2 and the PI3 kinase Ss-AGE-1 block arrest of L3i and promote their developmental reactivation in the host and whether insulin-like peptides Ss-ILP-6 and Ss-ILP-7 promote developmental reactivation and arrest of L3i, respectively. Our approach will involve analyzing phenotypes that result from expressing dominant transgene constructs based on these molecules in S. stercoralis.
Specific Aim 2 will ask whether signaling through the Ss-DAF-12 NHR augments regulatory ILS effects in S. stercoralis and whether this small molecule receptor could be a target for chemotherapy based on naturally occurring steroids or their analogs. We propose to identify the natural ligands of Ss-DAF-12 and compare their activity in regulating L3i arrest and reactivation to the DAF-12 ligands from C. elegans, D4- and D7-dafachronic acids (DA). We will use chemical inhibitors to probe endogenous NHR DAF-12 function in S. stercoralis and use a gerbil model of infection to determine whether administered Ss-daf-12 inhibitors or DA can prevent development of L3i, clear adult worm infections and/or block fulminant autoinfection, a potentially fatal complication of human strongyloidiasis. These experiments will directly reflect the potential of DAF-12 NHR function as a chemotherapeutic target in parasitic nematodes.
Parasitic roundworms adversely affect the health of over a billion people worldwide. Although a small number of effective drugs are now available to treat these infections, there are early signs that some parasitic roundworms are becoming resistant to them. This application proposes to study aspects of parasite metabolism that could form the basis for new drugs to prevent or treat roundworm infection.
|Albarqi, Mennatallah M Y; Stoltzfus, Jonathan D; Pilgrim, Adeiye A et al. (2016) Regulation of Life Cycle Checkpoints and Developmental Activation of Infective Larvae in Strongyloides stercoralis by Dafachronic Acid. PLoS Pathog 12:e1005358|
|Hunt, Vicky L; Tsai, Isheng J; Coghlan, Avril et al. (2016) The genomic basis of parasitism in the Strongyloides clade of nematodes. Nat Genet 48:299-307|
|Lok, J B; Shao, H; Massey, H C et al. (2016) Transgenesis in Strongyloides and related parasitic nematodes: historical perspectives, current functional genomic applications and progress towards gene disruption and editing. Parasitology :1-16|
|Mohandas, Namitha; Hu, Min; Stroehlein, Andreas J et al. (2016) Reconstruction of the insulin-like signalling pathway of Haemonchus contortus. Parasit Vectors 9:64|
|Wang, Zhu; Stoltzfus, Jonathan; You, Young-Jai et al. (2015) The nuclear receptor DAF-12 regulates nutrient metabolism and reproductive growth in nematodes. PLoS Genet 11:e1005027|
|Yuan, Wang; Lok, James B; Stoltzfus, Jonathan D et al. (2014) Toward understanding the functional role of Ss-RIOK-1, a RIO protein kinase-encoding gene of Strongyloides stercoralis. PLoS Negl Trop Dis 8:e3062|
|Stoltzfus, Jonathan D; Bart, Stephen M; Lok, James B (2014) cGMP and NHR signaling co-regulate expression of insulin-like peptides and developmental activation of infective larvae in Strongyloides stercoralis. PLoS Pathog 10:e1004235|
|Li, Fa-Cai; Gasser, Robin B; Lok, James B et al. (2014) Exploring the role of two interacting phosphoinositide 3-kinases of Haemonchus contortus. Parasit Vectors 7:498|
|Yuan, Wang; Liu, Yingying; Lok, James B et al. (2014) Exploring features and function of Ss-riok-3, an enigmatic kinase gene from Strongyloides stercoralis. Parasit Vectors 7:561|
|Bonne-AnnÃ©e, Sandra; Kerepesi, Laura A; Hess, Jessica A et al. (2014) Extracellular traps are associated with human and mouse neutrophil and macrophage mediated killing of larval Strongyloides stercoralis. Microbes Infect 16:502-11|
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