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.

Public Health Relevance

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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI050668-10
Application #
8738598
Study Section
Pathogenic Eukaryotes Study Section (PTHE)
Program Officer
Mcgugan, Glen C
Project Start
2002-04-01
Project End
2018-08-31
Budget Start
2014-09-01
Budget End
2015-08-31
Support Year
10
Fiscal Year
2014
Total Cost
Indirect Cost
Name
University of Pennsylvania
Department
Pathology
Type
Schools of Veterinary Medicine
DUNS #
City
Philadelphia
State
PA
Country
United States
Zip Code
19104
Lok, J B; Shao, H; Massey, H C et al. (2017) Transgenesis in Strongyloides and related parasitic nematodes: historical perspectives, current functional genomic applications and progress towards gene disruption and editing. Parasitology 144:327-342
Shao, Hongguang; Li, Xinshe; Lok, James B (2017) Heritable genetic transformation of Strongyloides stercoralis by microinjection of plasmid DNA constructs into the male germline. Int J Parasitol 47:511-515
Lok, James B (2016) Signaling in Parasitic Nematodes: Physicochemical Communication Between Host and Parasite and Endogenous Molecular Transduction Pathways Governing Worm Development and Survival. Curr Clin Microbiol Rep 3:186-197
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
Mohandas, Namitha; Hu, Min; Stroehlein, Andreas J et al. (2016) Reconstruction of the insulin-like signalling pathway of Haemonchus contortus. Parasit Vectors 9:64
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
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
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
Li, Facai; Lok, James B; Gasser, Robin B et al. (2014) Hc-daf-2 encodes an insulin-like receptor kinase in the barber's pole worm, Haemonchus contortus, and restores partial dauer regulation. Int J Parasitol 44:485-96

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