- Molecular control of infective larval development in parasitic nematodes.
- Sensory and neuronal regulation of the infective process in parasitic nematodes.
- Molecular signaling between parasites and their hosts.
Key words: Strongyloides, Caenorhabditis, transcription factor, dauer, G protein, TGF beta, parasite, nematode.
Description of Research
The Lok lab's primary interest is the endogenous mechanisms governing developmental arrest and lifespan in parasitic nematodes. In the free-living nematode Caenorhabditis elegans, output from an insulin/IGF-like signal transduction pathway is critical to both these factors. We are currently using the intestinal parasite Strongyloides stercoralis and S. ratti to test the hypothesis that insulin signaling also regulates arrest and reactivation of infective, autoinfective and hypobiotic third-stage larvae, as well as lifespan in these chronic latent stages of parasitic nematodes. In testing this hypothesis we have determined that genes encoding key elements of the C. elegans insulin/IGF pathway are conserved in Strongyloides spp. We are now using C. elegans as a genetic surrogate to assess function of Strongyloides daf-2, age-1 and daf-16, orthologs of the insulin receptor, PI3 kinase and forkhead transcription factor, respectively in the C. elegans insulin pathway. Specifically we are asking whether these genes can complement loss-of-function mutations in their orthologs when expressed in C. elegans as heterologous transgenes. We are also developing a system for transgenesis in Strongyloides spp. and are now using it to study functions of these genes using transgene-encoded dominant mutations predicted to confer gain or loss of function in insulin-like signaling molecules. In addition to our work with insulin-like signaling, we have also determined that S. stercoralis has also conserved elements of three other signal transduction pathways that regulate dauer development in C. elegans, a steroid nuclear hormone receptor (NHR) pathway, a G protein-mediated odorant receptor pathway and a TGF-ß-like signal pathway. We are currently investigating links between the insulin-like and DAF-12 NHR signaling. The steroid ligands of Ss-DAF-12 are being evaluated as drug candidates in Strongyloides infection.
1. Mobilizing transposable elements in the genome of Strongyloides spp.
2. Developmental function of the DAF-12 nuclear hormone receptor in Strongyloides spp.
4. Structure and function of a TGF-beta superfamily growth factor in Strongyloides spp.
• Holman Massey, Jr., Ph.D. – Research Specialist
• Xinshi Li, M.D. – Research Specialist
• Hongguang Shao, Ph.D. – Research Specialist
• Najju Ranjit, Ph.D. – Postdoctoral Fellow
• He Zhu, Ph.D. – Postdoctoral Fellow
• Jonathan Stoltzfus – Predoctoral Student
• Beth Maguire – Lab Manager/Technician
• Sara Haus – Technician
Ramanathan R, Varma S, Ribeiro JMC, Myers TG, Nolan TJ, Abraham D, Lok JB, Nutman TB Microarray-based analysis of differential gene expression between infective and noninfective larvae of Strongyloides stercoralis. PLoS Neg. Trop. Dis. 5: , 2011.Li X, Shao H, Junio A, Nolan TJ, Massey HC Jr, Pearce EJ, Viney ME, Lok JB: Transgenesis in the parasitic nematode Strongyloides ratti. Mol. Biochem. Parasit. : , 2011.Zhu H, Li J, Nolan TJ, Schad GA, Lok JB Sensory neuroanatomy of Parastrongyloides trichosuri, a nematode parasite of mammals: amphidial neurons of the first-stage larva J. Comp. Neurol : , 2011.Hu, M, LOK, JB, Ranjit, N, Massey, HC Jr., Sternberg, PW, Gasser, RB Structural and functional characterization of the fork head transcription factor-encoding gene, Hc-daf-16, from the parasitic nematode Haemonchus contortus (Strongylida). Int. J. Parasitol. 40: 405-415, 2010.Wang Z, Zhou XE, Motola DL, Gao X, Suino-Powell K, Conneely A, Ogata C, Sharma KK, Auchus RJ, Lok JB, Hawdon JM, Kliewer SA, Xu HE, Mangelsdorf DJ Identification of the nuclear receptor DAF-12 as a therapeutic target in parasitic nematodes. Proc Natl Acad Sci U S A 106: 9138-9143, 2009.Castelletto M, Massey HC, Jr., LOK JB. (2009) Morphogenesis of Strongyloides stercoralis infective larvae requires the DAF-16 ortholog FKTF-1. PLoS Pathogens 5: , 2009.Junio, AJ, Li, X, Massey, HC Jr., Nolan, TJ, Lamitina, ST, Sundaram, MV and LOK, JB Strongyloides stercoralis: cell- and tissue-specific transgene expression and co-transformation with vector constructs incorporating a common multifunctional 3’ UTR. Exp. Parasitol. 118: 253-265., 2008.Ashton, F.T, Zhu, X., Boston, R., Lok, J.B., Schad, G.A. Strongyloides stercoralis: amphidial neuron pair ASJ triggers significant resumption of development by infective larvae of under host-mimicking in vitro conditions. Exp. Parasitol. 115: 92-97, 2007.Li X, Massey HC, Nolan TJ, Schad GA, Kraus K, Sundaram M, Lok JB Successful transgenesis of the parasitic nematode Strongyloides stercoralis requires endogenous non-coding control elements International Journal for Parasitology 36: 671-679, 2006.Massey HC, Bhopale MK, Li X, Castelletto M, Lok JB. The fork head transcription factor FKTF-1b from Strongyloides stercoralis restores DAF-16 developmental function to mutant Caenorhabditis elegans International Journal for Parasitology 36: 347-352, 2006.
B.S. (Biology) University of Southern Mississippi, Hattiesburg, Mississippi, 1975M.S. (Entomology; ) Cornell University, Ithaca, New York, , 1979Ph.D. (Entomology) Cornell University, Ithaca, New York, 1981M.S. (Honorary) University of Pennsylvania, Philadelphia, Pennsylvania, 1989