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Signaling Proteins of the Human Liver Fluke, Opisthorchis Viverrini Signaling Proteins of the Human Liver Fluke, Opisthorchis viverrini by Sandi K. Parriott B.S. in Biomedical Science, May 1984, Texas A&M University B.S. in Animal Science, May 1985, Texas A&M University DVM in Veterinary Medicine, May 1992, Texas A&M University A dissertation submitted to The Faculty of Columbian College of Arts and Sciences of The George Washington University in partial fulfillment of the requirements for the degree of Doctor of Philosophy August 31, 2012 Dissertation directed by Paul J. Brindley Professor of Microbiology, Immunology, and Tropical Medicine The Columbian College of Arts and Sciences of The George Washington University certifies that Sandi Kay Parriott has passed the Final Examination for the degree of Doctor of Philosophy as of May 31, 2012. This is the final and approved form of the dissertation. “Signaling Proteins of the Human Liver Fluke, Opisthorchis viverrini” Sandi K. Parriott Dissertation Research Committee: Paul J. Brindley, Professor of Microbiology, Immunology, & Tropical Medicine, Dissertation Director John M. Hawdon, Associate Professor of Microbiology & Tropical Medicine & of Biological Sciences, Committee Member Alexander Loukas, Adjunct Assistant Professor of Microbiology, Immunology, & Tropical Medicine, Committee Member ii ©Copyright 2012 by Sandi K. Parriott All rights reserved iii Dedication The author wishes to dedicate this work to my loving husband, Daniel J. Simons, and my parents, Robert and Joan Parriott, whose constant support and encouragement kept me focused on the ultimate goal. I’d also like to dedicate this work to my mentors and colleagues at Walter Reed Army Institute of Research, primarily LTC Michael T. O’Neil, LTC Mark R. Hickman, Dr. Thomas Hudson, and COL Michael Kozar, who pushed, prodded, and cajoled me to finish despite my ‘just trying to keep up with my day job”. iv Acknowledgement The author wishes to acknowledge Dr. Sutas Suttiprapa who brought his knowledge of proteins, Opisthorchis viverrini, positive attitude, and patience to our laboratory during his post-doctoral studies. You are a wonderful mentor and teacher. It was a great pleasure working with and learning from you. I’d also like to thank Dr. Paul J. Brindley, my advisor, for his guidance and willingness to take on a veterinarian with no molecular biology background but a desire to learn. Thank you. No laboratory would be complete without its own cast of characters. I’d like to thank all the graduate students that worked with me in our laboratory – Dr. Maria Morales, Dr. Kristine Kines, Dr. Gabriel Rinaldi, Dr. Tunika Okatcha, Dr. Yousef Alrefaei, Danielle Skinner, and our lab manager, Dr. Victoria Mann. Thanks for sharing the ups and downs. A very special thanks goes to Jordan Pleiskett whose expertise helped to make a much improved second anti-O.viverrini caspase 9 antibody for use in the immunolocalization studies. Finally, this work was supported by NIH award UO1AI065871 and the Long Term Health Education Training (LTHET) program of the Veterinary Corps, Medical Command, United States Army. v Abstract of Dissertation Signaling proteins of the human liver fluke, Opisthorchis viverrini Cholangiocarcinoma (CCA) – cancer of the bile ducts – is associated with chronic infection with the oriental liver fluke, Opisthorchis viverrini. Despite being one of only three eukaryotic organisms designated as a ‘Group 1 carcinogen” by the International Agency of Research on Cancer (IARC), research into the transcriptome and genome of this enigmatic parasite is still in its infancy. A gene discovery project for O. viverrini using the expressed sequence tag (EST) approach was begun in 2007 (Laha, 2007). Among other genes, EST’s representing putatively secreted or transmembrane proteins with known roles in tumor induction and progression were identified. The characterization of three of these secreted or transmembrane proteins, an orthologue of caspase 9, fibroblast growth factor receptor substrate 2 (FRS2), and transforming growth factor – β receptor type 1 (TGF-βR1) are presented here. All three are members of signaling pathways involved in practically all aspects of cell behavior and homeostasis (Cooper and Hausman, 2007). Apoptosis – programmed cell death – is a fundamental physiological process of metazoan growth and development as well as a protective mechanism against pathogenic changes. Proteases termed caspases are key mediators in the control and pathways of apoptosis. Function and role of component caspases have been the subjects of concentrated scrutiny over the past decade or so. Caspase 9 is the apical caspase of the intrinsic pathway of apoptosis which is activated by cytochrome c release from the vi mitochondrion in response to ionizing radiation, chemotherapeutic drugs, mitochondrial damage, and specific developmental cues. Once activated, caspase 9 functions downstream to activate the caspase 3, 7 executioner caspases which stimulate DNase production and cell death. In studies described here, low levels of apoptosis were noted in adult liver flukes infecting hamster bile ducts by TUNEL analysis. Bioinformatic and phylogenetic analyses of the O. viverrini caspase 9 elucidated the conserved domains found in all caspases and those orthologues specific to caspase 9 such as the caspase activating and recruitment domain or CARD, catalytic site containing the active cysteine residue, and conserved aspartate acid residues. Cloning, expression, and purification were carried out in two different expression vector constructs allowing thorough analyses of the protein. O. viverrini caspase 9 substrate specificity was verified using the Caspase Glo-9® luciferase-based assay (Promega) followed by inhibition of O. viverrini caspase 9 activity by a caspase 9 specific reversible aldehyde, Ac-LEHD-CHO. As expected for the initiator of one apoptotic process crucial to homeostasis and development in eukaryotes, O. viverrini caspase 9 was found in all developmental stages evaluated by reverse transcription-PCR. The TGF-β pathway is involved in all aspects of cell behavior and growth. It is activated by TGF-β binding with TGF-β receptor type 2 (TGF-βR2) which then binds to TGF-βR1 and stimulates the cascade effect culminating in changes in gene expression affecting cell growth and behavior. This is one of the best characterized of the signaling pathways in trematodes especially in Schistosoma mansoni. A putative O. viverrini TGF- βR1 was identified through multiple sequence alignments and bioinformatics analyses. Only a portion of the serine threonine kinase domain has been found in the 197 aa vii residues. 5’ RACE was only able to find 15 additional amino acids in the contig to total 212aa. The O. viverrini partial serine threonine kinase domain is extremely well conserved when compared with other well-known trematode orthologues such as S. mansoni and Echinococcus multilocularis. Future studies and evaluation of other contigs may help to complete the 5’ end of the O. viverrini TGF-βR1. Fibroblast growth factors (FGF) induce biological responses by binding to and activating a family of cell surface receptors called FGF receptors. Docking or adaptor proteins lack catalytic action but relay key events of signal transduction from upstream to downstream elements are the FGF receptor substrates. FRS2 is a lipid-anchored docking protein crucial to FGF stimulation of Ras/MAPK and Ras/ERK pathways. Bioinformatic analyses and multiple sequence alignments indicated the presence of conserved domains found in orthologous FRS2 such as myristylation sites, Grb2 and Shp2 binding sites, and protein tyrosine binding (PTB) domain in the O. viverrini FRS2. Cloning, expression, and purification of the O. viverrini FRS2 have been completed. Developmental stage evaluation using reverse transcription (RT)- PCR has shown, as expected, O. viverrini FRS2 is present in all life cycle stages tested: eggs, metacercariae, juvenile flukes < 1 month of age, and adult flukes. Disruption of signaling pathways controlling homeostasis and physiologic activities have been shown to result in pathology in many species. The O. viverrini signaling proteins in this dissertation are all factors in essential signaling pathways whose roles within the parasite have yet to be discovered but may provide future targets of intervention for chemotherapeutic and/or vaccine targets. The findings presented here characterizing, to varying degrees, O. viverrini caspase 9, FRS2, and TGF-βR1 can be viii expected to provide a foundation for further studies into the physiology of the human liver fluke. ix Table of Contents Dedication………………………………………………………………...………. .iv Acknowledgement………………………………………………………..………. v Abstract of Dissertation…………………………………………………...………. vi Table of Contents…………………………………………………………..…….. x List of Figures………………………………………………………..…………… xi List of Tables………………………………………………………………..……. xiv List of Abbreviations……………………………………………………..………. xv Chapter 1: Background and Literature Review…………………………….…..…. 1 Chapter 2: Hypothesis and Aims……………………………...………..….……… 28 Chapter 3: Materials and Methods………………………….. ……….……...……. 32 Chapter 4: Results...…………………………………………………….…...…….. 58 Chapter 5: Discussion.……………………………………………….....…………. 110 References.……………………………………………………….…….....……….. 123 Appendices ………………………………………………………….….....………. 142 Appendix A (permissions for image use).………………….…...……..…... 142 Appendix B (protein sequencing report) …………………….…………… 154 x List of Figures Figure 1. Distribution and prevalence of O.viverrini in the northeast of Thailand (surveyed
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