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Novel Therapeutic Approach for Regulating the Susceptibility NOVEL THERAPEUTIC APPROACH FOR REGULATING THE SUSCEPTIBILITY OF EPITHELIA TO ADENOVIRUS INFECTION A Dissertation submitted in partial fulfillment of the requirements for the degree of Doctor of Philosophy By Mahmoud S Alghamri B.Pharm, Alazhar University, Gaza, Palestine M.S., Wright State University, Dayton, USA 2016 Wright State University COPYRIGHT BY MAHMOUD S ALGHAMRI 2016 WRIGHT STATE UNIVERSITY GRADUATE SCHOOL August 1, 2016 I HEREBY RECOMMEND THAT THE DISSERTATION PREPARED UNDER MY SUPERVISION BY Mahmoud S Alghamri ENTITLED Novel Therapeutic Approach for Regulating the Susceptibility of Epithelia to Adenovirus Infection BE ACCEPTED IN PARTIAL FULFILMENT OF THE REQUIREMENTS FOR THE DEGREE OF Doctor of Philosophy Katherine J.D.A. Excoffon, Ph.D. Dissertation Director Mill W. Miller, Ph.D. Director, Biomedical Sciences Ph.D program Robert E. W. Fyffe, Ph.D. Vice President for Research and Dean of the Committee on Final Examination Graduate School David R. Cool, Ph.D. David R. Ladle, Ph.D. Quan Zhong, Ph.D. Weiwen Long, Ph.D. Abstract Mahmoud S Alghamri Ph.D. Biomedical Sciences Ph.D. Program. Wright State University, 2016. Novel therapeutic approach for regulating the susceptibility of epithelia to adenovirus infection. Human Adenoviruses (AdVs) are etiologic agents for respiratory tract, digestive tract, heart, and eye infections. Although most AdV infections are self-resolving, some infections progress to acute respiratory disease with up to 50% mortality, particularly in immunosuppressed people. Except for vaccines for serotypes, 4 and 7, serotypes that are prevalent in the military, no vaccines or therapeutics that specifically prevent or treat AdV infection exist. On the other hand, AdV remains the most common vector system used in gene therapy clinical trials worldwide and several AdV vectors show promise in phase III clinical trials. The majority of AdVs use the coxsackievirus and adenovirus receptor (CAR) as a primary receptor. We have characterized an alternatively spliced eight-exon containing isoform (CAREx8) that localizes at the apical surface of epithelial cells and is responsible for the initiation of apical AdV infection. A cellular scaffold protein named Membrane Associated Guanylate Kinase, WW and PDZ Domain Containing 1 (MAGI-1) directly interacts with and alternatively regulates CAREx8 through the C-terminal PDZ-binding domain. The alternative regulation is due to the interaction with two different domains, namely PDZ1 and PDZ3, within the same molecule (MAGI-1). I hypothesized that cell permeable peptides that target the interaction between MAGI-1 PDZ1 domain and CAREx8 (TAT-PDZ1) would be able to decrease CAREx8 protein levels and prevent AdV iv infection. On the other hand, peptides that target the interaction between MAGI-1 PDZ3 domain and CAREx8 (TAT-PDZ3) would be able to increase CAREx8 and enhance AdV mediated gene therapy. Decoy peptides that target the assigned domain were synthesized and conjugated to TAT cell permeable peptide to facilitate peptide entry (TAT-PDZ1; TAT-NET1, TAT-E6) or (TAT-PDZ3; TAT-CAREx8-9c, TAT-ESAM). Peptide entry into the polarized epithelia was confirmed by mass spectroscopy and fluorescence microscopy. Treatment with TAT-PDZ1 peptides decreased the cellular levels of CAREx8 and suppressed AdV transduction in MDCK, human airway epithelia (HAE), as well as epithelia from cotton rats, an animal model of AdV pathogenicity. To determine the mechanism of peptide action, CAREx8 localization was tracked by immunofluorescence. Interestingly, TAT-PDZ1 caused nuclear translocation of CAREx8 C-term domain, an effect that was reversed by ADAM17 inhibitor (TIMP3) and γ-secretase inhibitor (Comp E), implicating the regulated intramembrane proteolysis (RIP) pathway. Immunoprecipitation and direct ligand binding assays showed that ADAM17 interacts specifically with MAGI-1 PDZ2 domain, suggesting that TAT-PDZ1 peptides caused CAREx8 degradation by enhancing the proximity of the substrate (CAREx8) and enzyme (ADAM17). Finally, ADAM17 caused CAREx8 extracellular domain (ECD) shedding that was able to significantly decrease AdV-GFP transduction, indicating a second protective role against AdV entry by the shed ECD of CAREx8. By contrast, TAT-PDZ3 peptides increased the levels of CAREx8 and significantly increased AdV entry and transduction in MDCK, HAE, and cotton rat epithelia. Upon TAT-PDZ3 peptide administration, CAREx8 was localized in vesicular pattern compartments distinct from MAGI-1 and spread throughout the apical trafficking pathway and at the apical surface of the epithelium. v Investigation of the trafficking pathway of CAREx8 using Rabs reveal the possibility of CAREx8 is residing within the recycling Endosomal-Golgi pathway. Neither TAT-PDZ1 nor TAT-PDZ3 binding peptides altered epithelium formation, as measured by transepithelial resistance (TER) as well as dextran permeability across the epithelia, indicating the safety of the peptides on epithelial integrity. Moreover, intranasal administration of TAT-PDZ3 peptides increased AdV transduction by 300-500% while TAT-PDZ1 peptides decreased AdV transduction by 80-95% after intranasal administration in mice demonstrating in vivo activity. Taken together, these results validate a potential therapeutic approach of TAT-PDZ1 that can be used as a prophylactic agent to protect susceptible populations from AdV infections or the TAT-PDZ3 which can enhance adenovirus transduction and offer the potential to increase the efficacy of adenovirus-mediated gene therapy. vi CONTENTS CHAPTER1: INTRODUCTION ..................................................................................... 1 ADENOVIRUSES ................................................................................................................ 1 CURRENT VACCINATION AND THERAPEUTIC STRATEGIES TO CONTROL ADV INFECTION .. 6 TARGETING THE HOST CELL AS POTENTIAL NEW ANTI-ADV OR PRO-GENE THERAPY STRATEGIES ...................................................................................................................... 7 ADENOVIRUS AS A VECTOR FOR GENE THERAPY ............................................................... 8 COXSACKIE AND ADENOVIRUS RECEPTOR (CAR) ......................................................... 10 CAR EXPRESSION ........................................................................................................... 11 SPLICING OF CAR .......................................................................................................... 12 CAREX8 MEDIATES ADENOVIRUS INFECTION OF PRIMARY AIRWAY EPITHELIA ................ 15 PDZ INTERACTIONS ....................................................................................................... 20 CAR INTERACTIONS WITH PDZ DOMAINS CONTAINING PROTEIN ................................... 22 MAGI-1, AN EASY VIRAL TARGET .................................................................................. 25 TARGETING PROTEIN INTERACTIONS BY CELL PERMEABLE PEPTIDES ............................. 25 MODEL FOR ALTERING CAR TRAFFICKING AND DEGRADATION IN POLARIZED CELLS .... 26 HYPOTHESIS ................................................................................................................... 30 SPECIFIC AIMS ................................................................................................................ 30 CHAPTER 2: MATERIALS AND METHODS .......................................................... 33 MATERIALS .................................................................................................................. 33 CELL LINES .................................................................................................................... 33 CULTURE MEDIA ............................................................................................................ 33 COMPETENT CELLS ........................................................................................................ 34 TAT-PDZ PEPTIDES ...................................................................................................... 34 ANTIBODIES ................................................................................................................... 34 PRIMERS ......................................................................................................................... 34 SIRNA ........................................................................................................................... 34 INHIBITORS ..................................................................................................................... 34 METHODS ...................................................................................................................... 41 CELL CULTURE MAINTENANCE ....................................................................................... 41 DETERMINATION OF CELL CONCENTRATION (HEMOCYTOMETER) ................................... 41 vii PEPTIDE PREPARATION AND TREATMENT ....................................................................... 42 MATRIX ASSISTED LASER DESORPTION IONIZATION-MASS SPECTROMETRY (MALDI- MS) ................................................................................................................................ 42 FLUORESCENTLY-LABELLED PEPTIDE INTERNALIZATION ............................................... 43 TESTING FOR EXPRESSION OF PROTEINS IN E. COLI ......................................................... 44 COOMASSIE BLUE STAINING ..........................................................................................
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