XIAP-p47 Pairing Activates the Immune Deficiency Pathway in the Lyme Disease Tick Ixodes scapularis Item Type dissertation Authors McClure Carroll, Erin Publication Date 2019 Abstract Globally, vector-borne diseases account for 17% of all infectious diseases. Most vectors are blood-feeding arthropods, which transmit bacterial, viral, and parasitic diseases to humans and animals. The tick Ixodes scapularis transmits seven pathogens... Keywords IMD pathway; ubiquitin ligase; vector biology; Lyme Disease; Rickettsia Infections; Ticks Download date 25/09/2021 20:55:28 Link to Item http://hdl.handle.net/10713/9604 CURRICULUM VITAE Erin E. McClure Carroll Department of Microbiology and Immunology 685 W. Baltimore St., HSFI Room 380 Baltimore, MD 21201 [email protected] Doctor of Philosophy to be conferred on May 17, 2019 Education 2014 – 2019 University of Maryland Baltimore, Baltimore, MD Graduate Program in Life Sciences Molecular Microbiology and Immunology Thesis advisor: Joao Pedra, Ph.D. 2009 – 2013 Juniata College, Huntingdon, PA B.S. Biochemistry and minor in German, magna cum laude Bachelor thesis: “The temporal dysbiosis of the gut microbiota in IBD” Thesis advisor: Regina Lamendella, Ph.D. Professional Positions Held 2019 – present Medical Writer Regulatory & Quality Solutions, LLC 2014 - 2019 Graduate Research Assistant Department of Microbiology and Immunology University of Maryland School of Medicine Thesis advisor: Joao Pedra, Ph.D. 2013 – 2014 Fulbright Fellow Department of Microbial Ecology, University of Vienna Supervised by David Berry, Ph.D. & Alexander Loy, Ph.D. 2012 – 2013 Undergraduate Research Student Biology Department, Juniata College Supervised by Regina Lamendella, Ph.D. 2011 Undergraduate Summer Research Fellow Dept. of Anesthesiology, Perioperative, and Pain Medicine, Brigham & Women's Hospital Supervised by Laura La Bonte, Ph.D. and Gregory L. Stahl, Ph.D. Publications 1. McClure Carroll EE, Wang X, Shaw DK, O’Neal AJ, Oliva Chávez AS, Brown LJ, Boradia VM, Hammond HL, Pedra JHF. p47 licenses activation of the immune deficiency pathway in the tick Ixodes scapularis. Proc Natl Acad Sci USA. 2019; 116(1):205-210. doi: 10.1073/pnas.1808905116. 2. McClure EE, Oliva Chávez AS, Shaw DK, Carlyon JA, Ganta RR, Noh SM, Wood DO, Bavoil PM, Brayton KA, Martinez JJ, McBride JW, Valdivia RH, Munderloh UG, Pedra JH. Engineering of obligate intracellular bacteria: Progress, challenges, and paradigms. Nat Rev Microbiol. 2017; (9):544-558. doi: 10.1038/nrmicro.2017.59. 3. Shaw DK, Wang X, Brown LJ, Oliva Chávez AS, Reif KE, Smith AA, Scott AJ, McClure EE, Boradia VM, Hammond HL, Sundberg EJ, Snyder GA, Liu L, DePonte K, Villar M, Ueti MW, de la Fuente J, Ernst RK, Pal U, Fikrig E, Pedra JHF. Infection- derived lipids elicit an immune deficiency circuit in arthropods. Nat Commun. 2017; 8:14401. doi: 10.1038/ncomms14401. 4. Halfvarson J, Brislawn CJ, Lamendella R, Vazquez-Baeza Y, Walters WA, Bramer LM, D’Amato M, Bonfiglio F, McDonald D, Gonzalez A, McClure EE, Dunklebarger MJ, Knight R, Jansson JK. Dynamics of the human gut microbiome in inflammatory bowel disease. Nat Microbiol. 2017; 2:17004. doi: 10.1038/nmicrobiol.2017.4. 5. Shaw DK, McClure EE, Wang X, Pedra JHF. Deviant behavior: Tick-borne pathogens and inflammasome signaling. Vet. Sci. 2016, 3, 27. 6. Blanchette K, Shenoy A, Milner J, Gilley R, McClure E, Hinojosa C, Kumar N, Daughtery S, Tallon L, Ott S, King S, Ferriera D, Gordon S, Tettelin H, Orihuela C. Neuraminidase A exposed galactose promotes Streptococcus pneumoniae biofilm formation during colonization. Infect Immun. 2016; 84(10):2922-32. 7. Ulrich N, Rosenberger A, Brislawn C, Wright J, Kessler C, Toole D, Solomon C, Strutt S, McClure E, Lamendella R. Aquatic bacterial community is restructured by hydric dynamics associated with Superstorm Sandy. Appl Environ Microbiol. 2016; 82(12):3525-36. 8. Pavlov VI, Tan YS, McClure EE, La Bonte LR, Zou C, Gorsuch WB, Stahl GL. Human mannose-binding lectin inhibitor prevents myocardial injury and arterial thrombogenesis in a novel animal model. Am J Pathol. 2015; 185(2):347-55. 9. Trexler R, Solomon C, Brislawn CJ, Wright JR, Rosenberger A, McClure EE, Grube AM, Peterson MP, Keddache M, Mason OU, Hazen TC, Grant CJ, Lamendella R. Assessing impacts of unconventional natural gas extraction on microbial communities in headwater stream ecosystems in northwestern Pennsylvania. Front Microbiol. 2014; 5:522. Book Chapters 1. Tick saliva and microbial effector molecules: two sides of the same coin. Shaw DK, McClure EE, Kotsyfakis M, Pedra JHF. Chapter 11 of Arthropod Vector: Controller of Disease Transmission (Volume 2): Vector Saliva-Host-Pathogen Interactions. Elsevier. 2017. Grant Support 02/04/2018 – 02/03/2020 Principal Investigator: E. McClure (Sponsor: J. Pedra) NIH NIAID 1F31AI138440 “Characterization of an E3 Ubiquitin Ligase Substrate in the Tick Immune Deficiency Pathway” Presentations 1. McClure EE, Wang X, & Pedra JHF. P47 restricts Anaplasma phagocytophilum acquisition by Ixodes scapularis ticks. American Society of Rickettsiology Annual Meeting, Milwaukee, WI. June 16-19, 2018. Oral presentation. 2. McClure EE & Pedra JHF. P47 restricts Borrelia burgdorferi colonization of Ixodes scapularis ticks. Biology of Spirochetes Gordon Research Seminar, Ventura Beach, CA. January 20, 2018. Oral presentation. 3. McClure EE & Pedra JHF. P47 restricts Borrelia burgdorferi colonization of Ixodes scapularis ticks. Biology of Spirochetes Gordon Research Conference, Ventura Beach, CA. January 21-26, 2018. Poster presentation. 4. McClure EE. The tick-pathogen interface: p47 restricts Borrelia burgdorferi colonization. Crosstalk. 2017 June 21. Oral presentation. 5. McClure EE, Nelson C, Felsheim R, Munderloh UG, Pedra JHF. High-Throughput Screening of Genes Associated with Host-Pathogen Interactions for an Obligate Intracellular Bacterium. Gordon Research Seminar and Conference in Tropical Infectious Diseases, Galveston, TX. March 11-17, 2017. Poster Presentation. 6. McClure E, Dunklebarger M, Li K, Halfvarsson J, Tysk C, McDonald D, Vázquez Baeza Y, Walters W, Knight R, Lamendella R, Jannson JK. Shifts in the Gut Microbiota of Inflammatory Bowel Disease Patients in a Longitudinal Study. American Society for Microbiology General Meeting, Denver, CO. May 18-21, 2013. 7. McClure E, La Bonte LR, Stahl GL. Mannose-Binding Lectin Concentrations Correlate with Enhanced Whole Blood Aggregation and Thrombin-Like Activity in Humans. Experimental Biology, San Diego, CA. April 21-25, 2012. Awards, Honors, and Fellowships 2018 Office of Technology Transfer Graduate Translational Research Award 2018 Graduate Research Conference Outstanding Oral Presentation 2018 Ruth L. Kirschstein National Research Service Award F31 Predoctoral Fellowship 2016 T32 Infection & Immunity training grant recipient (09/01/16 – 02/03/18) 2013 Fulbright Full Research Fellowship, U.S. Department of State 2013 Distinction in Biochemistry, Juniata College 2011 German Academic Exchange (DAAD) Undergraduate Fellowship 2011 Undergraduate Summer Research Fellowship, American Physiological Society Professional Service Volunteer, Baltimore Underground Science Space (BUGSS) (Sept. 2018 – present) Co-developed rotation project and mentored rotation student (June – August 2018) Co-organizer of 2018 Graduate Student Symposium (March 2018 – June 2018) Co-organizer of Immunology Journal Club (July 2016 – May 2017) Student representative for MMI program on GPILS 2016 Awards Committee Moderated oral presentations at UM School of Medicine Summer Research Training Programs Student Research Forum (July 29, 2016 & July 28, 2017) Member of GPILS Student Advisory Council (Sept. 2015 – May 2017) Helped prepare students for qualifying exam twice per year (Feb. 2017 – present) ABSTRACT Title of Dissertation: XIAP-p47 Pairing Activates the Immune Deficiency Pathway in the Lyme Disease Tick Ixodes scapularis Erin E. McClure Carroll, Doctor of Philosophy, 2019 Dissertation Directed by: Joao Pedra, Ph.D., Associate Professor, Department of Microbiology and Immunology Globally, vector-borne diseases account for 17% of all infectious diseases. Most vectors are blood-feeding arthropods, which transmit bacterial, viral, and parasitic diseases to humans and animals. The tick Ixodes scapularis transmits seven pathogens, including Borrelia burgdorferi, the agent of Lyme disease. Lyme disease is the most important vector-borne disease in the United States and causes an estimated 329,000 infections annually. Best described in the model organism Drosophila melanogaster, the arthropod immune deficiency (IMD) pathway responds to microbial infection through activation of Relish, a nuclear factor (NF)-κB family transcription factor. In I. scapularis ticks, the E3 ubiquitin ligase X-linked inhibitor of apoptosis (XIAP) regulates the IMD pathway through ubiquitylation. Yet, the tick genome notably lacks homologs to genes encoding key IMD pathway proteins as described in Drosophila. How XIAP activates the IMD pathway in response to microbial infection is poorly characterized and targets of XIAP- mediated ubiquitylation remain unknown. In this study, we identified the XIAP enzymatic substrate p47 as a positive regulator of the I. scapularis IMD network. XIAP polyubiquitylates p47 in a lysine (K)63-dependent manner and interacts with the ubiquitin-like (UBX) domain of p47. p47 also binds to Kenny (IKKγ/NF-κB essential modulator [NEMO]), the regulatory subunit of the inhibitor of NF-κB kinase (IKK) complex. Replacement of the amino