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Effects of Influenza Infection on Murine Alveolar Type II Cell Function THESIS Presented in Partial Fulfillment of the Requireme

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Effects of Influenza Infection on Murine Alveolar Type II Cell Function THESIS Presented in Partial Fulfillment of the Requireme Effects of Influenza Infection on Murine Alveolar Type II Cell Function THESIS Presented in Partial Fulfillment of the Requirements for the Degree Master of Science in the Graduate School of The Ohio State University By Christian Carlisle Hofer Graduate Program in Veterinary Biosciences The Ohio State University 2014 Master's Examination Committee: Ian C. Davis, DVM, PhD – Advisor Matthew Allen, DVM, PhD Valerie K. Bergdall, DVM, ACLAM Estelle Cormet-Boyaka, PhD Copyrighted by Christian Carlisle Hofer 2014 Abstract Influenza A virus infections result in 250,000 to 500,000 deaths annually during seasonal epidemics and pandemic outbreaks have historically killed millions. The ability of the influenza A virus genome to undergo minor changes through “antigenic drift” and major changes through “antigenic shift” poses significant challenges in developing effective annual vaccines. More importantly, these genetic alterations may yield novel strains leading to the next global pandemic. Severe respiratory disease from influenza A viruses leads to acute respiratory distress syndrome where viral replication occurs in the epithelial cells lining the alveolus. Damage to the alveolar type I (ATI) and type II (ATII) cells leads to flooding of the alveolus with edematous fluid, fibrin, erythrocytes, and other inflammatory mediators. This study investigated the effects of influenza A virus infection on those alveolar epithelial cells in a mouse model. We demonstrated that influenza infection reduces the number of ATII cells as well as dramatically alters their production of surfactant proteins. We observed a transition of ATII cells into a ATI cell phenotype by measuring the production of at ATI cell specific marker T1α/Podoplanin by ATII cells isolated from mice post infection. Continued examination and characterization of ex-vivo isolated ATII cells can provide important information into the role of ATII cells in restoring the normal epithelial lining of a damaged alveolus. Restoration of an intact respiratory epithelium is essential in the recovery from acute lung injury. ii Acknowledgments I would like to thank Matthew Hogan, Tara Martin, Parker Woods, Famke Aeffner, and Lisa Joseph for their assistance and technical expertise while working together in the Davis Lab and at OSU throughout my residency. Your knowledge and friendship has been a great source of support to me over the last several years. I would also like to thank all the members of the University Laboratory Animal Resources department. Your dedication to research animal welfare and promotion of high quality science is often overlooked, but never unappreciated by me. Finally, I would like to thank the members of my MS committee: Ian Davis, Matthew Allen, Valerie Bergdall, and Estelle Cormet- Boyaka. Your professional advice and guidance has helped develop my critical thinking and scientific writing/presentation skills which will no doubt serve me well as my career progresses. iii Vita June 1987 .......................................................Whitewater Sr. High School May 2001 .......................................................B.S. Animal Science & Zoology, University of Florida May 2005 .......................................................D.V.M., University of Florida August 2011 to present .................................Resident Veterinarian, University Laboratory Animal Resources, The Ohio State University Publications Bowman AS, Nelson SW, Edwards JL, Hofer CC, Nolting JM, Davis IC, Slemmons RD. 2013. Comparative effectiveness of isolation techniques for contemporary Influenza A virus strains circulating in exhibition swine. J Vet Diagn Invest 25(1): 82-90. Melendez P, Hofer CC, Donovan GA. 2006. Risk factors for udder edema and its association with lactation performance on primiparous Holstein cows in a large Florida herd, U.S.A. Prev Vet Med 76(3-4):211-21. iv Landolt GA, Karasin AI, Hofer C, Mahaney J, Svaren J, Olsen CW. 2005. Use of real- time reverse transcriptase polymerase chain reaction assay and cell culture methods for detection of swine influenza A viruses. Am J Vet Res 66(1):119-24. Fields of Study Major Field: Veterinary Biosciences v Table of Contents Abstract ............................................................................................................................... ii Vita ..................................................................................................................................... iv Table of Contents ............................................................................................................... vi List of Figures .................................................................................................................... ix Chapter 1: Literature Review .............................................................................................. 1 Influenza .......................................................................................................................... 1 Influenza Epidemiology .............................................................................................. 1 Influenza Virology ....................................................................................................... 2 Influenza Clinical Disease and Pathophysiology ........................................................ 3 Alveolus Anatomy and Physiology ................................................................................. 4 The Alveolus................................................................................................................ 4 Alveolar Type I Epithelial Cells (ATI Cells) .............................................................. 5 Alveolar Type II Epithelial Cells (ATII Cells) ............................................................ 5 Alveolar Epithelial Cell Markers ................................................................................. 6 Pulmonary Surfactant ...................................................................................................... 6 Effects of Influenza A Virus on Alveolar Epithelial Cells .............................................. 7 vi Chapter 2: Study Design ..................................................................................................... 9 Chapter 3: Materials and Methods .................................................................................... 10 Mice ............................................................................................................................... 10 Influenza Virus Inoculation ........................................................................................... 10 Alveolar Type II Cell Isolation ..................................................................................... 10 In-Vivo Imaging System (IVIS) .................................................................................... 11 Flow Cytometry............................................................................................................. 12 Protein Analysis by Western Blot ................................................................................. 12 Gene Expresion Analysis by rtPCR .............................................................................. 13 Other Methods ............................................................................................................... 13 Statistical Analysis ........................................................................................................ 13 Chapter 4: Results ............................................................................................................. 14 Effects of influenza A virus infection on C57BL/6 mice.............................................. 14 Effects of influenza A virus infection on SP-C expression at the whole lung level ..... 14 Effects of influenza A virus infection on ATII cells ..................................................... 14 Gene expression in isolated ATII cells following influenza A virus infection ............. 15 Protein expression in isolated ATII cells following influenza A virus infection .......... 15 Chapter 5: Discussion ....................................................................................................... 17 References ......................................................................................................................... 21 vii Appendix A: Figures ......................................................................................................... 32 viii List of Figures Figure 1. Effects of influenza A virus infection on C57BL/6 mice. ............................ 33 Figure 2. Effects of influenza A virus infection on SP-C expression at the whole lung level. .................................................................................................................................. 35 Figure 3. Effects of influenza A virus infection on ATII cells. .................................... 36 Figure 4. Gene expression in isolated ATII cells following influenza A virus infection. ........................................................................................................................... 38 Figure 5. Protein expression in isolated ATII cells following influenza A virus infection. ........................................................................................................................... 39 ix Chapter 1: Literature Review Influenza Influenza Epidemiology Influenza A virus is a respiratory pathogen that causes significant disease
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