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Neutrophil Products Inhibit LLO Secretion and Activity, and Listeria Monocytogenes Intracellular Growth

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Neutrophil Products Inhibit LLO Secretion and Activity, and Listeria Monocytogenes Intracellular Growth Neutrophil products inhibit LLO secretion and activity, and Listeria monocytogenes intracellular growth Dissertation Presented in Partial Fulfillment of the Requirements for the Degree Doctor of Philosophy in the Graduate School of The Ohio State University By Eusondia Arnett Graduate Program in Microbiology The Ohio State University 2013 Dissertation Committee: Dr. Stephanie Seveau, Advisor Dr. John Gunn Dr. Mike Ibba Dr. Larry Schlesinger Copyright by Eusondia Arnett 2013 Abstract Listeria monocytogenes is a facultative intracellular pathogen that infects a large variety of host cells, including macrophages and diverse non-phagocytic cells. To avoid the phagosome microbicidal environment, L. monocytogenes secretes a pore-forming toxin (listeriolysin O; LLO) that releases the bacterium into the cytoplasm. Once in the cytosol, L. monocytogenes proliferates and infects adjacent cells through cell-to-cell spreading. Innate immune cells like neutrophils play an important role in the control of infection, yet the interaction between neutrophils, other host cells, and L. monocytogenes is not well understood. Neutrophils produce a high concentration and variety of antimicrobial molecules, including defensins and proteases; thus it is likely that these cells enhance the anti-listerial response of other host cells. This dissertation addresses if: i) human defensins, which can be released into the extracellular milieu by neutrophils, enable macrophages to control intracellular replication of L. monocytogenes; ii) L. monocytogenes is able to replicate in human neutrophils in a LLO-dependent manner as observed in macrophages; and iii) human neutrophils cooperate with macrophages to prevent L. monocytogenes replication in human macrophages. Addressing i), we found that the α-defensin HNP-1 (one of the most abundant proteins in neutrophil primary granules) cooperates with macrophages to inhibit L. ii monocytogenes phagosomal escape and intracellular growth. Importantly, HNP-1 is acquired by macrophages and trafficked to the phagocytosed bacteria. Finally, HNP-1 inhibits LLO secretion from the bacteria and directly blocks LLO activity. In conclusion, neutrophil defensins inhibit LLO function through two mechanisms (secretion and activity), and inhibit L. monocytogenes escape from macrophage phagosomes. Addressing ii), we found that LLO enhances the phagocytic efficiency of neutrophils and does not protect L. monocytogenes from neutrophil intracellular killing. L. monocytogenes produces multiple virulence factors, including LLO, that induce rapid neutrophil degranulation, even before closure of the phagosome. Intriguingly, degranulation protects neutrophils from LLO-mediated membrane damage. Neutrophils degranulate matrix metalloproteases, which degrade LLO, irreversibly blocking its activity. In summary, upon interaction with L. monocytogenes, neutrophils rapidly release matrix metalloproteases that degrade LLO, likely maintaining the bacterium in a bactericidal phagosome from which it cannot escape. Addressing iii), we determined that co-incubating neutrophils with macrophages during L. monocytogenes infection does not significantly alter L. monocytogenes association with or phagocytosis by macrophages but does markedly reduce L. monocytogenes growth in macrophages. In conclusion, human neutrophils produce molecules that inhibit LLO activity and intracellular replication of L. monocytogenes. Furthermore, neutrophils help limit L. monocytogenes replication in macrophages. We propose that during infection, macrophage internalization of neutrophils and/or neutrophil granule components enables iii macrophages to limit L. monocytogenes replication. Thus, at the site of infection the cooperation between neutrophils and macrophages likely plays a critical role in the innate immune defense against L. monocytogenes. iv Dedication This document is dedicated to my family and friends for their support and encouragement. I would especially like to thank my husband, Matt Arnett, for all of his help. v Acknowledgments I would like to thank my advisor, Dr. Stephanie Seveau, for her encouragement, instruction, and guidance during my scientific training. I would also like to thank my committee members, Dr. Mike Ibba, Dr. John Gunn, and Dr. Larry Schlesinger for their comments and insights regarding my project, and their willingness to write recommendation letters at the last minute. I would especially like to thank Dr. Seveau and Dr. Schlesinger for all the career advice they have provided. I am grateful for past and present members of the Seveau lab, including Anne Cecile-Haghighat, who trained me in many of these techniques, and Stephen Vadia for insightful conversations and help with experiments. I am also thankful for the undergraduate students in the lab who provided valuable assistance, particularly Colleen Nackerman, Ben Foreman, and Eric Weber. Lastly, I am grateful for Dr. Chad Rappleye and his lab members, especially Dr. Jessica Edwards and Dr. Eric Holbrook for all of their help and endless advice. I would like to thank all of our collaborators who provided materials and insightful conversations to help move the projects forward: Dr. Dan A. Portnoy (University of California, Berkeley, CA) for the L. monocytogenes DP10403S wild type and DP-L2161 Δhly strains and the pET29b plasmid encoding native LLO; Dr. Pascale vi Cossart (Pasteur Institute, Paris, France) for the L. monocytogenes L028 wild type and hly::Tn917 strains, Dr. Rodney K. Tweten (University of Oklahoma Health Sciences Center, Oklahoma City, OK) for the pQE30 plasmid encoding PLY and Dr. Philipp C. Hanna (University of Michigan Medical School, Ann Arbor, MI) for the pET15 plasmid encoding ALO. I also thank Tracy Tan and Grace Jung (David Geffen School of Medicine at UCLA, Los Angeles, CA) for technical assistance with the defensins and Sriram Satagopan (Ohio State University) for assistance with Chimera. I am grateful for Dr. J.-Q. Wu (Departments of Molecular Genetics and Molecular and Cellular Biochemistry) for use of the confocal microscope and I-Ju Lee (Dr. J.-Q. Wu’s lab) for assistance with confocal image acquisition and deconvolution. I would like to acknowledge funding support through the OSU Presidential Fellowship. vii Vita 2003 ..............................................................................High School Diploma with Honors Fairborn High School 2003 to 2006 ...........................................................National Commended Scholarship and Honors Competitive Scholarship Wright State University 2006 ................................................................................................ Honors Research Grant Wright State University 2006 .............................................................................................. B.S. Biological Sciences Magna Cum Laude Wright State University 2007 to 2011 ...........................................................................Graduate Teaching Associate Department of Microbiology The Ohio State University 2010 ........................................................................................................M.S. Microbiology The Ohio State University 2011 to 2012 ....................................................................................Presidential Fellowship The Ohio State University 2012 to present........................................................................Graduate Teaching Associate viii Department of Microbiology The Ohio State University 2012 ............................................................................................................... Travel Award Public Health Preparedness for Infectious Diseases Annual Member Meeting Ohio State University 2013 ............................................................................................................... Travel Award Wexner Medical Center Annual Research Day Ohio State University Publications Arnett E, Vadia S, Nackerman CC, Oghumu S, Satoskar A, McLeish KR, Uriarte SM, and Seveau S. 2013. The pore-forming toxin listeriolysin O is degraded by neutrophil proteases and fails to protect L. monocytogenes against intracellular killing. Manuscript submitted for publication. Arnett E and Seveau S. 2011. The multifaceted activities of mammalian defensins. Current Pharmaceutical Design, 17: 4254-4269. Vadia S, Arnett E, Haghighat AC, Wilson-Kubalek EM, Tweten RK, Seveau S. 2011. The pore-forming toxin listeriolysin O mediates a novel entry pathway of L. monocytogenes into human hepatocytes. PLoS Pathogens, 7: e1002356. ix Arnett E, Lehrer RI, Pratikya P, Lu W, Seveau S. 2011. Defensins enable macrophages to inhibit the intracellular proliferation of Listeria monocytogenes. Cellular Microbiology, 13: 635-651. Fields of Study Major Field: Microbiology. x Table of Contents Abstract...................................................................................................................................... ii Dedication ..................................................................................................................................v Acknowledgments ..................................................................................................................vi Vita............................................................................................................................................viii Table of Contents ....................................................................................................................xi List of Tables.........................................................................................................................
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