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Discovery and Characterization of an Anti-Inflammatory Lipid Derived from Mycobacterium Vaccae

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Discovery and Characterization of an Anti-Inflammatory Lipid Derived from Mycobacterium Vaccae Discovery and characterization of an anti-inflammatory lipid derived from Mycobacterium vaccae By David G. Smith B.S., The Ohio State University, 2010 A thesis submitted to the Faculty of the Graduate School of the University of Colorado in partial fulfillment of the requirement for the degree of Doctor of Philosophy Department of Chemistry and Biochemistry 2017 i This thesis entitled: Discovery and characterization of an anti-inflammatory lipid derived from Mycobacterium vaccae written by David G. Smith has been approved by the Department of Chemistry and Biochemistry ________________________________________________ Christopher A. Lowry, PhD ________________________________________________ Dylan J. Taatjes, PhD Date______________________ The final copy of this thesis has been examined by the signatories, and we find that both the content and the form meet acceptable presentation standards of scholarly work in the above-mentioned discipline. ii Smith, Gregory David (PhD, Chemistry and Biochemistry) Discovery and characterization of an anti-inflammatory lipid derived from Mycobacterium vaccae Thesis directed by Christopher A. Lowry, PhD. In modern urban environments there is an increased prevalence of allergies, asthma, inflammatory bowel diseases (IBD), and anxiety disorders. The underlying cause for these disorders, as postulated by the Hygiene Hypothesis, is chronic inflammation, and the imbalance in the immune system is caused by a lack of interaction with microbes that have been removed from the urban space and lifestyle. One such microbe is the environmental saprophyte, Mycobacterium vaccae. In animal models, immunization with M. vaccae protects against the development of these prevalent inflammatory disorders. This immunoregulatory effect has been shown to occur due to the expansion of regulatory T cells, but it is still unclear how M. vaccae is interacting with the immune cells. To better understand the mechanisms of immune suppression, we screened secreted molecules and whole cell preparations for anti-inflammatory properties. We were able to isolate and determine the structure of a single fatty acid, 10(Z)-hexadecenoic acid. The fatty acid was an effective immunosuppressant both in vivo in a murine model of allergic asthma, and ex vivo, as observed by decreased release of proinflammatory cytokines, like interleukin-5 from splenocytes. We next investigated how the anti-inflammatory effects are achieved using macrophages as a model system. The mRNA transcriptional profile of macrophages treated with 10(Z)- iii hexadecenoic acid suggested that peroxisome proliferator-activated receptor (PPAR)α was mediating the effects. It was subsequently confirmed, using transfection assays, that 10(Z)- hexadecenoic acid increases PPARα signaling. Furthermore, PPARα was demonstrated to be necessary for the anti-inflammatory effects, as a PPARα antagonist blocked the effects of 10(Z)- hexadecenoic acid, and 10(Z)-hexadecenoic acid had no effect in macrophages isolated from -/- PPARα mice. Collectively, these data define 10(Z)-hexadecenoic acid as an immunosuppressant metabolite that may contribute to the immunomodulatory effects of M. vaccae immunization. Furthermore, to our knowledge, 10(Z)-hexadecenoic acid is not synthesized de novo in mammals, and its biosynthesis appears to be unique to mycobacteria.. This is also the first instance where a Mycobacterium or Mycobacterium-derived molecule has been shown to have anti-inflammatory effects mediated through PPARα. iv Acknowledgements I am grateful to many people for the opportunity to train as a scientist. Throughout my life, my family has been extremely supportive of my academic career. My mother has been a huge inspiration and has always been there through the emotional ride of this process. Even during my graduate career, I sought her writing advice. My father is also instrumental in where I am today. Since my childhood, he strived to make science fun and interesting and is the reason I love problem solving. Lastly, my wife, Monica, has been absolutely necessary through my training. She has made me a more passionate, driven, proud person. I know I can always rely on her support. I am thankful to Chris for allowing me to train in his lab—which was especially generous since it is a lab outside the department. I am continually impressed with the breadth of Chris’ knowledge. He is creative and truly inspirational. My research has taken me in a lot of challenging directions, and Chris was there leading and learning with me. The science has been a lot of fun, which has made everything so much more rewarding. When the science wasn’t super fun, or I had my moments of fear and anxiety, he always knew what to say or do to make me feel better. He has cultivated the greatest lab environment I have ever experienced. I am thankful for all the past and current lab members and am very fortunate to have found such great friendships among them. I would also like to thank all my other committee members: Dylan Taatjes, Hubert Yin, Xuedong Liu, and Robin Dowell. I faltered and struggled some my first year, so I am very grateful that they accepted the responsibility of guiding me. They have all taught me so much. v The course of this PhD has had me scrambling all over campus. At various points I have received help, resources, or guidance from the Fleshner lab, Seals lab, Palmer lab, Jinsen Chen, Annette Erbse, and Jamie Kershner. Robin Dowell and Mary Allen have been very generous with their time and literally taught me everything I know about RNA-seq. Mary was with me at the lab bench watching every single pipette transfer. She showed me all the tips and tricks that are not included in the protocols. During the buggy process of analyzing the data, she and Robin were always around to get their hands dirty too. I owe so much to all the talented collaborators I have been able to work with. Xiang Wang’s lab seeded most of this work by synthesizing our lipid. From Jon Clardy’s group, Alexandra was an excellent partner to have while screening mycobacteria. I would also like to thank Del Besra’s lab and Laura Rosa Brunet’s lab for their excellent collaborations. Del and his student, Petr Illarionov, were invaluable for synthesizing the lipids, and László Nagy for running the PPAR reporter gene assays, and thanks to Laura’s student, Roberta Martinelli, who ran the in vivo mouse allergy models. Finally, I would like to thank the funding sources that made this work possible including gifts through the CU Foundation. I’m also grateful for the various awards and competitions offered by the University of Colorado Boulder, which have afforded me to purchase necessary reagents and equipment. vi Table of Contents Chapter 1: Introduction ................................................................................................................... 1 1.1 The Hygiene Hypothesis ........................................................................................... 1 1.1.1 The “Old Friends” Hypothesis .......................................................................... 3 1.1.2 Immunoregulatory mechanisms of “Old Friends” ............................................. 4 1.2 Mycobacterium vaccae ............................................................................................. 7 1.3 LPS signaling in macrophages .................................................................................. 9 Chapter 2. Suppression of airway allergic inflammation by a novel bacterially-derived lipid isolated from Mycobacterium vaccae ........................................................................................... 12 2.1 Introduction ............................................................................................................. 12 2.1.1 The hygiene hypothesis and inflammatory disease ......................................... 12 2.1.2 The mycobacterial cell wall and therapeutic applications ............................... 13 2.2 Materials and methods ............................................................................................ 18 2.2.1 Animals ............................................................................................................ 18 2.2.2 Mycobacterium vaccae .................................................................................... 18 2.2.3 Isolation of the lipids ....................................................................................... 19 2.2.4 Synthesis of triacylglycerol ............................................................................. 20 2.2.5 Synthesis of 10(Z)-hexadecenoic acid; (10Z)-hexadec-10-enoic acid (CAS No. 2511-97-9) ........................................................................................................................ 22 2.2.6 Thp1 cell assay ................................................................................................ 24 2.2.7 Murine model of allergic pulmonary inflammation: prevention studies ......... 24 2.2.8 Murine model of allergic pulmonary inflammation: treatment studies ........... 25 2.2.9 Ex vivo splenocyte culture .............................................................................. 25 2.2.10 Murine peritoneal macrophage isolation and screening .................................. 26 2.2.11 Dynamic light scattering of lipid micelles ....................................................... 27 vii 2.2.12 Lipid extraction................................................................................................ 27 2.2.13 Cytokine measurements
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