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1 Histoplasma Circumvents Nutrition Limitations to Proliferate Within Macrophages Dissertation Presented in Partial Fulfillment

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1 Histoplasma Circumvents Nutrition Limitations to Proliferate Within Macrophages Dissertation Presented in Partial Fulfillment Histoplasma circumvents nutrition limitations to proliferate within macrophages Dissertation Presented in Partial Fulfillment of the Requirements for the Degree Doctor of Philosophy in the Graduate School of The Ohio State University By Qian Shen Graduate Program in Microbiology The Ohio State University 2019 Dissertation Committee Dr. Chad A. Rappleye, Advisor Dr. Birgit E. Alber Dr. John S. Gunn Dr. Natividad Ruiz 1 Copyrighted by Qian Shen 2019 2 Abstract Histoplasma capsulatum is a dimorphic fungal organism that switches between mycelium and yeast phase upon sensing environmental temperature changes. Histoplasma lives in the soil as avirulent mycelium. Upon encountering elevated temperature in the mammalian host during infection, Histoplasma differentiates into pathogenic yeast phase. Histoplasma yeasts survive and proliferate in the host phagocytes, especially within the macrophage phagosome. However, the phagosome is a nutrient-depleted environment, yet it does not prevent the growth of Histoplasma yeasts. The goal of this dissertation is to advance the understandings of molecular mechanisms by which Histoplasma yeasts rely on to proliferate in the nutrient-depleted phagosomal environment. Through a genetic screen, we isolated a mutant that had a disruption in the CTR3 gene encoding a high affinity copper transporter. Loss of Ctr3 function prevented Histoplasma growth under copper limited conditions. Depletion of Ctr3 did not impair intracellular growth in non-activated macrophages but resulted in growth defect in IFN-γ activated macrophages. Ctr3-deficient yeasts were fully virulent during innate immunity but attenuated after the onset of adaptive immunity. This indicates that the phagosomal environment switches from high copper to lower copper upon IFN-γ mediated ii macrophage activation, which subsequently forces Histoplasma to rely on Ctr3 to acquire sufficient copper. In order to proliferate within macrophages, Histoplasma must be able to assimilate carbon substrates in the phagosomal environment to meet its nutritional needs. We isolated a mutant containing a lesion in the PCK1 gene, which encodes the phosphoenolpyruvate carboxykinase, an enzyme catalyzing the first committed step of gluconeogenesis. Transcriptional analysis showed that Histoplasma yeasts down- regulated glycolysis and fatty acid utilization but up-regulated gluconeogenesis within macrophages. Depletion of glycolysis or fatty acid utilization pathway neither prevented Histoplasma growth within macrophages, nor impaired virulence in vivo. However, loss of function in Pck1 resulted in intramacrophage growth defect and severely attenuated virulence in vivo, indicating that Histoplasma yeasts rely on catabolizing gluconeogenic substrates to proliferate within macrophages. Furthermore, Histoplasma yeasts lacking the GDH2 gene, which encodes a glutamate dehydrogenase involved in glutamate catabolism, showed impaired intramacrophage growth and severely attenuated virulence in vivo. Taken together, glutamate catabolism in Histoplasma produces α-ketoglutarate, which further is utilized to produce all key precursor metabolites to support its cellular biosynthesis through gluconeogenesis. In addition, we isolated mutants that had disruption in genes encoding proteins involved in peroxisome biogenesis. Loss of Pex10 or Pex33 function prevented Histoplasma iii growth within macrophages and resulted in complete loss of virulence in vivo. Compared to wild type, peroxisome-deficient yeasts showed increased susceptibility to iron restricted conditions, suggesting that peroxisomes are required for siderophore production for iron acquisition. However, depletion of siderophore biosynthetic pathway did not impair Histoplasma’s virulence in vivo, indicating that peroxisomes do not contribute to Histoplasma pathogenesis through siderophore production. iv Dedication This humble work is dedicated to my beloved families, my friends, past and future Histoplasma researchers And above all, To the Almighty God! v Acknowledgments First of all, I would like to thank my advisor Dr. Chad Rappleye. His generous support and guidance created a healthy environment for me to develop as a scientist. His forward looking attitude always encouraged me throughout my graduate career. In addition, I want to thank all members in the Alber lab for sharing equipment and expertise on my enzymatic assays. I also want to thank my thesis committee members for their insights and suggestions on my research projects. I am grateful for having great colleagues (past and present) in the Rappleye lab. I want to thank Matthew, Andrew, Kristie, Stephanie, and Peter for their help and companionship to survive and enjoy graduate school life. I also want to thank all my friends at Columbus Chinese Christian Church and Christian Graduate Student Alliance for their support during my stay in Columbus. vi Vita 2010 ...............................................................B.E. Viticulture and Enology Engineering, China Agricultural University 2013................................................................M.S. Food Science and Technology, Mississippi State University 2013 to 2018 .................................................Graduate Teaching and Research Associate, Department of Microbiology, The Ohio State University 2018 to present ..............................................Graduate Fellow, Department of Microbiology, The Ohio State University Publications Qian Shen, Matthew J. Beucler, Stephanie C. Ray, and Chad A. Rappleye. Macrophage activation by IFN-γ triggers restriction of phagosomal copper from intracellular pathogens (2018) PLoS Pathogens 14(11): e1007444. Qian Shen and Chad A. Rappleye. Differentiation of the fungus Histoplasma capsulatum into a pathogen of phagocytes (2017) Current Opinion in Microbiology 40, 1-7. vii Garfoot AL, Shen Q, Wüthrich M, Klein BS, Rappleye CA. The Eng1 β-glucanase enhances Histoplasma virulence by reducing β-glucan exposure. mBio. 2016 Apr 19;7(2). pii: e01388-15. Fields of Study Major Field: Microbiology viii Table of Contents Abstract ............................................................................................................................... ii Dedication ........................................................................................................................... v Acknowledgments.............................................................................................................. vi Vita .................................................................................................................................... vii List of Tables .................................................................................................................... xv List of Figures .................................................................................................................. xvi Chapter 1. Introduction ....................................................................................................... 1 1.1 Histoplasma capsulatum ........................................................................................... 1 1.2 Differentiation and the pathogenic program ............................................................. 2 1.3 Yeast-phase effector molecules facilitating pathogenesis ........................................ 7 1.4 Histoplasma yeast responses to host immunity ...................................................... 12 1.5 Intracellular carbon metabolism ............................................................................. 17 1.6 Conclusions ............................................................................................................. 20 Chapter 2. Macrophage activation by IFN-γ triggers restriction of phagosomal copper from intracellular pathogens ............................................................................................. 21 ix 2.1 Introduction ............................................................................................................. 21 2.2 Materials and Methods ............................................................................................ 24 2.2.1 H. capsulatum strains and growth .................................................................... 24 2.2.2 Macrophage cell culture ................................................................................... 28 2.2.3 Mutagenesis and isolation of H. capsulatum mutants with attenuated intramacrophage growth ........................................................................................... 29 2.2.4 Mapping of H. capsulatum T-DNA insertional mutants ................................. 30 2.2.5 Complementation of the ctr3 mutation ............................................................ 33 2.2.6 Phylogenetic analysis of fungal copper transporters ....................................... 33 2.2.7 Determination of yeast sensitivity to metal ion chelation and toxicity ............ 34 2.2.8 Intracellular copper or iron measurement by inductively coupled plasma mass spectrometry (ICP-MS) ............................................................................................. 34 2.2.9 CTR gene expression determination ................................................................ 35 2.2.10 Estimation of phagosome copper concentrations .......................................... 37 2.2.11 Intramacrophage proliferation of H. capsulatum yeasts ................................ 39 2.2.12 Murine model of pulmonary histoplasmosis.................................................
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