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Identification of Bhlhe40 and Irg1 As Essential Regulators of the Inflammatory Response to Mycobacterium Tuberculosis Jeremy Peter Huynh Washington University in St

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Identification of Bhlhe40 and Irg1 As Essential Regulators of the Inflammatory Response to Mycobacterium Tuberculosis Jeremy Peter Huynh Washington University in St Washington University in St. Louis Washington University Open Scholarship Arts & Sciences Electronic Theses and Dissertations Arts & Sciences Summer 8-15-2018 Identification of Bhlhe40 and Irg1 as essential regulators of the inflammatory response to Mycobacterium tuberculosis Jeremy Peter Huynh Washington University in St. Louis Follow this and additional works at: https://openscholarship.wustl.edu/art_sci_etds Part of the Allergy and Immunology Commons, Immunology and Infectious Disease Commons, Medical Immunology Commons, and the Microbiology Commons Recommended Citation Huynh, Jeremy Peter, "Identification of Bhlhe40 and Irg1 as essential regulators of the inflammatory response to Mycobacterium tuberculosis" (2018). Arts & Sciences Electronic Theses and Dissertations. 1628. https://openscholarship.wustl.edu/art_sci_etds/1628 This Dissertation is brought to you for free and open access by the Arts & Sciences at Washington University Open Scholarship. It has been accepted for inclusion in Arts & Sciences Electronic Theses and Dissertations by an authorized administrator of Washington University Open Scholarship. For more information, please contact [email protected]. WASHINGTON UNIVERSITY IN ST. LOUIS Division of Biology and Biomedical Sciences Program in Molecular Microbiology and Microbial Pathogenesis Dissertation Examination Committee: Christina L. Stallings, Chair Adrianus C.M. Boon Brian T. Edelson Michael J. Holtzman Shabaana A. Khader L. David Sibley Identification of Bhlhe40 and Irg1 as Essential Regulators of the Inflammatory Response to Mycobacterium tuberculosis by Jeremy P. Huynh A dissertation presented to The Graduate School of Washington University in Saint Louis in partial fulfillment of the requirements for the degree of Doctor of Philosophy August 2018 Saint Louis, Missouri © 2018, Jeremy P. Huynh Table of Contents List of Figures ................................................................................................................................ iv List of Tables ................................................................................................................................. vi List of Abbreviations .................................................................................................................... vii Acknowledgments.......................................................................................................................... ix Abstract of the Dissertation ........................................................................................................... xi Chapter 1: Introduction ............................................................................................................... 1 Tuberculosis .................................................................................................................................... 2 The immune response to Mycobacterium tuberculosis .................................................................. 4 Bhlhe40 ......................................................................................................................................... 10 Irg1 ................................................................................................................................................ 12 Chapter 2: the role of Bhlhe40 in control of Mycobacterium tuberculosis infection ............. 17 Introduction ................................................................................................................................... 18 Results ........................................................................................................................................... 20 Lower BHLHE40 expression is associated with active tuberculosis ........................................ 20 Bhlhe40 is required to control mycobacterial infection ............................................................ 20 Bhlhe40 deficiency leads to severe lung inflammation ............................................................ 22 -/- Neutrophil and monocyte inflammation do not drive susceptibility in Bhlhe40 mice. .......... 26 Bhlhe40 is required within hematopoietic cells ........................................................................ 28 Bhlhe40 enables control of Mtb in the context of T cell deficiency ......................................... 31 + + Bhlhe40 is required in CD11c , Zbtb46 , and T cells ............................................................... 32 Bhlhe40 deficiency alters cytokine transcription after exposure to Mtb ................................... 37 Bhlhe40 suppresses IL-10 production during in vivo Mtb infection ......................................... 40 Bhlhe40 suppresses IL-10 expression in myeloid cells in vitro ................................................ 43 Bhlhe40 binds directly to the Il10 locus in TH1 cells and myeloid cells .................................. 47 IL-10 deficiency protects Bhlhe40−/− mice from Mtb infection ................................................ 48 Discussion ..................................................................................................................................... 50 Experimental Procedures .............................................................................................................. 55 ii Chapter 3: the role of Irg1 in control of Mycobacterium tuberculosis infection .................... 69 Abstract ......................................................................................................................................... 70 Results ........................................................................................................................................... 73 Irg1 enables resistance to a subset of pathogenic mycobacteria. .............................................. 73 Irg1 modulates lung inflammatory responses after Mtb infection. ........................................... 77 Neutrophil depletion extends the survival of Irg1-/- mice during Mtb infection. ...................... 79 Expression of Irg1 in LysM+ and CD11c+ cells enables survival of Mtb infection. ................. 83 Susceptibility of Irg1-/- mice is dependent on Mtb expression of PDIM and ESX-1, but not ICL1 .......................................................................................................................................... 85 Irg1 is not required for induction of ROS and NOS2 or control of Mtb in macrophages ......... 88 Irg1 regulates inflammatory responses in myeloid cells during Mtb infection. ........................ 91 Irg1 is the sole source of itaconate in the lung during Mtb infection ........................................ 95 Discussion ..................................................................................................................................... 96 Experimental Procedures .............................................................................................................. 99 Chapter 4: Conclusions ............................................................................................................ 110 Introduction ................................................................................................................................. 111 Discussion and Future Directions ............................................................................................... 111 Bhlhe40 expression patterns.................................................................................................... 111 Bhlhe40 and IL-10-dependent control of Mtb infection ......................................................... 113 IL-10-independent roles for Bhlhe40 in Mtb infection ........................................................... 117 Irg1 and restriction of neutrophil-mediated immunopathology .............................................. 119 Myeloid cell-specific requirements for Irg1............................................................................ 120 Impact of Irg1 on adaptive immunity ...................................................................................... 121 Direct antibacterial roles for Irg1 in Mtb infection ................................................................. 122 Explanations for virulence of Δicl1 Mtb in Irg1-/- mice .......................................................... 124 Itaconate catabolism and vitamin B12 deficiency................................................................... 125 Possible cross-talk between Bhlhe40 and Irg1 ........................................................................ 126 Closing remarks .......................................................................................................................... 127 References ................................................................................................................................... 129 iii List of Figures Chapter 2: The role of Bhlhe40 in control of Mycobacterium tuberculosis infection Figure 1. Lower BHLHE40 expression is specifically associated with active tuberculosis. ........ 21 Figure 2. Bhlhe40 is required to control mycobacterial infection. ............................................... 23 Figure 3. Bhlhe40 deficiency leads to severe lung inflammation. ................................................ 24 Figure 4. Bhlhe40 deficiency leads to neutrophil-dominated inflammation. ............................... 27 Figure 5. Neutrophils and monocytes do not drive susceptibility in Bhlhe40−/− mice. ................ 29 Figure 6. Bhlhe40
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