Autophagy in Tuberculosis

Summary

Principal Investigator: VOJO P DERETIC
Abstract: Mycobacterium tuberculosis is responsible for millions of deaths annually, including a large proportion of HIV co-infected patients. The host defenses controlling M. tuberculosis remain to be fully delineated. Recently, several groups, including ours, have demonstrated that autophagic degradation is a major, previously unrecognized mechanism for elimination of intracellular microbes. Our work has shown that autophagy is a process that can inhibit intracellular survival of M. tuberculosis, and that in addition to pharmacological and physiological agonists, autophagy can be controlled by immunological means. Autophagy is a fundamental biological process defined as a cytoplasmic homeostasis pathway whereby cytoplasm portions become sequestered by membrane for delivery to lysosomes. This leads to removal of damaged or surplus organelles and turnover of stable, long-lived macromolecules. Autophagy has been previously implicated in both health-promoting and disease-associated states in cancer, neurodegeneration, development, and aging. Its recently demonstrated protective role in infectious diseases represents a previously unrecognized innate and adaptive immunity mechanism. Our long-term goals are to dissect the molecular mechanisms of autophagy in the context of elimination of M. tuberculosis during macrophage infection. Our main hypothesis is that induction of autophagy by pharmacological, physiological, and immunological means eliminates intracellular M. tuberculosis. The specific aims of our proposal are: 1) Delineate autophagy pathways eliminating intracellular M. tuberculosis. This will be accomplished using macrophages derived from transgenic mice defective in a key autophagy gene, ATG5, and other recently developed molecular tools for autophagy investigations. 2) Define autophagy as an immunological effector of M. tuberculosis control. The focus will be on IFN-y and its downstream effectors modulating autopjiagy. 3) Determine how other known agonists and antagonists of mycobacterial intracellular survival affect autophagy and examine their mode of action in mechanistic studies. This project will delineate autophagic mechanisms that control intracellular M. tuberculosis, and show that autophagy can be induced and modulated by immunological and pharmacological means. Our studies will provide novel pharmacological and immunological approaches in treatment and prophylaxis of tuberculosis, with strong implications for immunity and infectious diseases in general.
Funding Period: ----------------2006 - ---------------2011-
more information: NIH RePORT

Top Publications

  1. ncbi T helper 2 cytokines inhibit autophagic control of intracellular Mycobacterium tuberculosis
    James Harris
    Department of Molecular Genetics and Microbiology, University of New Mexico Health Sciences Center, University of New Mexico School of Medicine, 915 Camino de Salud NE, Albuquerque, NM 87131, USA
    Immunity 27:505-17. 2007
  2. pmc TBK-1 promotes autophagy-mediated antimicrobial defense by controlling autophagosome maturation
    Manohar Pilli
    Department of Molecular Genetics and Microbiology, University of New Mexico Health Sciences Center, 915 Camino de Salud, NE, Albuquerque, NM 87131, USA
    Immunity 37:223-34. 2012
  3. pmc Autophagy: an emerging immunological paradigm
    Vojo Deretic
    Department of Molecular Genetics and Microbiology, University of New Mexico Health Sciences Center, Albuquerque, NM 87131, USA
    J Immunol 189:15-20. 2012
  4. pmc Autophagy intersections with conventional and unconventional secretion in tissue development, remodeling and inflammation
    Vojo Deretic
    Department of Molecular Genetics and Microbiology, University of New Mexico Health Sciences Center, 915 Camino de Salud, NE, Albuquerque, NM 87131, USA
    Trends Cell Biol 22:397-406. 2012
  5. pmc Autophagy protects against active tuberculosis by suppressing bacterial burden and inflammation
    Eliseo F Castillo
    Department of Molecular Genetics and Microbiology, University of New Mexico Health Sciences Center, Albuquerque, NM 87131, USA
    Proc Natl Acad Sci U S A 109:E3168-76. 2012
  6. pmc Monitoring autophagy during Mycobacterium tuberculosis infection
    Marisa Ponpuak
    Department of Molecular Genetics and Microbiology, University of New Mexico, Health Sciences Center, Albuquerque, New Mexico, USA
    Methods Enzymol 452:345-61. 2009
  7. pmc Toll-like receptors control autophagy
    Monica A Delgado
    Department of Molecular Genetics and Microbiology, University of New Mexico, Health Sciences Center, Albuquerque, NM 87131, USA
    EMBO J 27:1110-21. 2008
  8. pmc Autophagosome-independent essential function for the autophagy protein Atg5 in cellular immunity to intracellular pathogens
    Zijiang Zhao
    Department of Pathology and Immunology, Washington University School of Medicine, St Louis, MO 63110, USA
    Cell Host Microbe 4:458-69. 2008
  9. ncbi Autophagosome and phagosome
    Vojo Deretic
    Health Sciences Center, Department of Molecular Genetics and Microbiology, University of New Mexico Health Sciences Center, Albuquerque, NM, USA
    Methods Mol Biol 445:1-10. 2008
  10. ncbi Autophagic proteolysis of long-lived proteins in nonliver cells
    Esteban A Roberts
    Department of Molecular Genetics and Microbiology, University of New Mexico School of Medicine, Albuquerque, NM, USA
    Methods Mol Biol 445:111-7. 2008

Scientific Experts

  • VOJO P DERETIC
  • Isabelle Vergne
  • David C Rubinsztein
  • James Harris
  • Marisa Ponpuak
  • Esteban A Roberts
  • Christina Dinkins
  • Monica A Delgado
  • Nicolas Dupont
  • Manohar Pilli
  • Wojciech Ornatowski
  • Shanya Jiang
  • John Arko-Mensah
  • Esteban Roberts
  • Sharon Master
  • Sudha B Singh
  • George B Kyei
  • Monica Delgado
  • Alexander S Davis
  • Zijiang Zhao
  • Michael A Mandell
  • Eliseo F Castillo
  • Dhruva Bhattacharya
  • Terje Johansen
  • Viktor I Korolchuk
  • Herbert W Virgin
  • M A Delgado
  • Rasha A Elmaoued
  • Chengyu Liang
  • Monica Delgado-Vargas
  • Karen M Dobos
  • Steven B Bradfute
  • Jack Ansgar Bruun
  • Graham S Timmins
  • Alexander Dekonenko
  • Julie Hutt
  • Tom Egil Hansen
  • C Rick Lyons
  • Hongliang Yang
  • Shinji Saiki
  • Sovan Sarkar
  • Cahir J O'Kane
  • Maike Lichtenberg
  • Marie Futter
  • Luca Jahreiss
  • Fiona M Menzies
  • Farah H Siddiqi
  • Sara Imarisio
  • Masaaki Komatsu
  • John Naylor
  • Eileen White
  • Sudha Singh
  • Chunsheng Dong
  • Sergio de Haro
  • Antonito Panganiban
  • Maurizio Federico
  • Li Wu
  • Eiki Kominami
  • Takashi Ueno
  • Akitsugu Yamamoto
  • Blima Fux
  • Brian C Miller
  • Kyung Soo Inn
  • Chihiro Akazawa
  • Megan Goodwin
  • Qinglin Li
  • George Kyei
  • Jong Soo Lee
  • Ken Cadwell
  • Noboru Mizushima
  • Jae U Jung
  • Robert E Schmidt
  • Ildiko R Dunay
  • Michaela U Gack
  • Karen G Green
  • L David Sibley
  • Pinghui Feng
  • David Strong

Detail Information

Publications34

  1. ncbi T helper 2 cytokines inhibit autophagic control of intracellular Mycobacterium tuberculosis
    James Harris
    Department of Molecular Genetics and Microbiology, University of New Mexico Health Sciences Center, University of New Mexico School of Medicine, 915 Camino de Salud NE, Albuquerque, NM 87131, USA
    Immunity 27:505-17. 2007
    ..These findings establish a mechanism through which Th1-Th2 polarization differentially affects the immune control of intracellular pathogens...
  2. pmc TBK-1 promotes autophagy-mediated antimicrobial defense by controlling autophagosome maturation
    Manohar Pilli
    Department of Molecular Genetics and Microbiology, University of New Mexico Health Sciences Center, 915 Camino de Salud, NE, Albuquerque, NM 87131, USA
    Immunity 37:223-34. 2012
    ..Thus, TBK-1 is a key regulator of immunological autophagy and is responsible for the maturation of autophagosomes into lytic bactericidal organelles...
  3. pmc Autophagy: an emerging immunological paradigm
    Vojo Deretic
    Department of Molecular Genetics and Microbiology, University of New Mexico Health Sciences Center, Albuquerque, NM 87131, USA
    J Immunol 189:15-20. 2012
    ..Collectively, the unique features of autophagy as an immunological process and its contributions to other arms of the immune system represent a new immunological paradigm...
  4. pmc Autophagy intersections with conventional and unconventional secretion in tissue development, remodeling and inflammation
    Vojo Deretic
    Department of Molecular Genetics and Microbiology, University of New Mexico Health Sciences Center, 915 Camino de Salud, NE, Albuquerque, NM 87131, USA
    Trends Cell Biol 22:397-406. 2012
    ....
  5. pmc Autophagy protects against active tuberculosis by suppressing bacterial burden and inflammation
    Eliseo F Castillo
    Department of Molecular Genetics and Microbiology, University of New Mexico Health Sciences Center, Albuquerque, NM 87131, USA
    Proc Natl Acad Sci U S A 109:E3168-76. 2012
    ..Thus, autophagy acts in vivo by suppressing both M. tuberculosis growth and damaging inflammation...
  6. pmc Monitoring autophagy during Mycobacterium tuberculosis infection
    Marisa Ponpuak
    Department of Molecular Genetics and Microbiology, University of New Mexico, Health Sciences Center, Albuquerque, New Mexico, USA
    Methods Enzymol 452:345-61. 2009
    ..The described assays can be used to investigate and identify factors important for autophagic elimination of mycobacteria that could potentially provide new therapeutic targets to defeat this disease...
  7. pmc Toll-like receptors control autophagy
    Monica A Delgado
    Department of Molecular Genetics and Microbiology, University of New Mexico, Health Sciences Center, Albuquerque, NM 87131, USA
    EMBO J 27:1110-21. 2008
    ....
  8. pmc Autophagosome-independent essential function for the autophagy protein Atg5 in cellular immunity to intracellular pathogens
    Zijiang Zhao
    Department of Pathology and Immunology, Washington University School of Medicine, St Louis, MO 63110, USA
    Cell Host Microbe 4:458-69. 2008
    ....
  9. ncbi Autophagosome and phagosome
    Vojo Deretic
    Health Sciences Center, Department of Molecular Genetics and Microbiology, University of New Mexico Health Sciences Center, Albuquerque, NM, USA
    Methods Mol Biol 445:1-10. 2008
    ..Autophagy and phagocytosis cooperate in the latter two processes. In this chapter, we briefly review the regulatory and execution stages of both autophagy and phagocytosis...
  10. ncbi Autophagic proteolysis of long-lived proteins in nonliver cells
    Esteban A Roberts
    Department of Molecular Genetics and Microbiology, University of New Mexico School of Medicine, Albuquerque, NM, USA
    Methods Mol Biol 445:111-7. 2008
    ..Here we describe a protocol to quantify autophagic degradation of longlived proteins in macrophages. This chapter details the method of analyzing autophagic proteolysis in RAW264.7 mouse macrophages...
  11. pmc Beclin1-binding UVRAG targets the class C Vps complex to coordinate autophagosome maturation and endocytic trafficking
    Chengyu Liang
    Department of Molecular Microbiology and Immunology, University of Southern California, Los Angeles, CA 90033, USA
    Nat Cell Biol 10:776-87. 2008
    ....
  12. ncbi The Mycobacterium tuberculosis phagosome
    Esteban A Roberts
    Department of Molecular Genetics and Microbiology, University of New Mexico School of Medicine, Albuquerque, NM, USA
    Methods Mol Biol 445:439-49. 2008
    ....
  13. pmc Autophagy, an immunologic magic bullet: Mycobacterium tuberculosis phagosome maturation block and how to bypass it
    Vojo Deretic
    University of New Mexico Health Sciences Center, Department of Molecular Genetics and Microbiology, Albuquerque, NM 87131 001, USA
    Future Microbiol 3:517-24. 2008
    ..This is a new, rapidly growing field replete with possibilities for novel, previously untried immunologic and pharmacologic interventions applicable not only to TB but to other stubborn bacterial, parasitic and viral diseases...
  14. pmc Th1-Th2 polarisation and autophagy in the control of intracellular mycobacteria by macrophages
    James Harris
    Institute of Molecular Medicine, Trinity College Dublin and St James s Hospital, Dublin 8, Ireland
    Vet Immunol Immunopathol 128:37-43. 2009
    ..We discuss how differential modulation of autophagy by Th1 and Th2 cytokines may represent an important feature of the host response to mycobacteria...
  15. pmc Human IRGM regulates autophagy and cell-autonomous immunity functions through mitochondria
    Sudha B Singh
    Department of Molecular Genetics and Microbiology, University of New Mexico Health Sciences Center, 915 Camino de Salud, NE, Albuquerque, NM 87131 USA
    Nat Cell Biol 12:1154-65. 2010
    ..By acting on mitochondria, IRGM confers autophagic protection or cell death, explaining IRGM action both in defence against tuberculosis and in the damaging inflammation caused by Crohn's disease...
  16. pmc Autophagy in immunity and cell-autonomous defense against intracellular microbes
    Vojo Deretic
    Department of Molecular Genetics and Microbiology, University of New Mexico Health Sciences Center, Albuquerque, NM 87131, USA
    Immunol Rev 240:92-104. 2011
    ....
  17. pmc Lysosomal positioning coordinates cellular nutrient responses
    Viktor I Korolchuk
    Department of Medical Genetics, Cambridge Institute for Medical Genetics, Wellcome Trust MRC Building, Hills Road, Cambridge, CB2 0XY, UK
    Nat Cell Biol 13:453-60. 2011
    ..Our findings provide a physiological role for the dynamic state of lysosomal positioning in cells as a coordinator of mTORC1 signalling with autophagic flux...
  18. pmc Autophagy-based unconventional secretory pathway for extracellular delivery of IL-1β
    Nicolas Dupont
    Department of Molecular Genetics and Microbiology, University of New Mexico Health Sciences Center, Albuquerque, NM, USA
    EMBO J 30:4701-11. 2011
    ..It enables a subset of cytosolic proteins devoid of signal peptide sequences, and thus unable to access the conventional pathway through the ER, to enter an autophagy-based secretory pathway facilitating their exit from the cytoplasm...
  19. pmc Autophagy as an innate immunity paradigm: expanding the scope and repertoire of pattern recognition receptors
    Vojo Deretic
    Department of Molecular Genetics and Microbiology, University of New Mexico Health Sciences Center, 915 Camino de Salud, NE, Albuquerque, NM 87131, USA
    Curr Opin Immunol 24:21-31. 2012
    ....
  20. pmc A master conductor for aggregate clearance by autophagy
    Vojo Deretic
    Department of Molecular Genetics and Microbiology, University of New Mexico Health Sciences Center, 915 Camino de Salud NE, Albuquerque, NM 87131, USA
    Dev Cell 18:694-6. 2010
    ..provide evidence that the phosphatidylinositol 3-phosphate (PI3P) binding protein, Alfy, interacts with p62, Atg5, and PI3P to coordinate target recognition with site-specific activation of autophagic components...
  21. pmc Autophagy and pattern recognition receptors in innate immunity
    Monica Delgado
    Department of Molecular Genetics and Microbiology, University of New Mexico Health Sciences Center, Albuquerque, NM 87131, USA
    Immunol Rev 227:189-202. 2009
    ....
  22. pmc Multiple regulatory and effector roles of autophagy in immunity
    Vojo Deretic
    Department of Molecular Genetics and Microbiology, University of New Mexico Health Sciences Center, Albuquerque, 87131, USA
    Curr Opin Immunol 21:53-62. 2009
    ..A properly functioning autophagy helps prevent autoimmunity and assists in clearing pathogens. When aberrant, it contributes to human inflammatory disorders such as Crohn's disease...
  23. pmc Strange bedfellows expose ancient secrets of autophagy in immunity
    Vojo Deretic
    Department of Molecular Genetics and Microbiology, University of New Mexico Health Sciences Center, 915 Camino de Salud, NE, Albuquerque, NM 87131 001, USA
    Immunity 30:479-81. 2009
    ..In this issue of Immunity, Shelly et al. (2009) use VSV infection in Drosophila to show the role of autophagy genes in controlling viruses...
  24. pmc Toll-like receptors in control of immunological autophagy
    M A Delgado
    Department of Molecular Genetics and Microbiology, University of New Mexico Health Sciences Center, 915 Camino de Salud NE, Albuquerque, NM 87131, USA
    Cell Death Differ 16:976-83. 2009
    ....
  25. pmc Autophagy, immunity, and microbial adaptations
    Vojo Deretic
    Department of Molecular Genetics and Microbiology, University of New Mexico Health Sciences Center, 915 Camino de Salud, NE, Albuquerque, NM 87131, USA
    Cell Host Microbe 5:527-49. 2009
    ..Thus, a complex interplay between autophagy and microbial adaptations against autophagy governs the net outcome of host-microbe encounters...
  26. pmc Autophagy pathway intersects with HIV-1 biosynthesis and regulates viral yields in macrophages
    George B Kyei
    Department of Molecular Genetics and Microbiology, University of New Mexico School of Medicine, Albuquerque, NM 87131, USA
    J Cell Biol 186:255-68. 2009
    ..The role of Nef in the latter process enhances yields of infectious HIV and may be of significance for progression to clinical AIDS...
  27. pmc Autophagy in immunity against mycobacterium tuberculosis: a model system to dissect immunological roles of autophagy
    Vojo Deretic
    Department of Molecular Genetics and Microbiology, University of New Mexico Health Sciences Center, 915 Camino de Salud NE, Albuquerque, NM 87131, USA
    Curr Top Microbiol Immunol 335:169-88. 2009
    ..This work and related studies by others have led us to propose a model of how autophagy, an ancient innate immunity defense, became integrated over the course of evolution with other immune mechanisms of ever-increasing complexity...
  28. pmc The role of PI3P phosphatases in the regulation of autophagy
    Isabelle Vergne
    Department of Molecular Genetics and Microbiology, University of New Mexico School of Medicine, Albuquerque, NM 87131, USA
    FEBS Lett 584:1313-8. 2010
    ..This review sums up our knowledge on PI3P phosphatases and discusses the recent progress on their role in autophagy...
  29. pmc Delivery of cytosolic components by autophagic adaptor protein p62 endows autophagosomes with unique antimicrobial properties
    Marisa Ponpuak
    Department of Molecular Genetics and Microbiology, University of New Mexico School of Medicine, Albuquerque, NM 87131, USA
    Immunity 32:329-41. 2010
    ..tuberculosis. Thus, p62 brings cytosolic proteins to autolysosomes where they are processed from innocuous precursors into neo-antimicrobial peptides, explaining in part the unique bactericidal properties of autophagic organelles...
  30. pmc Autophagy and HIV
    Christina Dinkins
    Department of Molecular Genetics and Microbiology, University of New Mexico Health Sciences Center, 915 Camino de Salud NE, Albuquerque, NM 87131, USA
    Semin Cell Dev Biol 21:712-8. 2010
    ..Here we review these relationships and underscore the untapped potential of autophagy as a druggable antiviral process...
  31. pmc Autophagy in infection
    Vojo Deretic
    Department of Molecular Genetics and Microbiology, University of New Mexico Health Sciences Center, 915 Camino de Salud NE, Albuquerque, NM 87131, USA
    Curr Opin Cell Biol 22:252-62. 2010
    ....