Dying to Live: How the Death Modality of the Infected Macrophage Affects Immunity to Tuberculosis

Chapter
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 783)

Abstract

Virulent Mycobacterium tuberculosis (Mtb) inhibits apoptosis and triggers necrosis of host macrophages to evade innate delay in the initiation of adaptive immunity. Necrosis is a mechanism used by bacteria to exit macrophage, evade the host defenses, and disseminate while apoptosis is associated with diminished pathogen viability. We have recently demonstrated that eicosanoids regulate cell death program of either human or murine macrophages infected with Mtb. We have defined prostaglandin E2 (PGE2) as a pro-apoptotic host lipid mediator which protects against necrosis. In contrast, lipoxin A4 (LXA4) is a pro-necrotic lipid mediator which suppresses PGE2 synthesis, resulting in mitochondrial damage and inhibition of plasma membrane repair mechanisms; this ultimately leads to the induction of necrosis. Thus, the balance between PGE2 and LXA4 determines whether Mtb-infected macrophages undergo apoptosis or necrosis and this balance determines the outcome of infection.

Keywords

Mycobacterium tuberculosis (MtbMacrophages Necrosis Apoptosis Extrinsic pathway Intrinsic pathway Mitochondrial outer membrane permeabilization (MOMP) Mitochondrial permeability transition (MPT) Cell death program B-cell lymphoma 2 (Bcl-2) BH3 interacting domain (BID) Bcl-2 associated X Protein (BAX) Bcl-2 homologous antagonist killer (BAK) FLICE-inhibitory protein (FLIPS) Lipoxins (LX) Prostaglandins (PG) Eicosanoids Plasma membrane microdisruptions Mycobacterial antigens BCG vaccine T cell response 

Notes

Acknowledgments

M.D. is supported by the Canadian Institute of Health Research-New Investigator Award. Work in his laboratory is supported by the Canadian Institute of Health Research (CIHR) and The Natural Sciences and Engineering Research Council of Canada (NSERC).

References

  1. 1.
    WHO (2012) World health organization: global tuberculosis control 2010Google Scholar
  2. 2.
    Behar SM, Martin CJ, Nunes-Alves C, Divangahi M, Remold HG (2011) Lipids, apoptosis, and cross-presentation: links in the chain of host defense against Mycobacterium tuberculosis. Microbes Infect 13:749–756PubMedCrossRefGoogle Scholar
  3. 3.
    Dye C, Williams BG (2010) The population dynamics and control of tuberculosis. Science 328:856–861PubMedCrossRefGoogle Scholar
  4. 4.
    Kaufmann SH (2001) How can immunology contribute to the control of tuberculosis? Nat Rev Immunol 1:20–30PubMedCrossRefGoogle Scholar
  5. 5.
    Chen M, Gan H, Remold HG (2006) A mechanism of virulence: virulent Mycobacterium tuberculosis strain H37Rv, but not attenuated H37Ra, causes significant mitochondrial inner membrane disruption in macrophages leading to necrosis. J Immunol 176:3707–3716PubMedGoogle Scholar
  6. 6.
    Keane J, Remold HG, Kornfeld H (2000) Virulent Mycobacterium tuberculosis strains evade apoptosis of infected alveolar macrophages. J Immunol 164:2016–2020PubMedGoogle Scholar
  7. 7.
    Hinchey J et al (2007) Enhanced priming of adaptive immunity by a proapoptotic mutant of Mycobacterium tuberculosis. J Clin Invest 117:2279–2288PubMedCrossRefGoogle Scholar
  8. 8.
    Velmurugan K et al (2007) Mycobacterium tuberculosis nuoG is a virulence gene that inhibits apoptosis of infected host cells. PLoS Pathog 3:e110PubMedCrossRefGoogle Scholar
  9. 9.
    Molloy A, Laochumroonvorapong P, Kaplan G (1994) Apoptosis, but not necrosis, of infected monocytes is coupled with killing of intracellular bacillus Calmette-Guerin. J Exp Med 180:1499–1509PubMedCrossRefGoogle Scholar
  10. 10.
    Fratazzi C, Arbeit RD, Carini C, Remold HG (1997) Programmed cell death of Mycobacterium avium serovar 4-infected human macrophages prevents the mycobacteria from spreading and induces mycobacterial growth inhibition by freshly added, uninfected macrophages. J Immunol 158:4320–4327PubMedGoogle Scholar
  11. 11.
    Divangahi M et al (2009) Mycobacterium tuberculosis evades macrophage defenses by inhibiting plasma membrane repair. Nat Immunol 10:899–906PubMedCrossRefGoogle Scholar
  12. 12.
    Chen M et al (2008) Lipid mediators in innate immunity against tuberculosis: opposing roles of PGE2 and LXA4 in the induction of macrophage death. J Exp Med 205:2791–2801PubMedCrossRefGoogle Scholar
  13. 13.
    Constance et al (2012) Efferocytosis is an innate antibacterial mechanism. Cell Host Microbe 12:289Google Scholar
  14. 14.
    Bergsbaken T, Fink SL, Cookson BT (2009) Pyroptosis: host cell death and inflammation. Nat Rev Microbiol 7:99–109PubMedCrossRefGoogle Scholar
  15. 15.
    Vandenabeele P, Galluzzi L, Vanden BT, Kroemer G (2010) Molecular mechanisms of necroptosis: an ordered cellular explosion. Nat Rev Mol Cell Biol 11:700–714PubMedCrossRefGoogle Scholar
  16. 16.
    Duprez L, Wirawan E, Vanden BT, Vandenabeele P (2009) Major cell death pathways at a glance. Microbes Infect 11:1050–1062PubMedCrossRefGoogle Scholar
  17. 17.
    Cohen JJ (1993) Apoptosis. Immunol Today 14:126–130PubMedCrossRefGoogle Scholar
  18. 18.
    Fadok VA et al (1992) Exposure of phosphatidylserine on the surface of apoptotic lymphocytes triggers specific recognition and removal by macrophages. J Immunol 148:2207–2216PubMedGoogle Scholar
  19. 19.
    Fadok VA et al (2000) A receptor for phosphatidylserine-specific clearance of apoptotic cells. Nature 405:85–90PubMedCrossRefGoogle Scholar
  20. 20.
    Henson PM, Tuder RM (2008) Apoptosis in the lung: induction, clearance and detection. Am J Physiol Lung Cell Mol Physiol 294:L601–L611PubMedCrossRefGoogle Scholar
  21. 21.
    Krysko DV, D’Herde K, Vandenabeele P (2006) Clearance of apoptotic and necrotic cells and its immunological consequences. Apoptosis 11:1709–1726PubMedCrossRefGoogle Scholar
  22. 22.
    Duan L, Gan H, Arm J, Remold HG (2001) Cytosolic phospholipase A2 participates with TNF-alpha in the induction of apoptosis of human macrophages infected with Mycobacterium tuberculosis H37Ra. J Immunol 166:7469–7476PubMedGoogle Scholar
  23. 23.
    Christofferson DE, Yuan J (2010) Necroptosis as an alternative form of programmed cell death. Curr Opin Cell Biol 22:263–268PubMedCrossRefGoogle Scholar
  24. 24.
    Thornberry NA, Lazebnik Y (1998) Caspases: enemies within. Science 281:1312–1316PubMedCrossRefGoogle Scholar
  25. 25.
    Balcewicz-Sablinska MK, Keane J, Kornfeld H, Remold HG (1998) Pathogenic Mycobacterium tuberculosis evades apoptosis of host macrophages by release of TNF-R2, resulting in inactivation of TNF-alpha. J Immunol 161:2636–2641PubMedGoogle Scholar
  26. 26.
    Green DR, Kroemer G (2004) The pathophysiology of mitochondrial cell death. Science 305:626–629PubMedCrossRefGoogle Scholar
  27. 27.
    Kim JS, He L, Lemasters JJ (2003) Mitochondrial permeability transition: a common pathway to necrosis and apoptosis. Biochem Biophys Res Commun 304:463–470PubMedCrossRefGoogle Scholar
  28. 28.
    Chipuk JE, Green DR (2008) How do BCL-2 proteins induce mitochondrial outer membrane permeabilization? Trends Cell Biol 18:157–164PubMedCrossRefGoogle Scholar
  29. 29.
    Bossy-Wetzel E, Newmeyer DD, Green DR (1998) Mitochondrial cytochrome c release in apoptosis occurs upstream of DEVD-specific caspase activation and independently of mitochondrial transmembrane depolarization. EMBO J 17:37–49PubMedCrossRefGoogle Scholar
  30. 30.
    Ricci JE et al (2004) Disruption of mitochondrial function during apoptosis is mediated by caspase cleavage of the p75 subunit of complex I of the electron transport chain. Cell 117:773–786PubMedCrossRefGoogle Scholar
  31. 31.
    Martinvalet D, Dykxhoorn DM, Ferrini R, Lieberman J (2008) Granzyme A cleaves a mitochondrial complex I protein to initiate caspase-independent cell death. Cell 133:681–692PubMedCrossRefGoogle Scholar
  32. 32.
    Baines CP et al (2005) Loss of cyclophilin D reveals a critical role for mitochondrial permeability transition in cell death. Nature 434:658–662PubMedCrossRefGoogle Scholar
  33. 33.
    Gan H et al (2005) Enhancement of antimycobacterial activity of macrophages by stabilization of inner mitochondrial membrane potential. J Infect Dis 191:1292–1300PubMedCrossRefGoogle Scholar
  34. 34.
    Connern CP, Halestrap AP (1992) Purification and N-terminal sequencing of peptidyl-prolyl cis-trans isomerase from rat liver mitochondrial matrix reveals the existence of a distinct mitochondrial cyclophilin. Biochem J 284(2):381–385PubMedGoogle Scholar
  35. 35.
    Maertzdorf J et al (2011) Human gene expression profiles of susceptibility and resistance in tuberculosis. Genes Immun 12:15–22PubMedCrossRefGoogle Scholar
  36. 36.
    Abebe M et al (2010) Expression of apoptosis-related genes in an Ethiopian cohort study correlates with tuberculosis clinical status. Eur J Immunol 40:291–301PubMedCrossRefGoogle Scholar
  37. 37.
    Herb F et al (2008) ALOX5 variants associated with susceptibility to human pulmonary tuberculosis. Hum Mol Genet 17:1052–1060PubMedCrossRefGoogle Scholar
  38. 38.
    Tobin DM et al (2010) The lta4 h locus modulates susceptibility to mycobacterial infection in zebrafish and humans. Cell 140:717–730PubMedCrossRefGoogle Scholar
  39. 39.
    Tobin DM et al (2012) Host genotype-specific therapies can optimize the inflammatory response to mycobacterial infections. Cell 148:434–446PubMedCrossRefGoogle Scholar
  40. 40.
    Divangahi M, Desjardins D, Nunes-Alves C, Remold HG, Behar SM (2010) Eicosanoid pathways regulate adaptive immunity to Mycobacterium tuberculosis. Nat Immunol 11:751–758PubMedCrossRefGoogle Scholar
  41. 41.
    Wolf LA, Laster SM (1999) Characterization of arachidonic acid-induced apoptosis. Cell Biochem Biophys 30:353–368PubMedCrossRefGoogle Scholar
  42. 42.
    Chang DJ, Ringold GM, Heller RA (1992) Cell killing and induction of manganous superoxide dismutase by tumor necrosis factor-alpha is mediated by lipoxygenase metabolites of arachidonic acid. Biochem Biophys Res Commun 188:538–546PubMedCrossRefGoogle Scholar
  43. 43.
    Peterson DA et al (1988) Polyunsaturated fatty acids stimulate superoxide formation in tumor cells: a mechanism for specific cytotoxicity and a model for tumor necrosis factor? Biochem Biophys Res Commun 155:1033–1037PubMedCrossRefGoogle Scholar
  44. 44.
    Jayadev S, Linardic CM, Hannun YA (1994) Identification of arachidonic acid as a mediator of sphingomyelin hydrolysis in response to tumor necrosis factor alpha. J Biol Chem 269:5757–5763PubMedGoogle Scholar
  45. 45.
    Finstad HS et al (1998) Cell proliferation, apoptosis and accumulation of lipid droplets in U937–1 cells incubated with eicosapentaenoic acid. Biochem J 336(2):451–459PubMedGoogle Scholar
  46. 46.
    Rocca B, FitzGerald GA (2002) Cyclooxygenases and prostaglandins: shaping up the immune response. Int Immunopharmacol 2:603–630PubMedCrossRefGoogle Scholar
  47. 47.
    Murakami M et al (2000) Regulation of prostaglandin E2 biosynthesis by inducible membrane-associated prostaglandin E2 synthase that acts in concert with cyclooxygenase-2. J Biol Chem 275:32783–32792PubMedCrossRefGoogle Scholar
  48. 48.
    Sugimoto Y, Narumiya S (2007) Prostaglandin E receptors. J Biol Chem 282:11613–11617PubMedCrossRefGoogle Scholar
  49. 49.
    D’Avila H et al (2006) Mycobacterium bovis bacillus Calmette-Guerin induces TLR2-mediated formation of lipid bodies: Intracellular domains for eicosanoid synthesis in vivo. J Immunol 176:3087–3097PubMedGoogle Scholar
  50. 50.
    Almeida PE et al (2009) Mycobacterium bovis bacillus Calmette-Guerin infection induces TLR2-dependent peroxisome proliferator-activated receptor gamma expression and activation: functions in inflammation, lipid metabolism, and pathogenesis. J Immunol 183:1337–1345PubMedCrossRefGoogle Scholar
  51. 51.
    Levy BD, Clish CB, Schmidt B, Gronert K, Serhan CN (2001) Lipid mediator class switching during acute inflammation: signals in resolution. Nat Immunol 2:612–619PubMedCrossRefGoogle Scholar
  52. 52.
    Serhan CN, Chiang N, Van Dyke TE (2008) Resolving inflammation: dual anti-inflammatory and pro-resolution lipid mediators. Nat Rev Immunol 8:349–361PubMedCrossRefGoogle Scholar
  53. 53.
    Tobin DM et al (2010) The lta4 h locus modulates susceptibility to mycobacterial infection in zebrafish and humans. Cell 140:717–730PubMedCrossRefGoogle Scholar
  54. 54.
    Smith J et al (2008) Evidence for pore formation in host cell membranes by ESX-1-secreted ESAT-6 and its role in Mycobacterium marinum escape from the vacuole. Infect Immun 76:5478–5487PubMedCrossRefGoogle Scholar
  55. 55.
    de Jonge MI et al (2007) (2007) ESAT-6 from Mycobacterium tuberculosis dissociates from its putative chaperone CFP-10 under acidic conditions and exhibits membrane-lysing activity. J Bacteriol 189:6028–6034PubMedCrossRefGoogle Scholar
  56. 56.
    Roy D et al (2004) A process for controlling intracellular bacterial infections induced by membrane injury. Science 304:1515-1518Google Scholar
  57. 57.
    Togo T, Alderton JM, Bi GQ, Steinhardt RA (1999) The mechanism of facilitated cell membrane resealing. J Cell Sci 112(5):719–731PubMedGoogle Scholar
  58. 58.
    Granger BL et al (1990) Characterization and cloning of lgp110, a lysosomal membrane glycoprotein from mouse and rat cells. J Biol Chem 265:12036–12043PubMedGoogle Scholar
  59. 59.
    Novikoff PM, Tulsiani DR, Touster O, Yam A, Novikoff AB (1983) Immunocytochemical localization of alpha-D-mannosidase II in the Golgi apparatus of rat liver. Proc Natl Acad Sci U S A 80:4364–4368PubMedCrossRefGoogle Scholar
  60. 60.
    Martinez I et al (2000) Synaptotagmin VII regulates Ca(2 +)-dependent exocytosis of lysosomes in fibroblasts. J Cell Biol 148:1141–1149PubMedCrossRefGoogle Scholar
  61. 61.
    Burgoyne RD, O’Callaghan DW, Hasdemir B, Haynes LP, Tepikin AV (2004) Neuronal Ca2 + -sensor proteins: multitalented regulators of neuronal function. Trends Neurosci 27:203–209PubMedCrossRefGoogle Scholar
  62. 62.
    Togo T, Alderton JM, Steinhardt RA (2003) Long-term potentiation of exocytosis and cell membrane repair in fibroblasts. Mol Biol Cell 14:93–106PubMedCrossRefGoogle Scholar
  63. 63.
    Regan JW (2003) EP2 and EP4 prostanoid receptor signaling. Life Sci 74:143–153PubMedCrossRefGoogle Scholar
  64. 64.
    Bafica A et al (2005) Host control of Mycobacterium tuberculosis is regulated by 5-lipoxygenase-dependent lipoxin production. J Clin Invest 115:1601–1606PubMedCrossRefGoogle Scholar
  65. 65.
    Albert ML (2004) Death-defying immunity: do apoptotic cells influence antigen processing and presentation? Nat Rev Immunol 4:223–231PubMedCrossRefGoogle Scholar
  66. 66.
    Yrlid U, Wick MJ (2000) Salmonella-induced apoptosis of infected macrophages results in presentation of a bacteria-encoded antigen after uptake by bystander dendritic cells. J Exp Med 191:613–624PubMedCrossRefGoogle Scholar
  67. 67.
    Schaible UE et al (2003) Apoptosis facilitates antigen presentation to T lymphocytes through MHC-I and CD1 in tuberculosis. Nat Med 9:1039–1046PubMedCrossRefGoogle Scholar
  68. 68.
    Winau F et al (2006) Apoptotic vesicles crossprime CD8 T cells and protect against tuberculosis. Immunity 24:105–117PubMedCrossRefGoogle Scholar
  69. 69.
    Winau F, Kaufmann SH, Schaible UE (2004) Apoptosis paves the detour path for CD8 T cell activation against intracellular bacteria. Cell Microbiol 6:599–607PubMedCrossRefGoogle Scholar
  70. 70.
    Aronoff DM et al (2009) E-prostanoid 3 receptor deletion improves pulmonary host defense and protects mice from death in severe Streptococcus pneumoniae infection. J Immunol 183:2642–2649PubMedCrossRefGoogle Scholar
  71. 71.
    Medeiros AI, Serezani CH, Lee SP, Peters-Golden M (2009) Efferocytosis impairs pulmonary macrophage and lung antibacterial function via PGE2/EP2 signaling. J Exp Med 206:61–68PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2013

Authors and Affiliations

  1. 1.Meakins-Christie Laboratories, Department of Microbiology and Immunology, Department of MedicineMcGill University Health CentreMontrealCanada
  2. 2.Division of Rheumatology, Immunology, and Allergy, Department of MedicineBrigham and Women’s Hospital, Harvard Medical SchoolBostonCanada

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