Autophagy in Infection and Immunity pp 189-215

Part of the Current Topics in Microbiology and Immunology book series (CT MICROBIOLOGY, volume 335)

| Cite as

Autophagy in Immunity Against Intracellular Bacteria



Autophagy is an innate immune defense mechanism against various intracellular bacterial pathogens, such as Salmonella enterica serovar Typhimurium (S. typhimurium), Listeria monocytogenes and Shigella flexneri. S. typhimurium uses type three secretion systems (T3SSs) to invade mammalian cells and replicate in Salmonella-containing vacuoles (SCVs). A small population of intracellular S. typhimurium is targeted by autophagy shortly after infection. Evidence suggests that these bacteria are present within SCVs that have been damaged by high levels of T3SS activity. Autophagy limits the growth of S. typhimurium in host cells. Therefore, autophagy can be considered to protect the cytosol of eukaryotic cells from bacterial colonization. L. monocytogenes secretes the pore-forming cytolysin listeriolysin O (LLO) to disrupt the phagosome and escape into the cytosol, where it acquires actin-based motility. Autophagy can target L. monocytogenes in the cytosol under specific experimental conditions. However, L. monocytogenes utilizes several virulence factors to evade being killed by the autophagy system. A newly appreciated population of L. monocytogenes undergoes slow growth in specialized vacuoles termed spacious Listeria-containing phagosomes (SLAPs), the formation of which requires bacterial LLO and host autophagy. In the cytosol, S. flexneri can also be a target for autophagy in the absence of a T3SS effector, IcsB, that normally impairs the interaction between Atg5 and wild-type bacteria. Therefore, autophagy can recognize intracellular bacteria in a variety of ways, leading to different fates for these bacteria in host cells. The inefficient autophagy of enteric bacteria in genetically compromised individuals may contribute to the pathogenesis of Crohn’s disease.



Crohn’s disease


Early endosome antigen 1


Endoplasmic reticulum


Guanine nucleotide exchange factor


Immunity-related GTPase


Lysosome-associated membrane protein 1


Listeriolysin O




Mannose-6-phosphate receptor


Mouse embryonic fibroblast


NOD-like receptor


Nucleotide-binding oligomerization domain




Phospholipase C


Severe combined immunodeficiency


Salmonella-containing vacuole


Spacious Listeria-containing phagosome


Single nucleotide polymorphism


Salmonella pathogenicity island


Type three secretion system


Toll-like receptor


  1. Abubakar I, Myhill D, Aliyu SH, Hunter PR (2008) Detection of Mycobacterium avium subspecies paratuberculosis from patients with Crohn’s disease using nucleic acid-based techniques: a systematic review and meta-analysis. Inflamm Bowel Dis 14:401–410PubMedGoogle Scholar
  2. Alpuche-Aranda CM, Racoosin EL, Swanson JA, Miller SI (1994) Salmonella stimulate macrophage macropinocytosis and persist within spacious phagosomes. J Exp Med 179:601–608PubMedGoogle Scholar
  3. Alvarez-Dominguez C, Roberts R, Stahl PD (1997) Internalized Listeria monocytogenes modulates intracellular trafficking and delays maturation of the phagosome. J Cell Sci 110 (Pt 6):731–743PubMedGoogle Scholar
  4. Amre DK, Mack DR, Morgan K, Krupoves A, Costea I, Lambrette P, Grimard G, Dong J, Feguery H, Bucionis V, Deslandres C, Levy E, Seidman EG (2009) Autophagy gene ATG16L1 but not IRGM is associated with Crohn’s disease in Canadian children. Inflamm Bowel Dis 15:501–507PubMedGoogle Scholar
  5. Baumgart M, Dogan B, Rishniw M, Weitzman G, Bosworth B, Yantiss R, Orsi RH, Wiedmann M, McDonough P, Kim SG, Berg D, Schukken Y, Scherl E, Simpson KW (2007) Culture independent analysis of ileal mucosa reveals a selective increase in invasive Escherichia coli of novel phylogeny relative to depletion of Clostridiales in Crohn’s disease involving the ileum. Isme J 1:403–418PubMedGoogle Scholar
  6. Beuzon CR, Meresse S, Unsworth KE, Ruiz-Albert J, Garvis S, Waterman SR, Ryder TA, Boucrot E, Holden DW (2000) Salmonella maintains the integrity of its intracellular vacuole through the action of SifA. Embo J 19:3235–3249PubMedGoogle Scholar
  7. Bhardwaj V, Kanagawa O, Swanson PE, Unanue ER (1998) Chronic Listeria infection in SCID mice: requirements for the carrier state and the dual role of T cells in transferring protection or suppression. J Immunol 160:376–384PubMedGoogle Scholar
  8. Birmingham CL, Brumell JH (2006) Autophagy recognizes intracellular Salmonella enterica serovar Typhimurium in damaged vacuoles. Autophagy 2:156–158PubMedGoogle Scholar
  9. Birmingham CL, Jiang X, Ohlson MB, Miller SI, Brumell JH (2005) Salmonella-induced filament formation is a dynamic phenotype induced by rapidly replicating Salmonella enterica serovar typhimurium in epithelial cells. Infect Immunol 73:1204–1208Google Scholar
  10. Birmingham CL, Smith AC, Bakowski MA, Yoshimori T, Brumell JH (2006) Autophagy controls Salmonella infection in response to damage to the Salmonella-containing vacuole. J Biol Chem 281:11374–11383PubMedGoogle Scholar
  11. Birmingham CL, Canadien V, Gouin E, Troy EB, Yoshimori T, Cossart P, Higgins DE, Brumell JH (2007) Listeria monocytogenes evades killing by autophagy during colonization of host cells. Autophagy 3:442–451PubMedGoogle Scholar
  12. Birmingham CL, Canadien V, Kaniuk NA, Steinberg BE, Higgins DE, Brumell JH (2008a) Listeriolysin O allows Listeria monocytogenes replication in macrophage vacuoles. Nature 451:350–354PubMedGoogle Scholar
  13. Birmingham CL, Higgins DE, Brumell JH (2008b) Avoiding death by autophagy: interactions of Listeria monocytogenes with the macrophage autophagy system. Autophagy 4:368–371PubMedGoogle Scholar
  14. Brawn LC, Hayward RD, Koronakis V (2007) Salmonella SPI1 effector SipA persists after entry and cooperates with a SPI2 effector to regulate phagosome maturation and intracellular replication. Cell Host Microbe 1:63–75PubMedGoogle Scholar
  15. Brumell JH, Grinstein S (2004) Salmonella redirects phagosomal maturation. Curr Opin Microbiol 7:78–84PubMedGoogle Scholar
  16. Brumell JH, Steele-Mortimer O, Finlay BB (1999) Bacterial invasion: force feeding by Salmonella. Curr Biol 9:R277–280PubMedGoogle Scholar
  17. Brumell JH, Rosenberger CM, Gotto GT, Marcus SL, Finlay BB (2001) SifA permits survival and replication of Salmonella typhimurium in murine macrophages. Cell Microbiol 3:75–84PubMedGoogle Scholar
  18. Brumell JH, Goosney DL, Finlay BB (2002a) SifA, a type III secreted effector of Salmonella typhimurium, directs Salmonella-induced filament (Sif) formation along microtubules. Traffic 3:407–415PubMedGoogle Scholar
  19. Brumell JH, Tang P, Zaharik ML, Finlay BB (2002b) Disruption of the Salmonella-containing vacuole leads to increased replication of Salmonella enterica serovar typhimurium in the cytosol of epithelial cells. Infect Immun 70:3264–3270PubMedGoogle Scholar
  20. Cadwell K, Liu JY, Brown SL, Miyoshi H, Loh J, Lennerz JK, Kishi C, Kc W, Carrero JA, Hunt S, Stone CD, Brunt EM, Xavier RJ, Sleckman BP, Li E, Mizushima N, Stappenbeck TS, Virgin HW (2008) A key role for autophagy and the autophagy gene Atg16l1 in mouse and human intestinal Paneth cells. Nature 456:259–263PubMedGoogle Scholar
  21. Chen LM, Hobbie S, Galan JE (1996) Requirement of CDC42 for Salmonella-induced cytoskeletal and nuclear responses. Science 274:2115–2118PubMedGoogle Scholar
  22. Cirillo DM, Heffernan EJ, Wu L, Harwood J, Fierer J, Guiney DG (1996) Identification of a domain in Rck, a product of the Salmonella typhimurium virulence plasmid, required for both serum resistance and cell invasion. Infect Immun 64:2019–2023PubMedGoogle Scholar
  23. Cobrin GM, Abreu MT (2005) Defects in mucosal immunity leading to Crohn’s disease. Immunol Rev 206:277–295PubMedGoogle Scholar
  24. Consortium WTCC (2007) Genome-wide association study of 14,000 cases of seven common diseases and 3,000 shared controls. Nature 447:661–678Google Scholar
  25. Cossart P, Sansonetti PJ (2004) Bacterial invasion: the paradigms of enteroinvasive pathogens. Science 304:242–248PubMedGoogle Scholar
  26. de Chastellier C, Berche P (1994) Fate of Listeria monocytogenes in murine macrophages: evidence for simultaneous killing and survival of intracellular bacteria. Infect Immun 62:543–553PubMedGoogle Scholar
  27. Deiwick J, Nikolaus T, Shea JE, Gleeson C, Holden DW, Hensel M (1998) Mutations in Salmonella pathogenicity island 2 (SPI2) genes affecting transcription of SPI1 genes and resistance to antimicrobial agents. J Bacteriol 180:4775–4780PubMedGoogle Scholar
  28. del Cerro-Vadillo E, Madrazo-Toca F, Carrasco-Marin E, Fernandez-Prieto L, Beck C, Leyva-Cobian F, Saftig P, Alvarez-Dominguez C (2006) Cutting edge: a novel nonoxidative phagosomal mechanism exerted by cathepsin-D controls Listeria monocytogenes intracellular growth. J Immunol 176:1321–1325PubMedGoogle Scholar
  29. Delgado MA, Elmaoued RA, Davis AS, Kyei G, Deretic V (2008) Toll-like receptors control autophagy. EMBO J 27:1110–1121PubMedGoogle Scholar
  30. Dengjel J, Schoor O, Fischer R, Reich M, Kraus M, Muller M, Kreymborg K, Altenberend F, Brandenburg J, Kalbacher H, Brock R, Driessen C, Rammensee HG, Stevanovic S (2005) Autophagy promotes MHC class II presentation of peptides from intracellular source proteins. Proc Natl Acad Sci USA 102:7922–7927PubMedGoogle Scholar
  31. Drecktrah D, Knodler LA, Galbraith K, Steele-Mortimer O (2005) The Salmonella SPI1 effector SopB stimulates nitric oxide production long after invasion. Cell Microbiol 7:105–113PubMedGoogle Scholar
  32. Duerr RH, Taylor KD, Brant SR, Rioux JD, Silverberg MS, Daly MJ, Steinhart AH, Abraham C, Regueiro M, Griffiths A, Dassopoulos T, Bitton A, Yang H, Targan S, Datta LW, Kistner EO, Schumm LP, Lee AT, Gregersen PK, Barmada MM, Rotter JI, Nicolae DL, Cho JH (2006) A genome-wide association study identifies IL23R as an inflammatory bowel disease gene. Science 314:1461–1463PubMedGoogle Scholar
  33. Dussurget O, Pizarro-Cerda J, Cossart P (2004) Molecular determinants of Listeria monocytogenes virulence. Annu Rev Microbiol 58:587–610PubMedGoogle Scholar
  34. Eriksson S, Lucchini S, Thompson A, Rhen M, Hinton JC (2003) Unravelling the biology of macrophage infection by gene expression profiling of intracellular Salmonella enterica. Mol Microbiol 47:103–118PubMedGoogle Scholar
  35. Fang FC (2004) Antimicrobial reactive oxygen and nitrogen species: concepts and controversies. Nat Rev Microbiol 2:820–832PubMedGoogle Scholar
  36. Fink SL, Cookson BT (2007) Pyroptosis and host cell death responses during Salmonella infection. Cell Microbiol 9:2562–2570PubMedGoogle Scholar
  37. Finlay BB, Brumell JH (2000) Salmonella interactions with host cells: in vitro to in vivo. Philos Trans R Soc Lond B Biol Sci 355:623–631PubMedGoogle Scholar
  38. Fujita N, Itoh T, Omori H, Fukuda M, Noda T, Yoshimori T (2008) The Atg16L complex specifies the site of LC3 lipidation for membrane biogenesis in autophagy. Mol Biol Cell 19:2092–2100PubMedGoogle Scholar
  39. Galan JE (2001) Salmonella interactions with host cells: type III secretion at work. Annu Rev Cell Dev Biol 17:53–86PubMedGoogle Scholar
  40. Garcia-del Portillo F, Zwick MB, Leung KY, Finlay BB (1993) Salmonella induces the formation of filamentous structures containing lysosomal membrane glycoproteins in epithelial cells. Proc Natl Acad Sci USA 90:10544–10548PubMedGoogle Scholar
  41. Giacomodonato MN, Uzzau S, Bacciu D, Caccuri R, Sarnacki SH, Rubino S, Cerquetti MC (2007) SipA, SopA, SopB, SopD and SopE2 effector proteins of Salmonella enterica serovar Typhimurium are synthesized at late stages of infection in mice. Microbiology 153:1221–1228PubMedGoogle Scholar
  42. Glas J, Konrad A, Schmechel S, Dambacher J, Seiderer J, Schroff F, Wetzke M, Roeske D, Torok HP, Tonenchi L, Pfennig S, Haller D, Griga T, Klein W, Epplen JT, Folwaczny C, Lohse P, Goke B, Ochsenkuhn T, Mussack T, Folwaczny M, Muller-Myhsok B, Brand S (2008) The ATG16L1 gene variants rs2241879 and rs2241880 (T300A) are strongly associated with susceptibility to Crohn’s disease in the German population. Am J Gastroenterol 103:682–691PubMedGoogle Scholar
  43. Gouin E, Welch MD, Cossart P (2005) Actin-based motility of intracellular pathogens. Curr Opin Microbiol 8:35–45PubMedGoogle Scholar
  44. Gutierrez MG, Master SS, Singh SB, Taylor GA, Colombo MI, Deretic V (2004) Autophagy is a defense mechanism inhibiting BCG and Mycobacterium tuberculosis survival in infected macrophages. Cell 119:753–766PubMedGoogle Scholar
  45. Hamon M, Bierne H, Cossart P (2006) Listeria monocytogenes: a multifaceted model. Nat Rev Microbiol 4:423–434PubMedGoogle Scholar
  46. Hampe J, Franke A, Rosenstiel P, Till A, Teuber M, Huse K, Albrecht M, Mayr G, De La Vega FM, Briggs J, Gunther S, Prescott NJ, Onnie CM, Hasler R, Sipos B, Folsch UR, Lengauer T, Platzer M, Mathew CG, Krawczak M, Schreiber S (2007) A genome-wide association scan of nonsynonymous SNPs identifies a susceptibility variant for Crohn disease in ATG16L1. Nat Genet 39:207–211PubMedGoogle Scholar
  47. Haraga A, Ohlson MB, Miller SI (2008) Salmonellae interplay with host cells. Nat Rev Microbiol 6:53–66PubMedGoogle Scholar
  48. Henry R, Shaughnessy L, Loessner MJ, Alberti-Segui C, Higgins DE, Swanson JA (2006) Cytolysin-dependent delay of vacuole maturation in macrophages infected with Listeria monocytogenes. Cell Microbiol 8:107–119PubMedGoogle Scholar
  49. Hensel M, Shea JE, Waterman SR, Mundy R, Nikolaus T, Banks G, Vazquez-Torres A, Gleeson C, Fang FC, Holden DW (1998) Genes encoding putative effector proteins of the type III secretion system of Salmonella pathogenicity island 2 are required for bacterial virulence and proliferation in macrophages. Mol Microbiol 30:163–174PubMedGoogle Scholar
  50. Hernandez LD, Pypaert M, Flavell RA, Galan JE (2003) A Salmonella protein causes macrophage cell death by inducing autophagy. J Cell Biol 163:1123–1131PubMedGoogle Scholar
  51. Hersh D, Monack DM, Smith MR, Ghori N, Falkow S, Zychlinsky A (1999) The Salmonella invasin SipB induces macrophage apoptosis by binding to caspase-1. Proc Natl Acad Sci USA 96:2396–2401PubMedGoogle Scholar
  52. Huang J, Klionsky DJ (2007) Autophagy and human disease. Cell Cycle 6:1837–1849PubMedGoogle Scholar
  53. Hueffer K, Galan JE (2004) Salmonella-induced macrophage death: multiple mechanisms, different outcomes. Cell Microbiol 6:1019–1025PubMedGoogle Scholar
  54. Hugot JP, Chamaillard M, Zouali H, Lesage S, Cezard JP, Belaiche J, Almer S, Tysk C, O’Morain CA, Gassull M, Binder V, Finkel Y, Cortot A, Modigliani R, Laurent-Puig P, Gower-Rousseau C, Macry J, Colombel JF, Sahbatou M, Thomas G (2001) Association of NOD2 leucine-rich repeat variants with susceptibility to Crohn’s disease. Nature 411:599–603PubMedGoogle Scholar
  55. Ireton K (2007) Entry of the bacterial pathogen Listeria monocytogenes into mammalian cells. Cell Microbiol 9:1365–1375PubMedGoogle Scholar
  56. Kayal S, Charbit A (2006) Listeriolysin O: a key protein of Listeria monocytogenes with multiple functions. FEMS Microbiol Rev 30:514–529PubMedGoogle Scholar
  57. Kirchner M, Higgins DE (2008) Inhibition of ROCK activity allows InlF-mediated invasion and increased virulence of Listeria monocytogenes. Mol Microbiol 68:749–767PubMedGoogle Scholar
  58. Knodler LA, Steele-Mortimer O (2003) Taking possession: biogenesis of the Salmonella-containing vacuole. Traffic 4:587–599PubMedGoogle Scholar
  59. Kuballa P, Huett A, Rioux JD, Daly MJ, Xavier RJ (2008) Impaired autophagy of an intracellular pathogen induced by a Crohn’s disease associated ATG16L1 variant. PLoS ONE 3:e3391PubMedGoogle Scholar
  60. Kuma A, Mizushima N, Ishihara N, Ohsumi Y (2002) Formation of the approximately 350-kDa Apg12-Apg5.Apg16 multimeric complex, mediated by Apg16 oligomerization, is essential for autophagy in yeast. J Biol Chem 277:18619–18625PubMedGoogle Scholar
  61. Le Bourhis L, Benko S, Girardin SE (2007) Nod1 and Nod2 in innate immunity and human inflammatory disorders. Biochem Soc Trans 35:1479–1484PubMedGoogle Scholar
  62. Lecuit M (2007) Human listeriosis and animal models. Microbes Infect 9:1216–1225PubMedGoogle Scholar
  63. Maeda S, Hsu LC, Liu H, Bankston LA, Iimura M, Kagnoff MF, Eckmann L, Karin M (2005) Nod2 mutation in Crohn’s disease potentiates NF-kappaB activity and IL-1beta processing. Science 307:734–738PubMedGoogle Scholar
  64. Massey DC, Parkes M (2007) Genome-wide association scanning highlights two autophagy genes, ATG16L1 and IRGM, as being significantly associated with Crohn’s disease. Autophagy 3:649–651PubMedGoogle Scholar
  65. McCarroll SA, Huett A, Kuballa P, Chilewski SD, Landry A, Goyette P, Zody MC, Hall JL, Brant SR, Cho JH, Duerr RH, Silverberg MS, Taylor KD, Rioux JD, Altshuler D, Daly MJ, Xavier, RJ (2008) Deletion polymorphism upstream of IRGM associated with altered IRGM expression and Crohn’s disease. Nat Genet 40:1107–1112PubMedGoogle Scholar
  66. Miao EA, Scherer CA, Tsolis RM, Kingsley RA, Adams LG, Baumler AJ, Miller SI (1999) Salmonella typhimurium leucine-rich repeat proteins are targeted to the SPI1 and SPI2 type III secretion systems. Mol Microbiol 34:850–864PubMedGoogle Scholar
  67. Miller BC, Zhao Z, Stephenson LM, Cadwell K, Pua HH, Lee HK, Mizushima NN, Iwasaki A, He YW, Swat W, Virgin HWT (2008) The autophagy gene Atg5 plays an essential role in B lymphocyte development. Autophagy 4:309–314PubMedGoogle Scholar
  68. Mizoguchi A, Mizoguchi E (2008) Inflammatory bowel disease, past, present and future: lessons from animal models. J Gastroenterol 43:1–17PubMedGoogle Scholar
  69. Mizushima N, Kuma A, Kobayashi Y, Yamamoto A, Matsubae M, Takao T, Natsume T, Ohsumi Y, Yoshimori T (2003) Mouse Apg16L, a novel WD-repeat protein, targets to the autophagic isolation membrane with the Apg12-Apg5 conjugate. J Cell Sci 116:1679–1688PubMedGoogle Scholar
  70. Munz C (2006) Autophagy and antigen presentation. Cell Microbiol 8:891–898PubMedGoogle Scholar
  71. Nakagawa I, Amano A, Mizushima N, Yamamoto A, Yamaguchi H, Kamimoto T, Nara A, Funao J, Nakata M, Tsuda K, Hamada S, Yoshimori T (2004) Autophagy defends cells against invading group A Streptococcus. Science 306:1037–1040PubMedGoogle Scholar
  72. Ogata M, Hino S, Saito A, Morikawa K, Kondo S, Kanemoto S, Murakami T, Taniguchi M, Tanii I, Yoshinaga K, Shiosaka S, Hammarback JA, Urano F, Imaizumi K (2006) Autophagy is activated for cell survival after endoplasmic reticulum stress. Mol Cell Biol 26:9220–9231PubMedGoogle Scholar
  73. Ogawa M, Sasakawa C (2006) Intracellular survival of Shigella. Cell Microbiol 8:177–184PubMedGoogle Scholar
  74. Ogawa M, Yoshimori T, Suzuki T, Sagara H, Mizushima N, Sasakawa C (2005) Escape of intracellular Shigella from autophagy. Science 307:727–731PubMedGoogle Scholar
  75. Ohl ME, Miller SI (2001) Salmonella: a model for bacterial pathogenesis. Annu Rev Med 52:259–274PubMedGoogle Scholar
  76. Paludan C, Schmid D, Landthaler M, Vockerodt M, Kube D, Tuschl T, Munz C (2005) Endogenous MHC class II processing of a viral nuclear antigen after autophagy. Science 307:593–596PubMedGoogle Scholar
  77. Pamer EG (2004) Immune responses to Listeria monocytogenes. Nat Rev Immunol 4:812–823PubMedGoogle Scholar
  78. Parkes M, Barrett JC, Prescott NJ, Tremelling M, Anderson CA, Fisher SA, Roberts RG, Nimmo ER, Cummings FR, Soars D, Drummond H, Lees CW, Khawaja SA, Bagnall R, Burke DA, Todhunter CE, Ahmad T, Onnie CM, McArdle W, Strachan D, Bethel G, Bryan C, Lewis CM, Deloukas P, Forbes A, Sanderson J, Jewell DP, Satsangi J, Mansfield JC, Cardon L, Mathew CG (2007) Sequence variants in the autophagy gene IRGM and multiple other replicating loci contribute to Crohn’s disease susceptibility. Nat Genet 39:830–832PubMedGoogle Scholar
  79. Perrin AJ, Jiang X, Birmingham CL, So NS, Brumell JH (2004) Recognition of bacteria in the cytosol of mammalian cells by the ubiquitin system. Curr Biol 14:806–811PubMedGoogle Scholar
  80. Podolsky DK (2002) Inflammatory bowel disease. N Engl J Med 347:417–429PubMedGoogle Scholar
  81. Prescott NJ, Fisher SA, Franke A, Hampe J, Onnie CM, Soars D, Bagnall R, Mirza MM, Sanderson J, Forbes A, Mansfield JC, Lewis CM, Schreiber S, Mathew CG (2007) A nonsynonymous SNP in ATG16L1 predisposes to ileal Crohn’s disease and is independent of CARD15 and IBD5. Gastroenterology 132:1665–1671PubMedGoogle Scholar
  82. Priault M, Salin B, Schaeffer J, Vallette FM, di Rago JP, Martinou JC (2005) Impairing the bioenergetic status and the biogenesis of mitochondria triggers mitophagy in yeast. Cell Death Differ 12:1613–1621PubMedGoogle Scholar
  83. Pua HH, Dzhagalov I, Chuck M, Mizushima N, He YW (2007) A critical role for the autophagy gene Atg5 in T cell survival and proliferation. J Exp Med 204:25–31PubMedGoogle Scholar
  84. Py BF, Lipinski MM, Yuan J (2007) Autophagy limits Listeria monocytogenes intracellular growth in the early phase of primary infection. Autophagy 3:117–125PubMedGoogle Scholar
  85. Raelson JV, Little RD, Ruether A, Fournier H, Paquin B, Van Eerdewegh P, Bradley WE, Croteau P, Nguyen-Huu Q, Segal J, Debrus S, Allard R, Rosenstiel P, Franke A, Jacobs G, Nikolaus S, Vidal JM, Szego P, Laplante N, Clark HF, Paulussen RJ, Hooper JW, Keith TP, Belouchi A, Schreiber S (2007) Genome-wide association study for Crohn’s disease in the Quebec Founder Population identifies multiple validated disease loci. Proc Natl Acad Sci USA 104:14747–14752PubMedGoogle Scholar
  86. Rathman M, Barker LP, Falkow S (1997) The unique trafficking pattern of Salmonella typhimurium-containing phagosomes in murine macrophages is independent of the mechanism of bacterial entry. Infect Immun 65:1475–1485PubMedGoogle Scholar
  87. Rich KA, Burkett C, Webster P (2003) Cytoplasmic bacteria can be targets for autophagy. Cell Microbiol 5:455–468PubMedGoogle Scholar
  88. Rikihisa Y (1984) Glycogen autophagosomes in polymorphonuclear leukocytes induced by Rickettsiae. Anat Rec 208:319–327PubMedGoogle Scholar
  89. Rioux JD, Xavier RJ, Taylor KD, Silverberg MS, Goyette P, Huett A, Green T, Kuballa P, Barmada MM, Datta LW, Shugart YY, Griffiths AM, Targan SR, Ippoliti AF, Bernard EJ, Mei L, Nicolae DL, Regueiro M, Schumm LP, Steinhart AH, Rotter JI, Duerr RH, Cho JH, Daly MJ, Brant SR (2007) Genome-wide association study identifies new susceptibility loci for Crohn disease and implicates autophagy in disease pathogenesis. Nat Genet 39:596–604PubMedGoogle Scholar
  90. Roberts RL, Hollis-Moffatt JE, Gearry RB, Kennedy MA, Barclay ML, Merriman TR (2008) Confirmation of association of IRGM and NCF4 with ileal Crohn’s disease in a population-based cohort. Genes Immun 9:561–565PubMedGoogle Scholar
  91. Roy D, Liston DR, Idone VJ, Di A, Nelson DJ, Pujol C, Bliska JB, Chakrabarti S, Andrews NW (2004) A process for controlling intracellular bacterial infections induced by membrane injury. Science 304:1515–1518PubMedGoogle Scholar
  92. Saitoh T, Fujita N, Jang MH, Uematsu S, Yang BG, Satoh T, Omori H, Noda T, Yamamoto N, Komatsu M, Tanaka K, Kawai T, Tsujimura T, Takeuchi O, Yoshimori T, Akira S (2008) Loss of the autophagy protein Atg16L1 enhances endotoxin-induced IL-1beta production. Nature 456:264–268PubMedGoogle Scholar
  93. Sanjuan MA, Dillon CP, Tait SW, Moshiach S, Dorsey F, Connell S, Komatsu M, Tanaka K, Cleveland JL, Withoff S, Green DR (2007) Toll-like receptor signalling in macrophages links the autophagy pathway to phagocytosis. Nature 450:1253–1257PubMedGoogle Scholar
  94. Sansonetti PJ, Phalipon A, Arondel J, Thirumalai K, Banerjee S, Akira S, Takeda K, Zychlinsky A (2000) Caspase-1 activation of IL-1beta and IL-18 are essential for Shigella flexneri-induced inflammation. Immunity 12:581–590PubMedGoogle Scholar
  95. Sartor RB (2008) Microbial influences in inflammatory bowel diseases. Gastroenterology 134:577–594PubMedGoogle Scholar
  96. Schmid D, Dengjel J, Schoor O, Stevanovic S, Munz C (2006) Autophagy in innate and adaptive immunity against intracellular pathogens. J Mol Med 84:194–202PubMedGoogle Scholar
  97. Schnupf P, Portnoy DA (2007) Listeriolysin O: a phagosome-specific lysin. Microbes Infect 9:1176–1187PubMedGoogle Scholar
  98. Scortti M, Monzo HJ, Lacharme-Lora L, Lewis DA, Vazquez-Boland JA (2007) The PrfA virulence regulon. Microbes Infect 9:1196–1207PubMedGoogle Scholar
  99. Seveau S, Pizarro-Cerda J, Cossart P (2007) Molecular mechanisms exploited by Listeria monocytogenes during host cell invasion. Microbes Infect 9:1167–1175PubMedGoogle Scholar
  100. Shea JE, Hensel M, Gleeson C, Holden DW (1996) Identification of a virulence locus encoding a second type III secretion system in Salmonella typhimurium. Proc Natl Acad Sci USA 93:2593–2597PubMedGoogle Scholar
  101. Sinai AP, Joiner KA (1997) Safe haven: the cell biology of nonfusogenic pathogen vacuoles. Annu Rev Microbiol 51:415–462PubMedGoogle Scholar
  102. Singh SB, Davis AS, Taylor GA, Deretic V (2006) Human IRGM induces autophagy to eliminate intracellular mycobacteria. Science 313:1438–1441PubMedGoogle Scholar
  103. Suzuki T, Franchi L, Toma C, Ashida H, Ogawa M, Yoshikawa Y, Mimuro H, Inohara N, Sasakawa C, Nunez G (2007) Differential regulation of caspase-1 activation, pyroptosis, and autophagy via Ipaf and ASC in Shigella-infected macrophages. PLoS Pathog 3:e111PubMedGoogle Scholar
  104. Swaminathan B, Gerner-Smidt P (2007) The epidemiology of human listeriosis. Microbes Infect 9:1236–1243PubMedGoogle Scholar
  105. Swanson MS, Molofsky AB (2005) Autophagy and inflammatory cell death, partners of innate immunity. Autophagy 1:174–176PubMedGoogle Scholar
  106. Taylor GA (2007) IRG proteins: key mediators of interferon-regulated host resistance to intracellular pathogens. Cell Microbiol 9:1099–1107PubMedGoogle Scholar
  107. Tlaskalova-Hogenova H, Stepankova R, Hudcovic T, Tuckova L, Cukrowska B, Lodinova-Zadnikova R, Kozakova H, Rossmann P, Bartova J, Sokol D, Funda DP, Borovska D, Rehakova Z, Sinkora J, Hofman J, Drastich P, Kokesova A (2004) Commensal bacteria (normal microflora), mucosal immunity and chronic inflammatory and autoimmune diseases. Immunol Lett 93:97–108PubMedGoogle Scholar
  108. Tosi MF (2005) Innate immune responses to infection. J Allergy Clin Immunol 116:241–249; quiz 250PubMedGoogle Scholar
  109. Tsolis RM, Townsend SM, Miao EA, Miller SI, Ficht TA, Adams LG, Baumler AJ (1999) Identification of a putative Salmonella enterica serotype Typhimurium host range factor with homology to IpaH and YopM by signature-tagged mutagenesis. Infect Immun 67:6385–6393PubMedGoogle Scholar
  110. Vignal C, Singer E, Peyrin-Biroulet L, Desreumaux P, Chamaillard M (2007) How NOD2 mutations predispose to Crohn’s disease?. Microbes Infect 9:658–663PubMedGoogle Scholar
  111. Xavier RJ, Podolsky DK (2007) Unravelling the pathogenesis of inflammatory bowel disease. Nature 448:427–434PubMedGoogle Scholar
  112. Xu Y, Jagannath C, Liu XD, Sharafkhaneh A, Kolodziejska KE, Eissa NT (2007) Toll-like receptor 4 is a sensor for autophagy associated with innate immunity. Immunity 27:135–144PubMedGoogle Scholar
  113. Yano T, Mita S, Ohmori H, Oshima Y, Fujimoto Y, Ueda R, Takada H, Goldman WE, Fukase K, Silverman N, Yoshimori T, Kurata S (2008) Autophagic control of Listeria through intracellular innate immune recognition in Drosophila. Nat Immunol 9:908–916PubMedGoogle Scholar
  114. Yorimitsu T, Nair U, Yang Z, Klionsky DJ (2006) Endoplasmic reticulum stress triggers autophagy. J Biol Chem 281:30299–30304PubMedGoogle Scholar
  115. Zenewicz LA, Shen H (2007) Innate and adaptive immune responses to Listeria monocytogenes: a short overview. Microbes Infect 9:1208–1215PubMedGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2009

Authors and Affiliations

  1. 1.Cell Biology ProgramHospital for Sick ChildrenTorontoCanada
  2. 2.Department of Molecular Genetics and Institute of Medical ScienceUniversity of TorontoTorontoCanada

Personalised recommendations