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Potential role of the EPEC translocated intimin receptor (Tir) in host apoptotic events

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Abstract

Apoptosis, or programmed cell death, is a well-ordered process that allows damaged or diseased cells to be removed from an organism without severe inflammatory reactions. Multiple factors, including microbial infection, can induce programmed death and trigger reactions in both host and microbial cellular pathways. Whereas an ultimate outcome is host cell death, these apoptotic triggering mechanisms may also facilitate microbial spread and prolong infection. To gain a better understanding of the complex events of host cell response to microbial infection, we investigated the molecular role of the microorganism Enteropathogenic Escherichia coli (EPEC) in programmed cell death. We report that wild type strain of EPEC, E2348/69, induced apoptosis in cultured PtK2 and Caco-2 cells, and in contrast, infections by the intracellularly localized Listeria monocytogenes did not. Fractionation and concentration of EPEC-secreted proteins demonstrated that soluble protein factors expressed by the bacteria were capable of inducing the apoptotic events in the absence of organism attachment, suggesting adherence is not required to induce host cell death. Among the known EPEC proteins secreted via the Type III secretion (TTS) system, we identified the translocated intimin receptor (Tir) in the apoptosis-inducing protein sample. In addition, host cell ectopic expression of an EPEC GFP-Tir showed mitochondrial localization of the protein and produced apoptotic effects in transfected cells. Taken together, these results suggest a potential EPEC Tirmediated role in the apoptotic signaling cascade of infected host cells.

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References

  1. Elson CO. Genes, microbes, and T cells—new therapeutic targets in Crohn's disease. N Engl J Med 2002; 346: 614–616.

    Google Scholar 

  2. Galan JE. Salmonella interactions with host cells: Type III secretion at work. Annu Rev Cell Dev Biol 2001; 17: 53–86.

    Google Scholar 

  3. Lee MS, Yen CY, Ueng SW, Shih CH, Chao CC. Signal transduction pathways and apoptosis in bacteria infected chondrocytes. J Orthop Res 2001; 19: 696–702.

    Google Scholar 

  4. Neish AS. The gut microflora and intestinal epithelial cells: A continuing dialogue. Microbes Infect 2002; 4: 309–317.

    Google Scholar 

  5. Boise LH, Collins CM. Salmonella-induced cell death: Apoptosis, necrosis or programmed cell death? Trends Microbiol 2001; 9: 64–67.

    Google Scholar 

  6. Jendro MC, Kohler L, Kuipers JG, Zeidler H. Microbe-induced T cell apoptosis: Subversion of the host defense system? FEMS Microbiol Lett 2002; 207: 121–126.

    Google Scholar 

  7. Gao LY, Kwaik YA. The modulation of host cell apoptosis by intracellular bacterial pathogens. Trends Microbiol 2000; 8: 306–313.

    Google Scholar 

  8. Heczko U, Carthy CM, O'Brien BA, Finlay BB. Decreased apoptosis in the ileum and ileal Peyer's patches: A feature after infection with rabbit enteropathogenic Escherichia coli O103. Infect Immun 2001; 69: 4580–4589.

    Google Scholar 

  9. Esen M, Schreiner B, Jendrossek V, et al. Mechanisms of Staphylococcus aureus induced apoptosis of human endothelial cells. Apoptosis 2001; 6: 431–439.

    Google Scholar 

  10. Denecker G, Declercq W, Geuijen CA, et al. Yersinia enterocolitica YopP-induced apoptosis of macrophages involves the apoptotic signaling cascade upstream of bid. J Biol Chem 2001; 276: 19706–19714.

    Google Scholar 

  11. Monack DM, Mecsas J, Ghori N, Falkow S. Yersinia signals macrophages to undergo apoptosis and YopJ is necessary for this cell death. Proc Natl Acad Sci USA 1997; 94: 10385–10390.

    Google Scholar 

  12. Hersh D, Monack DM, Smith MR, Ghori N, Falkow S, Zychlinsky A. The Salmonella invasin SipB induces macrophage apoptosis by binding to caspase-1. Proc Natl Acad Sci USA 1999; 96: 2396–2401.

    Google Scholar 

  13. Leung WK, Yu J, To KF, et al. Apoptosis and proliferation in Helicobacter pylori-associated gastric intestinal metaplasia. Aliment Pharmacol Ther 2001; 15: 1467–1472.

    Google Scholar 

  14. Zychlinsky A, Prevost MC, Sansonetti PJ. Shigella flexneri induces apoptosis in infected macrophages. Nature 1992; 358: 167–169.

    Google Scholar 

  15. Clarke SC. Diarrhoeagenic Escherichia coli—An emerging problem? Diagn Microbiol Infect Dis 2001; 41: 93–98.

    Google Scholar 

  16. Ono K, Rai SK, Chikahira M, et al. Seasonal distribution of enteropathogens detected from diarrheal stool and water samples collected in Kathmandu, Nepal. Southeast Asian J Trop Med Public Health 2001; 32: 520–526.

    Google Scholar 

  17. Prasannan M, Jesudason MV, Kang G, Sridharan G. A study on some phenotypic virulence markers of enteropathogenic Escherichia coli. Indian J Med Res 2001; 114: 95–98.

    Google Scholar 

  18. Goosney DL, Gruenheid S, Finlay BB. Gut feelings: Enteropathogenic E. coli (EPEC) interactions with the host. Annu Rev Cell Dev Biol 2000; 16: 173–189.

    Google Scholar 

  19. Kenny B, DeVinney R, Stein M, Reinscheid DJ, Frey EA, Finlay BB. Enteropathogenic E. coli (EPEC) transfers its receptor for intimate adherence into mammalian cells. Cell 1997; 91: 511–520.

    Google Scholar 

  20. Kaper JB. EPEC delivers the goods. Trends Microbiol 1998; 6: 169–172; discussion 172–173.

    Google Scholar 

  21. Sanger JM, Chang R, Ashton F, Kaper JB, Sanger JW. Novel form of actin-based motility transports bacteria on the surfaces of infected cells. Cell Motil Cytoskeleton 1996; 34: 279–287.

    Google Scholar 

  22. Cantarelli VV, Takahashi A, Yanagihara I, et al. Talin, a host cell protein, interacts directly with the translocated intimin receptor, Tir, of enteropathogenic Escherichia coli, and is essential for pedestal formation. Cell Microbiol 2001; 3: 745–751.

    Google Scholar 

  23. Freeman NL, Zurawski DV, Chowrashi P, et al. Interaction of the enteropathogenic Escherichia coli protein, translocated intimin receptor (Tir), with focal adhesion proteins. Cell Motil Cytoskeleton 2000; 47: 307–318.

    Google Scholar 

  24. Goosney DL, DeVinney R, Pfuetzner RA, Frey EA, Strynadka NC, Finlay BB. Enteropathogenic E. coli translocated intimin receptor, Tir, interacts directly with alpha-actinin. Curr Biol 2000; 10: 735–738.

    Google Scholar 

  25. Huang L, Mittal B, Sanger JW, Sanger JM. Host focal adhesion protein domains that bind to the translocated intimin receptor (Tir) of enteropathogenic Escherichia coli (EPEC). Cell Motil Cytoskeleton 2002; 52: 255–265.

    Google Scholar 

  26. Abul-Milh M, Wu Y, Lau B, Lingwood CA, Foster DB. Induction of epithelial cell death including apoptosis by enteropathogenic Escherichia coli expressing bundle-forming pili. Infect Immun 2001; 69: 7356–7364.

    Google Scholar 

  27. Barnett Foster D, Abul-Milh M, Huesca M, Lingwood CA. Enterohemorrhagic Escherichia coli induces apoptosis which augments bacterial binding and phosphatidylethanolamine exposure on the plasma membrane outer leaflet. Infect Immun 2000; 68: 3108–3115.

    Google Scholar 

  28. Crane JK, Majumdar S, Pickhardt DF, 3rd. Host cell death due to enteropathogenic Escherichia coli has features of apoptosis. Infect Immun 1999; 67: 2575–2584.

    Google Scholar 

  29. Sanger JM, Sanger JW, Southwick FS. Host cell actin assembly is necessary and likely to provide the propulsive force for intracellular movement of Listeria monocytogenes. Infect Immun 1992; 60: 3609–3619.

    Google Scholar 

  30. Arends MJ, Morris RG, Wyllie AH. Apoptosis. The role of the endonuclease. Am J Pathol 1990; 136: 593–608.

    Google Scholar 

  31. Eschenfeldt WH, Puskas RS, Berger SL. Homopolymeric tailing. Methods Enzymol 1987; 152: 337–342.

    Google Scholar 

  32. Chou MM, Blenis J. The 70 kDa S6 kinase complexes with and is activated by the Rho family G proteins Cdc42 and Rac1. Cell 1996; 85: 573–583.

    Google Scholar 

  33. Ayoob JC, Turnacioglu KK, Mittal B, Sanger JM, Sanger JW. Targeting of cardiac muscle titin fragments to the Z-bands and dense bodies of living muscle and non-muscle cells. Cell Motil Cytoskeleton 2000; 45: 67–82.

    Google Scholar 

  34. Bernardi P, Petronilli V, Di Lisa F, Forte M. A mitochondrial perspective on cell death. Trends Biochem Sci 2001; 26: 112–117.

    Google Scholar 

  35. Kerr JF, Wyllie AH, Currie AR. Apoptosis: A basic biological phenomenon with wide-ranging implications in tissue kinetics. Br J Cancer 1972; 26: 239–257.

    Google Scholar 

  36. Nagata S. Apoptotic DNA fragmentation. Exp Cell Res 2000; 256: 12–18.

    Google Scholar 

  37. Zhang JH, Xu M. DNA fragmentation in apoptosis. Cell Res 2000; 10: 205–211.

    Google Scholar 

  38. Grassme H, Jendrossek V, Gulbins E. Molecular mechanisms of bacteria induced apoptosis. Apoptosis 2001; 6: 441–445.

    Google Scholar 

  39. Zychlinsky A, Sansonetti PJ. Apoptosis as a proinflammatory event: What can we learn from bacteria-induced cell death? Trends Microbiol 1997; 5: 201–204.

    Google Scholar 

  40. Frankel G, Phillips AD, Rosenshine I, Dougan G, Kaper JB, Knutton S. Enteropathogenic and enterohaemorrhagic Escherichia coli: More subversive elements. Mol Microbiol 1998; 30: 911–921.

    Google Scholar 

  41. McDaniel TK, Kaper JB. A cloned pathogenicity island from enteropathogenic Escherichia coli confers the attaching and effacing phenotype on E. coli K-12. Mol Microbiol 1997; 23: 399–407.

    Google Scholar 

  42. Kenny B. Mechanism of action of EPEC type III effector molecules. Int J Med Microbiol 2002; 291: 469–477.

    Google Scholar 

  43. Kenny B, Jepson M. Targeting of an enteropathogenic Escherichia coli (EPEC) effector protein to host mitochondria. Cell Microbiol 2000; 2: 579–590.

    Google Scholar 

  44. Muller A, Gunther D, Brinkmann V, Hurwitz R, Meyer TF, Rudel T. Targeting of the pro-apoptotic VDAC-like porin (PorB) of Neisseria gonorrhoeae to mitochondria of infected cells. Embo J 2000; 19: 5332–5343.

    Google Scholar 

  45. Knutton S, Rosenshine I, Pallen MJ, et al. A novel EspAassociated surface organelle of enteropathogenic Escherichia coli involved in protein translocation into epithelial cells. Embo J 1998; 17: 2166–2176.

    Google Scholar 

  46. Warawa J, Finlay BB, Kenny B. Type III secretion-dependent hemolytic activity of enteropathogenic Escherichia coli. Infect Immun 1999; 67: 5538–5540.

    Google Scholar 

  47. Wolff C, Nisan I, Hanski E, Frankel G, Rosenshine I. Protein translocation into host epithelial cells by infecting enteropathogenic Escherichia coli. Mol Microbiol 1998; 28: 143–155.

    Google Scholar 

  48. Bubeck P, Pistor S, Wehland J, Jockusch BM. Ligand recruitment by vinculin domains in transfected cells. J Cell Sci 1997; 110(Pt 12): 1361–1371.

    Google Scholar 

  49. Hilbi H, Moss JE, Hersh D, et al. Shigella-induced apoptosis is dependent on caspase-1 which binds to IpaB. J Biol Chem 1998; 273: 32895–32900.

    Google Scholar 

  50. Muller A, Rassow J, Grimm J, Machuy N, Meyer TF, Rudel T. VDAC and the bacterial porin PorB of Neisseria gonorrhoeae share mitochondrial import pathways. Embo J 2002; 21: 1916–1929.

    Google Scholar 

  51. Guzman CA, Domann E, Rohde M, et al. Apoptosis of mouse dendritic cells is triggered by listeriolysin, the major virulence determinant of Listeria monocytogenes. Mol Microbiol 1996; 20: 119–126.

    Google Scholar 

  52. Galmiche A, Rassow J, Doye A, et al. The N-terminal 34 kDa fragment of Helicobacter pylori vacuolating cytotoxin targets mitochondria and induces cytochrome c release. Embo J 2000; 19: 6361–6370.

    Google Scholar 

  53. Papini E, Zoratti M, Cover TL. In search of the Helicobacter pylori VacA mechanism of action. Toxicon 2001; 39: 1757–1767.

    Google Scholar 

  54. Jones BA, Gores GJ. Physiology and pathophysiology of apoptosis in epithelial cells of the liver, pancreas, and intestine. Am J Physiol 1997; 273: G1174–G1188.

    Google Scholar 

  55. Ramachandran A, Madesh M, Balasubramanian KA. Apoptosis in the intestinal epithelium: Its relevance in normal and pathophysiological conditions. J Gastroenterol Hepatol 2000; 15: 109–120.

    Google Scholar 

  56. Abrams GD, Bauer H, Sprinz H. Influence of the normal flora on mucosal morphology and cellular renewal in the ileum. Laboratory Investigation 1963; 12: 355–364.

    Google Scholar 

  57. Lesher S, Walburg HE, Sacher GA. Generation cycle in the duodenal crypt cells of germ-free an deconventional mice. Nature 1964; 202: 884–886.

    Google Scholar 

  58. Eastwood GL. Gastrointestinal epithelial renewal. Gastroenterology 1977; 72: 962–975.

    Google Scholar 

  59. Hall PA, Coates PJ, Ansari B, Hopwood D. Regulation of cell number in the mammalian gastrointestinal tract: The importance of apoptosis. J Cell Sci 1994; 107(Pt 12): 3569–3577.

    Google Scholar 

  60. DeVinney R, Gauthier A, Abe A, Finlay BB. Enteropathogenic Escherichia coli: A pathogen that inserts its own receptor into host cells. Cell Mol Life Sci 1999; 55: 961–976.

    Google Scholar 

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Authors and Affiliations

  1. Department of Cell and Developmental Biology, University of Pennsylvania School of Medicine, Philadelphia, PA, 19104-6058, USA

    H. R. Malish, N. L. Freeman, D. V. Zurawski, P. Chowrashi, J. C. Ayoob, J. W. Sanger & J. M. Sanger

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  1. H. R. Malish
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  2. N. L. Freeman
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Malish, H.R., Freeman, N.L., Zurawski, D.V. et al. Potential role of the EPEC translocated intimin receptor (Tir) in host apoptotic events. Apoptosis 8, 179–190 (2003). https://doi.org/10.1023/A:1022974710488

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