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and IFN-γ production by both mucosal and splenic lymphocytes (58). This effect did not depend on the expression of either EspA or EspB. However, it is unclear how relevant these interactions may be when taken in the context of the massive immune activation seen in the related C. rodentium model (32).


Research in recent years has made remarkable progress in our understanding of the molecular mechanisms underlying EPEC pathogenesis. Molecular biology, genetics, and cell biology have provided many new insights into how EPEC and related pathogens interact with and exploit host cells during infection. The identification of a type III secretion system within EPEC's genome, as well as the discovery of Tir, has improved our understanding of how EPEC subverts the host cytoskeleton to permit bacterial attachment. This research has identified features common to other enteric pathogens as well as strategies apparently unique to A/E lesion-causing bacteria, such as the translocation of the bacterial receptor Tir into the host membrane.

Although studying the molecular and cellular aspects of bacterial virulence factors has informed us about the mechanisms of bacterial disease, these factors can also function as tools to study various aspects of mammalian cell functions. As such, they have received much interest in the field of microbial pathogenesis, as well as from cell biologists interested in the mechanisms underlying actin dynamics and cytoskeletal rear-rangements (39). These studies also have relevance to unrelated pathogens, such as Helicobacter pylori, which produces A/E-like lesions (59). However, H. pylori-induced pedestals lack the intense actin accumulation observed with the A/E intestinal pathogens, and no homologues of the A/E genes have been found in H. pylori. There are also similarities between the immunopathology associated with A/E lesion-inducing bacteria, and that seen in inflammatory bowel diseases (31). Although no infectious causal agent has yet been identified in inflammatory bowel diseases, the potential contribution of maladaptive microbial-host interactions to the chronicity of these diseases has long been of great interest to gastroenterologists (60).

Despite this progress, more studies are needed characterizing EPEC 's effector molecules as well as their role in causing diarrhea and disease within the intact host. Other gene products that contribute to colonization of the host must be identified, and their role in the infectious process examined in vivo. Although it is true that infections may differ between animals and humans, the similarities will probably prove greater than the differences. Studies integrating host genetics, physiology, and the immune system, all of which are critical determinants to the outcome of infection, should provide a better understanding of EPEC and other A/E pathogens, and together these developments may lead to new therapeutic strategies. With our present knowledge of the factors that mediate bacterial adhesion to the host cell, and the demonstration that preventing bacterial adherence prevents most aspects of the disease, we have already identified potential targets for vaccination. Although the pathogenic effects of A/E lesion formation still need to be separated from other bacterial actions during infection, a successful approach may involve vaccination against the factors involved in bacterial adhesion such as the components and effectors of the type III secretion machinery. Alternatively, with the recent interest in microbe-microbe interactions, and in the use of probiotics, identifying bacterial species that can out-compete EPEC for attachment to host cells may be an attractive option. By continuing to characterize EPEC's effector molecules, their specific effects, and the host's response to infection, we should look forward to new advances in the prevention and treatment of A/E pathogen mediated diarrhea.

We thank Jean Celli, Annick Gauthier, and Carrie Rosenberger for helpful discussions and critical reading of the manuscript and Danika Goosney, Ursula Heczko, and Fern Ness for figures. Work in our laboratory is supported by operating grants from the Medical Research Council of Canada and a Howard Hughes International Scholar award (to B.B.F.). B.B.F. is a Medical Research Council Scientist.

1. Steele-Mortimer, O., Knodler L. A. & Finlay, B. B. ( 2000) Traffic 1, 107–118.

2. DeVinney, R., Gauthier, A., Abe, A. & Finlay, B. B. ( 1999) Cell Mol. Life Sci. 55, 961–976.

3. Nataro, J. P. & Kaper, J. B. ( 1998) Clin. Microbiol. Rev. 11, 142–201.

4. Kaper, J. B. ( 1998) Trends Microbiol. 6, 169–172.

5. Frankel, G., Philipps, A. D., Rosenshine, I., Dougan, G., Kaper, J. B. & Knutton, S. ( 1998) Mol. Microbiol. 30, 911–921.

6. Kenny, B., DeVinney, R. D., Stein, M., Reinscheid, D. J., Frey, E. A. & Finlay, B. B. ( 1997) Cell 91, 511–520.

7. DeVinney, R., Stein, M., Reinscheid, D., Abe, A., Ruschkowski, S. & Finlay, B. B. ( 1999) Infect. Immun. 67, 2389–2398.

8. Robins-Browne, R. M. ( 1987) Rev. Infect. Dis. 9, 28–53.

9. Bower, J. R., Congeni, B. L., Cleary, T. G., Stone, R. T., Wanger, A., Murray, B. E., Mathewson, J. J. & Pickering, L. K. ( 1989) J. Infect. Dis. 160, 243–247.

10. Senerwa, D., Olsvik O., Mutanda L. N., Lindqvist, K. J., Gathuma, J. M., Fossum, K. & Wachsmuth, K. ( 1989) J. Clin. Microbiol. 27, 1307–1311.

11. Blum, G., Ott, M., Lischewski, A., Ritter, A., Imrich, H., Tschape, H. & Hacker, J. ( 1994) Infect. Immun. 62, 606–614.

12. McNamara, B. P. & Donnenberg, M. S. ( 1998) FEMS Microbiol. Lett. 166, 71–78.

13. Wainwright, L. A. & Kaper, J. B. ( 1998) Mol. Microbiol. 27, 1247–1260.

14. Abe, A., de Grado, M., Pfuentzer, R. A., Sanchez-SanMartin, C., DeVinney, R., Puente, J. L., Strynadka, C. J. & Finlay, B. B. ( 1999) Mol. Microbiol. 33, 1162–1175.

15. McDaniel, T. K. & Kaper J. B. ( 1997) Mol. Microbiol. 23, 399–407.

16. Donnenberg, M. S., Kaper, J. B. & Finlay, B. B. ( 1997) Trends Microbiol. 5, 109–114.

17. Levine, M. M., Nataro, J. P., Karch, H., Baldini, M. M., Kaper, J. B., Black, R. E., Clements, M. L. & O'Brien, A. D. ( 1985) J. Infect. Dis. 152, 550–559.

18. Kenny, B., Abe, A., Stein, M. & Finlay, B. B. ( 1997) Infect. Immun. 65, 2606–2612.

19. Knutton, S., Rosenshine, I., Pallen, M. J., Nisan, I., Neves, B. C., Bain, C., Wolff, C., Dougan, G. & Frankel, G. ( 1998) EMBO J. 17, 2166–2176.

20. Kresse, A. U., Rohde, M. & Guzman, C. A. ( 1999) Infect. Immun. 67, 4834–4842.

21. Warawa, J., Finlay, B. B. & Kenny, B. ( 1999) Infect. Immun. 67, 5538–5540.

22. Taylor, K. A., Luther, P. W. & Donnenberg, M. S. ( 1999) Infect. Immun. 67, 120–125.

23. Rosenshine, I., Ruschkowski, S., Stein, M., Reinscheid, D. J., Mills, S. D. & Finlay, B. B. ( 1996) EMBO J. 15, 2613–2624.

24. Kenny, B. ( 1999) Mol. Microbiol. 31, 1229–1241.

25. de Grado, M., Abe. A., Gauthier, A., Steele-Mortimer, O., DeVinney, R. & Finlay B. B. ( 1999) Cell. Microbiol. 1, 7–17.

26. Hartland, E. L., Batchelor, M., Delahay, R. M., Hale, C., Matthews, S., Dougan, G., Knutton, S., Connerton, I. & Frankel, G. ( 1999) Mol. Microbiol. 32, 151–158.

27. Liu, H., Magoun, L., Luperchio, S., Schauer, D. B. & Leong, J. M. ( 1999) Mol. Microbiol. 34, 67–81.

28. Knutton, S., Adu-Bobie, J., Bain, C., Philipps, A. D., Dougan, G. & Frankel, G. ( 1997) Infect. Immun. 65, 1644–1652.

29. Frankel, G., Philips, A. D., Novakova, M., Batchelor, M., Hicks, S. & Dougan, G. ( 1998) Mol. Microbiol. 29, 559–570.

30. Clark, M. A., Hirst, B. H. & Jepson, M. A. ( 1998) Infect. Immun. 66, 1237–1243.

31. Higgins, L. M., Frankel, G., Douce, G., Dougan, G. & MacDonald, T. T. ( 1999) Infect. Immun. 67, 3031–3039.

32. Higgins, L. M., Frankel, G., Connerton, I., Goncalves, N. S., Dougan, G. & MacDonald, T. T. ( 1999) Science 285, 588–591.

33. Liu, H., Magoun, L. & Leong, J. M. ( 1999) Infect. Immun. 67, 2045–2049.

34. Knutton 359 Knutton, S., Baldwin, T, Williams, P. H. & McNeish, A. S. ( 1989) Infect. Immun. 57, 1290–1298.

35. Moon, H. W., Whipp, S. C., Argenzio, R. A., Levine, M. M. & Gianella R. A. ( 1983) Infect. Immun. 41, 1340–1351.

36. Goosney, D. L., Celli, J., Kenny, B. & Finlay, B. B. ( 1999) Infect. Immun. 67, 490–495.

37. Sanger, J. M., Change, R., Ashton, F., Kaper, J. B. & Sanger J. W. ( 1996) Cell Motil. Cytoskeleton 34, 279–287.

38. Ben-Ami, G., Ozeri, V., Hanski, E., Hofmann, F., Aktories, K., Hahn, K. M., Bokoch, G. M. & Rosenshine, I. ( 1998) Infect. Immun. 66, 1755–1758.

39. Kalman, D., Weiner, O. D., Goosney, D. L., Sedat, J. W., Finlay, B. B., Abo, A. & Bishop J. M. ( 1999) Nat. Cell Biol. 1, 389–391.

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