Chapter 19 : Signal Transduction in the Intestinal Mucosa

MyBook is a cheap paperback edition of the original book and will be sold at uniform, low price.

Preview this chapter:
Zoom in

Signal Transduction in the Intestinal Mucosa, Page 1 of 2

| /docserver/preview/fulltext/10.1128/9781555817619/9781555813239_Chap19-1.gif /docserver/preview/fulltext/10.1128/9781555817619/9781555813239_Chap19-2.gif


This chapter considers the remarkable signal transduction networks that have evolved between intestinal microbes and their host in trying to maintain the balance of health and disease. Resident bacteria serve a central line of resistance to colonization by exogenous microbes and thus assist in preventing the potential invasion of the intestinal mucosa by an incoming pathogen. A number of enteric pathogens and some opportunistic commensal bacteria possess the means to provoke NF-κB activation and, subsequently, intestinal inflammation. Innate epithelial defense mechanisms provide a rapid response whereby microbial pathogens in the host are quickly detected and signals are generated that activate mucosal antimicrobial defense mechanisms. The intimate interaction between enteropathogenic (EPEC) and the intestinal epithelium causes the induction of phosphate fluxes within the host cells, as well as the activation of protein kinase C (PKC), phospholipase C, and NF-κB. Chloride secretion in the intestinal mucosa involves the collaborative effort of several transporters. The current paradigm postulates that intestinal epithelial cells respond to serovar Typhimurium by the polarized release of distinct proinflammatory chemoattractants, which sequentially orchestrate neutrophil movement across the intestinal epithelium. Speculatively, microorganisms intimately associated with the intestinal mucosa may have evolved such mechanisms to dampen the host proinflammatory and immune responses without provoking apoptotic death. A more complete understanding of the signal transduction cascades that exist between the intestinal bacteria and the human host in the intestinal mucosa may uncover new insights into human diseases and reveal novel approaches to treating them.

Citation: McCormick B. 2005. Signal Transduction in the Intestinal Mucosa, p 265-282. In Nataro J, Cohen P, Mobley H, Weiser J (ed), Colonization of Mucosal Surfaces. ASM Press, Washington, DC. doi: 10.1128/9781555817619.ch19
Highlighted Text: Show | Hide
Loading full text...

Full text loading...


Image of Figure 1
Figure 1

Activation of the NF-κB pathway can be induced by a variety of bacterial constituents. In unstimulated cells, NF-κB is sequestered in the cytoplasm by IκB. Bacterial components such as LPS selectively bind to TLR4, while components of the peptidoglycan selectively interact with intracytoplasmic Nods (Nod1 or Nod2) to initiate signaling that sets in motion a series of enzymatic modifications of IκB, such as phosphorylation, ubiquitination, and degradation. Loss of IκB allows NF-κB to translocate to the nucleus, bind to the promoters of many proinflammatory effector genes, and activate the proinflammatory program. Many of these cellular events are also caused by bacterial effector proteins, which are delivered into the intestinal cells (by type III secretion systems) and directly modulate the activities of host cell proteins (e.g., SopB from serovar Typhimurium). Perturbation of any of these enzymatic steps (such as with YopJ from ) could inhibit the entire pathway.

Citation: McCormick B. 2005. Signal Transduction in the Intestinal Mucosa, p 265-282. In Nataro J, Cohen P, Mobley H, Weiser J (ed), Colonization of Mucosal Surfaces. ASM Press, Washington, DC. doi: 10.1128/9781555817619.ch19
Permissions and Reprints Request Permissions
Download as Powerpoint
Image of Figure 2
Figure 2

Intestinal bacteria have evolved different strategies to induce chloride secretion and regulate the tight-junction complex. Cholera toxin binds to the ganglioside receptor, GM1, and enters epithelial cells as an AB5 complex by retrograde trafficking through the Golgi and endoplasmic reticulum (ER). Dissociation and cleavage of the A subunit results in the A1 peptide- mediated ADP-ribosylation of Gsα. This results in sustained activation of adenylate cyclase and elevation of the cAMP concentration, which in turn increase electrogenic chloride secretion. Through a different pathway, TDH of V. parahemolyticus elevates the intracellular Ca2+ concentration, resulting in the activation of CaCC. Phosphorylated inositol derivatives are also involved in regulating Ca2+-mediated chloride secretion and have stimulatory or inhibitory effects. As shown here, the S. enterica serovar Typhimurium intracellular SopB protein affects inositol phosphate signaling events. One such event is the transient increase in the concentration of Ins(1,4,5,6)P4 (IP4), which antagonizes the closure of chloride channels, influencing net electrolyte transport and hence fluid secretion. Infection of epithelial cells also results in the production of PGs such as PGE2; this elevates cAMP levels, which can lead to further Cl− secretion. The epithelial tight junction is a macromolecular structure consisting of both transmembrane-spanning proteins, such as occludin, and a number of claudin isoforms. This complex provides a barrier to the paracellular space, preventing free access of bacteria or their products to the underlying compartment. Pathogens, however, have developed strategies to disrupt the tight-junction barrier. S. flexneri, for example, can modulate the function of the tight-junction components in a manner which allows passage of the organism through the paracellular space, which is particularly relevant for the ability of Shigella to infect the colon.

Citation: McCormick B. 2005. Signal Transduction in the Intestinal Mucosa, p 265-282. In Nataro J, Cohen P, Mobley H, Weiser J (ed), Colonization of Mucosal Surfaces. ASM Press, Washington, DC. doi: 10.1128/9781555817619.ch19
Permissions and Reprints Request Permissions
Download as Powerpoint
Image of Figure 3
Figure 3

(A) Model of proposed events affecting -induced PMN transmigration across the intestinal epithelium. evokes a potent inflammatory response in the host, the hallmark of which is the migration of PMN across the intestinal mucosa. This process includes extravasation of circulating PMN from the microvasculature, passage of PMN across the lamina propria, and paracellular movement of PMN across the epithelium. PMN recruitment is coordinated by the release of proinflammatory cytokines, among which are IL-8 and PEEC. By an unknown mechanism, invasion also causes the transcellular transport of flagellin to the basolateral membrane domain, where it promotes the release of IL-8 by interacting with TLR-5 and activates the NF-κB pathway. Concurrently, the type III secretion product, SipA, is necessary and sufficient for induction of PMN transmigration across model intestinal epithelia in a PKC-dependent manner, which leads to the apical secretion of PEEC. (B) Model of serovar Typhimurium-induced signaling in epithelial cells by the secreted protein SipA. Interaction of SipA with the apical domain of polarized epithelial cells leads to activation of ARF6 (GTPARF6) at the apical membrane, most probably through the mammalian guanine exchange factor ARNO. This leads to an increase in PLD activity and local production of phosphatidic acid (PA), which is metabolized to DAG by phosphatidic acid phosphohydrolase (PAP). Generation of DAG recruits PKC to the apical membrane. Activation of PKC at this site (PKC*) is necessary for the apical release of the chemokine PEEC and subsequent basolateral-to-apical PMN transepithelial migration.

Citation: McCormick B. 2005. Signal Transduction in the Intestinal Mucosa, p 265-282. In Nataro J, Cohen P, Mobley H, Weiser J (ed), Colonization of Mucosal Surfaces. ASM Press, Washington, DC. doi: 10.1128/9781555817619.ch19
Permissions and Reprints Request Permissions
Download as Powerpoint


1. Aderem, A.,, and R. J. Ulevitch. 2000. Toll-like receptors in the induction of the innate immune response. Nature 406: 782 787.
2. Alexopoulou, L.,, A. C. Holt,, R. Medzhitov,, and R. A. Flavell. 2001. Recognition of double stranded RNA and activation of NF-κB by toll-like receptor 3. Nature 413: 732 738.
3. Alicon, I.,, and P. Kubes. 1996. A critical role for nitric oxide in intestinal barrier function and dysfunction. Am. J. Physiol. Ser. G 270: G225 G237.>
4. Aliprantis, A.,, R.-B. Yang,, M. Mark,, S. Suggett,, B, Devaux,, J, Radolf,, G. Klimple,, P. Godowski,, and A. Zychlinsky. 1999. Cell activation and apoptosis by bacterial lipoproteins through toll-like receptor-2. Science 285: 736 739.
5. Altschuler, Y.,, S. Liu,, L. Katz,, K. Tang,, S. Hardy,, F. Brodsky,, G. Apodacca,, and K. Mostov. 1999. ADP-ribosylation factor 6 and endocytosis at the apical surface of Madin-Darby canine kidney cells. J. Cell Biol. 147: 7 12.
6. Anderson, J. M. 1996. Cell signalling: MAGUK magic. Curr. Biol. 6: 382 384.
7. Anderson, J. M. 2001. Molecular structure of tight junctions and their role in epithelial transport. News Physiol. Sci. 16: 126 130.
8. Baggiolini, M.,, B. Dewald,, and A. Walz,. 1992. Interleukin-8 and related cytokines, p. 247 263. In J. I. Gallin,, I. M. Golstein,, and R. Snyderman (ed.), Inflammation: Basic Principles and Clinical Correlates, 2nd ed. Raven Press, New York, N.Y.
9. Beagley, K. W.,, and A. J. Husband. 1998. Intraepithelial lymphocytes: origins, distributions, and function. Crit. Rev. Immunol. 18: 237 254.
10. Berkes, J.,, V. K. Viswanathan,, S. D. Savkovic,, and G. Hecht. 2003. Intestinal epithelial responses to enteric pathogens: effects on the tight junction barrier, ion transport, and inflammation. Gut 52: 439 451.
11. Bernet, M. F.,, D. Brassart,, J. R. Nesser,, and A. L. Servin. 1994. Lactobacillus LA binds to cultured human intestinal cell lines and inhibits cell attachment and cell invasion by enterovirulent bacteria. Gut 35: 483 489.
12. Bulut, Y.,, E. Faure,, L. Thomas,, O. Equils,, and M. Arditi. 2001. Cooperation of Toll-like receptor 2 and 6 for cellular activation by soluble tuberculosis factor and Borrelia burgdorferi outer protein A lipoprotein: role of Toll-interacting protein and IL-1 receptor signaling molecules in Toll-like receptor-2 signaling. J. Immunol. 167: 987 994.
13. Butler, J. E.,, J. Sun,, P. Weber,, P. Navarro,, and D. Francis. 2000. Antibody repertoire development in fetal and newborn piglets. III. Colonization of the gastrointestinal tract selectively diversifies the preimmune repertoire in mucosal lymphoid tissue. Immunology 100: 119 130.
14. Cario, E.,, and D. K. Podolsky. 2000. Differential alteration in intestinal epithelial cell expression of toll-like receptor 3 (TLR3) and TLR4 in inflammatory bowel disease. Infect. Immun. 68: 7010 7017.
15. Cebra, J. J.,, S. B. Periwal,, G. Lee,, F. Lee,, and K. E. Shroff. 1998. Development and maintenance of the gut-associated lymphoid tissue (GALT): the roles of enteric bacteria and viruses. Dev. Immunol. 6: 13 18.
16. Chen, L. M.,, S. Hobbie,, and J. E. Galan. 1996. Requirement of CDC42 for Salmonella-induced cytoskeletal and nuclear responses. Science 274: 2115 2118.
17. Collier-Hyams, L. S.,, H. Zeng,, J. Sun,, A. D. Tomlinson,, Z. O. Bao,, H. Chen,, J. L. Madara,, K. Orth,, and A. S. Neish. 2002. Cutting edge: Salmonella AvrA effector inhibits the key proinflammatory, anti-apoptotic NF-κB pathway. J. Immunol. 169: 2846 2850.
18. Criss, A. K.,, M. Silva,, J. E. Casanova,, and B. A. McCormick. 2001. Regulation of Salmonella-induced neutrophil transmigration by epithelial ADP-ribosylation factor 6. J. Biol. Chem. 276: 48431 48439.
19. Deng, L.,, C. Wang,, E. Spencer,, L. Yang,, A. Brqun,, X. You,, C. Slaughter,, C. Pickart,, and Z. Chen. 2000. Activation of the IκB kinase complex by TRAF6 requires a dimeric ubiquitin- conjugating enzyme complex and a unique polyubiquitin chain. Cell 103: 351 361.
20. Didonato, J. A.,, M. Hayakawa,, D. M. Rothwarf,, E. Zandi,, and M. Karin. 1997. A cytokine-responsive IkappaB kinase that activates the transcription factor NF-kappa-B. Nature 388: 548 554.
21. D’Souza-Shorey, C,, G. Li,, M. I. Colombo,, and P. D. Stahl. 1995. A regulatory role for ARF6 in receptor-mediated endocytosis. Science 267: 1175 1178.
22. Duchmann, R.,, E. Scmitt,, P. Knolle,, K. H. Meyer zum Buschenfelde,, and M. Neurath. 1996. Tolerance towards resident intestinal flora in mice is abrogated in experimental colitis and restored by treatment with interleukin 10 or antibodies to interleukin 12. Eur. J. Immunol. 26: 934 938.
23. Eberhart, C. E.,, and R. N. DuBois. 1995. Eicosanoids and the gastrointestinal tract. Gastroenterology 109: 285 301.
24. Eckmann, L.,, H.-C. Jung,, C.-C. Schuerer-Maly,, A. Panja,, E. Morzycka-Wroblewska,, and M. F. Kagnoff. 1993. Differential cytokine expression by human intestinal epithelial cell lines: regulated expression of interleukin-8. Gastroenterology 105: 1689 1697.
25. Eckmann, L.,, W. F. Stenson,, T. C. Savidge,, D. C. Lowe,, K. E. Barrett,, J. Fierer,, J. R. Smith,, and M. F. Kagnoff. 1997. Role of intestinal epithelial cells in the host secretory response to infection by invasive bacteria. J. Clin. Investig. 100: 296 309.
26. Eggermont, E. 1996. Gastrointestinal manifestations in cystic fibrosis. Eur. J. Gastrointerol. Hepatol. 8: 731 738.
27. Elliot, S. J.,, C. B. O’Connell,, A. Koutsouris,, C. Brinkley,, M. S. Donnenberg,, G. Hecht,, and J. B. Kaper. 2002. A gene from the locus of enterocyte effacement that is required for enteropathogenic Escherichia coli to increase tight-junction permeability encodes a chaperone for EspF. Infect. Immun. 70: 2271 2277.
28. Fang, F. 1997. Mechanisms of nitric oxide-related antimicrobial activity. J. Clin. Investig. 99: 2818 2825.
29. Fanning, A. S.,, B. J. Jameson,, L. A. Jesaitis,, and J. M. Anderson. 1998. The tight junction protein ZO-1 establishes a link between the transmembrane protein occludin and the actin cytoskeleton. J. Biol. Chem. 273: 29745 29753.
30. Fasano, A.,, T. Not,, W. Wang,, S. Uzzau,, I. Berti,, A. Tommasini,, and S. E. Goldblum. 2000. Zonulin, a newly discovered modulator of intestinal permeability, and its expression in coeliac disease. Lancet 355: 1518 1519.
31. Frankel, W. L.,, W. Zhang,, A. Singh,, D. M. Kurfield,, S. Don,, T. Sakata,, I. Modlin,, and J. L. Rombeau. 1994. Mediation of trophic effects of short chain fatty acids on the rat jejunum and colon. Gastroenterology 106: 375 380.
32. Fuller, C. M.,, I. I. Ismailov,, D. A. Keeton,, and D. J. Benos. 1994. Phosphorylation and activation of a bovine tracheal anion channel by Ca 2+/calmodulin-dependent protein kinase II. J. Biol. Chem. 269: 26642 26650.
33. Furuse, M.,, M. Itoh,, T. Hirase,, A. Nagafuchi,, S. Yonemura,, and S. Tsukita. 1994. Direct association of occludin with ZO-1 and its possible involvement in the localization of occludin at tight junctions. J. Cell Biol. 127: 1617 1626.
34. Gewirtz, A. T.,, A. T. Navas,, S. Lyons,, P. J. Godowski,, and J. L. Madara. 2001. Bacterial flagella activates basolaterally expressed TLR5 to induce epithelial proinflammatory gene expression. J. Immunol. 167: 1882 1885.
35. Gewirtz, A. T.,, A. M. Siber,, J. L. Madara,, and B. A. McCormick. 1999. Orchestration of neutrophil movement by intestinal epithelial cells in response to Salmonella typhimurium can be uncoupled from bacterial internalization. Infect. Immun. 67: 608 617.
36. Gewirtz, A. T.,, A. S. Rao,, P. O. Simon,, D. Merlin,, D. Carnes,, J. L. Madara,, and A. S. Neish. 2000. Salmonella typhimurium induces epithelial IL-8 expression via Ca 2+-mediated activation of the NF-κB pathway. J. Clin. Investig. 105: 79 92.
37. Gewirtz, A. T.,, P. O. Simon,, C. K. Schmidt,, L. J. Taylor,, C. H. Hagedor,, A. D. O’Brien,, A. S. Neish,, and J. L. Madara. 2001. Salmonella typhimurium translocates flagellin across the intestinal epithelia inducing a pro-inflammatory response. J. Clin. Investig. 107: 99 109.
38. Gewirtz, A. T.,, T. A. Navas,, S. Lyons,, P. J. Godowski,, and J. L. Madara. 2001. Cutting edge: bacterial flagellin activates basolaterally expressed TLR5 to induce epithelial pro-inflammatory genes expression. J. Immunol. 167: 1882 1885.
39. Girardin, S. E.,, I. G. Boneca,, L. A. M. Carnairo,, A. Antignac,, M. Jehanno,, J. Viala,, P. J. Sansonetti,, and D. J. Phillpot. 2003. Nod1 detects a unique muropeptide from Gram-negative bacterial peptidoglycan. Science 300: 1584 1587.
40. Girardin, S. E.,, I. G. Boneca,, J. Viala,, M. Chamaillard,, A. Labigne,, G. Thomas,, D. J. Phillpot,, and P. J. Sansonetti. 2003. Nod2 is a general sensor of peptidoglycan through muramyl dipeptide (MDP) detection. J. Biol. Chem. 278: 8869 8872.
41. Girardin, S. E.,, P. J. Sansonetti,, and D. J. Phillpot. 2002. Intracellular vs. extracellular recognition of pathogens-common concepts in mammals and flies. Trends Microbiol. 10: 193 199.
42. Gopalakrishnan, S.,, N. Raman,, S. J. Atkinson,, and J. A. Marrs. 1998. Rho GTPase signaling regulates tight junction assembly and protects tight junctions during ATP depletion. Am. J. Physiol. Ser. C 275: C798 C809.
43. Hayashi, F.,, K. D. Smith,, A. Ozinsky,, T. R. Hawn,, E. C. Yi,, D. R. Goodlett,, J. K. Eng,, S. Akira,, D. M. Underhill,, and A. Aderem. 2001. The innate immune response to bacterial flagellin is mediated by Toll-like receptor 5. Nature 410: 1099 1103.
44. Hayle, C.,, and G. Burnstock. 1989. Galanin-like immunoreactivity in enteric neurons of the human colon. J. Anat. 166: 23 33.
45. Hemmi, H. O.,, T. Takeuchi,, T. Kawai,, S. Kaisho,, H. Sato,, M. Sanjo,, K. Matsumoto,, H. Hoshino,, K. Wahner,, K, Takeda,, and S. Akira. 2000. A Toll-like receptor recognizes bacterial DNA. Nature 408: 740 745.
46. Hirst, T. R., 1995. Biogenesis of cholera and related oligomeric enterotoxins, p. 123 184. In J. Moss,, M. Vaughan,, B. Iglewski,, and A. T. Tu (ed.), Bacterial Toxins and Virulence Factors in Disease, vol 8. Marcel Dekker, Inc., New York, N.Y.
47. Hobbie, S.,, L. Chen,, R. Davis,, and J. E. Galan. 1997. Involvement of mitogen-activated protein kinase pathways in the nuclear responses and cytokine production induced by Salmonella typhimurium in cultured intestinal epithelial cells. J. Immunol. 159: 5550 5559.
48. Hoffman,, J. F. Kafatos,, C. Janeway,, and R. Ezekowitz. 1999. Phylogenic perspectives in innate immunity. Science 284: 1313 1318.
49. Hooper, L. V.,, J. Xu,, P. G. Falk,, T. Midvedt,, and J. I. Gordan. 1999. A molecular sensor that allows a gut commensal to control its nutrient foundation in a competitive ecosystem. Proc. Natl. Acad. Sci. USA 96: 9833 9838.
50. Horiguchi, Y.,, T. Senda,, N. Sugimoto,, J. Katahira,, and M. Matsuda. 1995. Bordetella bronchiseptica dermonecrotizing toxin stimulates assembly of actin stress fibers and focal adhesions by modifying the small GTP- binding protein rho. J. Cell. Sci. 108: 3243 3251.
51. Hugot, J. P.,, P. Laurent-Puig,, C. Gower-Rousseau,, J. M. Olson,, J. C. Lee,, L. Beaugerie,, I. Naom,, J. L. Dupas,, A. Van Gossum,, M. Orholm,, S. Bonaiti-Pellie,, J. Weissenbach,, C. G. Mathew,, J. E. Lennard-Jones,, A. Cortot,, J. F. Colombel,, and G. Thomas. 1996. Mapping of a susceptibility locus for Crohn’s disease. Nature 379: 821 823.
52. Inohara, N.,, and G. Nunez. 2003. Nods. Intracellular proteins involved in inflammation and apoptosis. Nat. Rev. Immunol. 3: 371 382.
53. Inohora, N.,, T. Koseki,, J. Lin,, L. del Paso,, P. C. Lucas,, F. F. Chen,, Y. Ogura,, and G. Nunez. 2000. An induced proximity model for NF-kappaB activation in the Nod1/Rick and RIP signaling pathways. J. Biol. Chem. 275: 27823 27831.
54. Itoh, M.,, K. Morita,, and S. Tsukita. 1999. Characterization of ZO-2 as a MAGUK family member associated with tight as well as adherens junctions with a binding affinity to occludin and alpha catenin. J. Biol. Chem. 274: 5981 5986.
55. Iyoda, S.,, T. Kamidoi,, K. Hirose,, K. Kutsukake,, and H. Watanabe. 2001. A flagellar gene fliz regulates the expression of invasion genes and virulence phenotype in Salmonella enterica serovar Typhimurium. Microb. Pathog. 30: 81 90.
56. Jesaitis, L. A.,, and D. A. Goodenough. 1994. Molecular characterization and tissue distribution of ZO-2, a tight junction protein homologous to ZO-1 and the Drosophila discslarge tumor suppressor protein. J. Cell Biol. 124: 949 961.
57. Jung, H. C.,, L. Eckmann,, S. K. Yang,, A. Panja,, J. Fierer,, E. Morzycka-Wroblewska,, and M. F. Kagnoff. 1995. A distinct array of proinflammatory cytokines is expressed in human colon epithelial cells in response to bacterial invasion. J. Clin. Investig. 95: 55 65.
58. Karin, M. 1999. The beginning of the end: I(B kinase (IKK) and NF-κB activation. J. Biol. Chem. 274: 27339 27342.
59. Katsoulis, S.,, A. Clemens,, C. Morys-Wortmann,, H. Schworer,, H. Schaube,, H. J. Klomp,, U. R. Folsch,, and W. E. Schmidt. 1996. Human galanin modulates colonic motility in vitro. Characterization of structural requirements. Scand. J. Gastroenterol. 31: 446 451.
60. Keely, S.,, and K. Barrett. 2000. Regulation of chloride secretion: novel pathways and messengers. Ann. N. Y. Acad. Sci. 915: 67 76.
61. Kenny, B.,, R. DeVinney,, M. Stein,, D. J. Reinscheid,, G. A. Frey,, and B. B. Finlay. 1997. Enteropathogenic E. coli (EPEC) transfers its receptor for intimate adherence into mammalian cells. Cell 91: 511 520.
62. Kopp, E.,, and S. Ghosh. 1995. NF-κB and Rel proteins in innate immunity. Adv. Immunol. 58: 1 12.
63. Kuhn, R.,, J. Lohler,, D. Rennick,, K. Rajewsky,, and W. Muller. 1993. Interleukin-10-deficient mice develop chronic enterocolitis. Cell 75: 263 274.
64. Lencer, W. I. 2001. Microbes and microbial toxins: paradigms for microbial mucosal interactions. V. Cholera: invasion of the intestinal epithelial barrier by a stably folded protein toxin. Am. J. Physiol. Ser. G 280: G781 G786.
65. Londono, I.,, V. Marshansky,, S. Bourgoin,, P. Vinay,, and M. Bendayan. 1999. Expression and distribution of adeno sine diphosphate ribosylation factorsin the rat kidney. Kidney Int. 55: 1407 1416.
66. Madara, J. L. 2000. Modulation of tight junction permeability. Adv. Drug Deliv. Rev. 41: 251 253.
67. Makishima, S.,, K. Komoriya,, S. Yamaguchi,, and S. I. Aizawa. 2001. Length of the flagella hook and the capacity of the type III export apparatus. Science 291: 2411 2413.
68. Matkowskyj, K. A.,, A. Danilkovich,, J. Marrero,, S. D. Savkovic,, G. Hecht,, and R.V. Benya. 2000. Galanin-1 receptor up-regulation mediates the excess colonic fliud production caused by infection with enteric pathogens. Nat. Med. 6: 1048 1051.
69. McCormick, B. A.,, C. A. Parkos,, S. P. Colgan,, D. K. Carnes,, and J. L. Madara. 1998. Apical secretion of a pathogen-elicited epithelial chemoattractant (PEEC) activity in response to surface colonization of intestinal epithelia by Salmonella typhimurium. J. Immunol. 160: 455 466.
70. McCormick, B. A.,, S. P. Colgan,, C. D. Archer,, S. I. Miller,, and J. L. Madara. 1993. Salmonella typhimurium attachment to human intestinal epithelial monolayers: transcellular signalling to subepithelial neutrophils. J. Cell. Biol. 123: 895 907.
71. McCormick, B. A.,, P. M. Hofman,, J. Kim,, D. K. Carnes,, S. I. Miller,, and J. L. Madara. 1995. Surface attachment of Salmonella typhimurium to intestinal epithelia imprints the subepithelial matrix with gradients chemotactic for neutrophils. J. Cell. Biol. 131: 1599 1608.
72. McCormick, B. A.,, S. I. Miller,, D. Carnes,, and J. L. Madara. 1995. Transepithelial signaling to neutrophils by salmonellae: a novel virulence mechanism for gastroenteritis. Infect. Immun. 63: 2302 2309.
73. McCormick, B. A.,, A. Nusrat,, L. D’Andrea,, C. A. Parkos,, P. M. Hofman,, D. K. Carnes,, and J. L. Madara. 1997. Unmasking of intestinal epithelial lateral membrane β 1-integrin consequent to transepithelial neutrophil migration in vitro facilitates inv-mediated invasion by Yersinia. Infect. Immun. 65: 1414 1421.
74. Medzhitov, R.,, and C. Janeway, Jr. 2000. Innate immunity. N. Engl. J. Med. 343: 338 344.
75. Molina, N.,, and J. Petterson. 1980. Cholera toxin-like toxin released by Salmonella species in the presence of mitomycin C. Infect. Immun. 30: 224 230.
76. Moreau, M. C.,, and V. Gaboriau-Routhiau. 1996. The absence of the gut flora, the doses of antigen ingested and aging affect the long-term peripheral tolerance induced by ovalbumin feeding in mice. Res. Immunol. 147: 49 59.
77. Mounier, J.,, T. Vasselon,, R. Hellio,, M. Lesourd,, and P. J. Sansonetti. 1992. Shigella flexneri enters human colonic Caco-2 epithelial cells through the basolateral pole. Infect. Immun. 60: 237 248.
78. Neish, A.,, A. Gewirtz,, H. Zeng,, A. Young,, M. Hobert,, V. Karmali,, A. Rao,, and J. Madara. 2000. Prokaryotic regulation of epithelial responses by inhibition of IκB-α ubiquitination. Science 289: 1563.
79. Norris, F. A.,, M. R. Wilson,, T. S. Wallis,, E. E. Galyov,, and P. W. Majerus. 1998. SopB a protein required for virulence of Salmonella Dublin is an inositol phosphate phosphatase. Proc. Natl. Acad. Sci. USA 95: 14057 14059.
80. Nusrat, A.,, M. Giry,, J. R. Turner,, S. P. Colgan,, C. A. Parkos,, D. Carnes,, E. Lemichez,, P. Boquet,, and J. L. Madara. 1995. Rho protein regulates tight junctions and perijunctional actin organization in polarized epithelia. Proc. Natl. Acad. Sci. USA 92: 10629 10633.
81. Ogura, Y.,, D. K. Bonen,, N. Inohara,, D. L. Nicolae,, F. F. Chen,, R. Rames,, H. Britton,, T. Moran,, R. Karaliuskas,, R. H. Duerr,, J. P. Achkar,, S. R. Brant,, P. M. Bayless,, B. S. Kirschner,, J. B. Hanaver,, G. Nunez,, and J. H. Cho. 2001. A frameshift mutation in Nod2 associated with susceptibility to Crohn’s disease. Nature 411: 603 608.
82. Orth, K.,, L. Palmer,, Z. Bao,, S. Stewart,, A. Rudolph,, J. Bliska,, and J. Dixon. 1999. Inhibition of the mitogen-activated protein kinase kinase superfamily by a Yersinia effector. Science 285: 1920 1923.
83. Orth, K.,, Z. Xu,, M. Mudgett,, Z. Bao,, L. Palmer,, J. Bliska,, W. Mangel,, B. Staskawicz,, and J. Dixon. 2000. Disruption of signaling by Yersinia effector YopJ, a ubiquitinin-like protein protease. Science 290: 1594 1597.
84. Oswald, E.,, M. Sugai,, A. Labigne,, H. C. Wu,, C. Fiorentini,, P. Boquet,, and A. D. O’Brien. 1994. Cytotoxic necrotizing factor type 2 produced by virulent Escherichia coli modifies the small GTP-binding proteins Rho involved in assembly of actin stress fibers. Proc. Natl. Acad. Sci. USA 91: 3814 3818.
85. Resta-Lenert, S.,, and K. Barrett. 2002. Enteroinvasive bacteria alter barrier and transport properties of human intestinal epithelium: role of iNOS and COX-2. Gastroenterology 122: 1070 1087.
86. Roberfroid, M. B.,, F. Bornet,, C. Bouley,, and J. H. Cummings. 1995. Colonic microflora: nutrition and health. Summary of conclusions of an Internattional Life Sciences Institute [(ILSI) Europe] Workshop held in Barcelona, Spain. Nutr. Rev. 53: 127 130.
87. Rodighiero, C.,, and W. I. Lencer,. 2003. Trafficking of cholera toxin and related bacterial enterotoxins: pathways and endpoints, p. 385 422. In G. Hecht (ed.) Microbial Pathogenesis and the Intestinal Epithelial Cell. ASM Press, Washington, D.C.
88. Sakaguchi, T.,, H. Kohler,, X. Gu,, B. A. McCormick,, and H. C. Reinecker. 2002. Shigella flexneri regulates tight junction- associated proteins in human intestinal epithelial cells. Cell. Microbiol. 6: 367 381.
89. Sears, C. L.,, and J. B. Kaper. 1996. Enteric bacterial toxins: mechanisms of action and linkage to intestinal secretion. Microbiol. Rev. 60: 167 215.
90. Sellon, R. K.,, S. Tonkonogy,, M. Shultz,, L. A. Dieleman,, W. Grenther,, E. Balish,, D. M. Rennick,, and R. B. Sartor. 1998. Resident enteric bacteria are necessary for the development of spontaneous colitis and immune system activation in interleukin-10-deficient mice. Infect. Immun. 66: 5224 5231.
91. Senda, T.,, Y. Horiguchi,, M. Umemoto,, N. Sugimoto,, and M. Matsuda. 1997. Bordetella bronchiseptica dermonecrotizing toxin, which activates a small GTP-binding protein rho, induces membrane organelle proliferation and caveolae formation. Exp. Cell Res. 230: 163 168.
92. Simonovic, I.,, J. Rosenberg,, A. Koutsouris,, and G. Hecht. 2000. Enteropathogenic Escherichia coli dephosphorylates and dissociates occluding from intestinal epithelial tight junctions. Cell. Microbiol. 4: 305 315.
93. Smith, W. L.,, and D. L. DeWitt. 1996. Prostaglandin endoperoxidae H synthase-1 and -2. Adv. Immunol. 62: 167 215.
94. Sonoda, N.,, M. Furuse,, H. Sasaki,, S. Yonemura,, J. Katahira,, Y. Horiguchi,, and S. Tsukita. 1999. Clostridium perfringens enterotoxin fragment removes specific claudins from tight junction strands. Evidence for direct involvement of claudins in tight junction barrier. J. Cell Biol. 147: 195 204.
95. Strober, W.,, I. J. Fuss,, and R. S. Blumberg. 2002. The immunology of mucosal models of inflammation. Annu. Rev. Immunol. 20: 495 549.
96. Strober, W.,, I. J. Fuss,, R. O. Ehrhardt,, M. Neurath , M. Boirivant,, and B. R. Ludviksson. 1998. Mucosal immunoregulation and inflammatory bowel disease: new insights from murine models of inflammation. Scand. J. Immunol. 30: 2101 2111.
97. Suau, A.,, R. Bonnet,, M. Sutren,, J. J. Gordan,, G. R. Gibson,, M. D. Collin,, and J. Dore. 1999. Direct rDNA community analysis reveals a myriad of novel bacterial lineages within the human gut. Appl. Environ. Microbiol. 65: 4799 4807.
98. Sudo, N.,, S. Sawamura,, K. Tanaka,, Y. Aiba,, C. Kubo,, and Y. Koga. 1997. The requirement of intestinal bacteria flora for the development of an IgE production system fully susceptible to oral tolerance induction. J. Immunol. 159: 1739 1745.
99. Takahashi, A.,, N. Kenjyo,, K. Imura,, Y. Myosum,, and T. Honda. 2000. Cl - secretion in colonic epithelial cells induced by Vibrio parahaemolyticus hemolytic toxin related to thermostable direct hemolysin. Infect. Immun. 68: 5435 5438.
100. Takeuchi, O.,, K. Hoshino,, T. Kawai,, H. Sanjo,, H. Takaada,, T. Ogawa,, K. Takeda,, and S. Akira. 1999. Differential roles of TLR-2 and TLR4 in recognition of Gram-negative and Gram-positive bacterial cell wall components. Immunity 11: 443 451.
101. Tannock, G. W. 2001. Molecular assessment of intestinal microflora. Am. J. Clin. Nutr. 73:(Suppl.): 54799 54807.
102. Umesaki, Y.,, H. Setoyama,, S. Matsumoto,, and Y. Okada. 1993. Expression of alpha beta T-cell receptor-bearing intestinal intraepithelial lymphocytes after microbial colonization in germ-free mice and its independence from the thymus. Immunology 79: 32 37.
103. Underhill, D. M.,, A. Ozinsky,, K. D. Smith,, and A. Aderem. 1999. Toll-like receptor-2 mediates mycobacteria-induced proinflammatory signaling in macrophage. Proc. Natl. Acad. Sci. USA 96: 14459 14463.
104. Vallance, B. A.,, and B. B. Finlay. 2000. Exploitation of host cells by enteropathogenic Escherichia coli. Proc. Natl. Acad. Sci. USA 97: 8799 8806.
105. Venkateswarlu, K.,, and P. J. Cullen. 2000. Signalling via ADP-ribosylation factor 6 lies downstream of phosphatidylinositide 3-kinase. Biochem. J. 345: 719 724.
106. Wallis, T. S.,, A. T. M. Vaughan,, G. J. Clarke,, G.-M. Qi,, K. J. Woron,, D. C. A. Candy,, M. P. Osborne,, and J. Stephen. 1990. The role of leucocytes in the induction of fluid secretion by Salmonella typhimurium. J. Med. Microbiol. 31: 27 35.
107. Wilson, K. H.,, and R. B. Blitchington. 1996. Human colonic biota studies by ribosomal DNA sequence analysis. Appl. Environ. Microbiol. 62: 2273 2278.
108. Wirtz, S.,, S. Finotto,, A. W. Lohse,, M. Blessing,, H. A. Lehr,, P. R. Galle,, and M. F. Neurath. 1999. Chronic intestinal inflammation in STAT-4 transgenic mice: characterization of disease and adoptive transfer by TNF-plus IFN gamma-producing CD4 + T cells that respond to bacterial antigens. J. Immunol. 162: 1884 1888.
109. Wittchen, E. S.,, J. Haskins,, and B. R. Stevenson. 1999. Protein interactions at the tight junction. Actin has multiple binding partners, and ZO-1 forms independent complexes with ZO-2 and ZO-3. J. Biol. Chem. 274: 35179 35185.
110. Woods, D. F.,, and P. J. Bryant. 1993. ZO-1, DlgA and PSD- 95/SAP90: homologous proteins in tight, septate and synaptic cell junctions. Mech. Dev. 44: 85 89.
111. Young, G. M.,, D. H. Schiel,, and V. L. Miller. 1999. A new pathway for the secretion of virulence factors by bacteria: the flagellar export apparatus functions as a protein secretion system. Proc. Natl. Acad. Sci. USA 96: 6456 6461.
112. Zhou, D.,, L. M. Chen,, L. Hernandez,, S. B. Shears,, and J. E. Galan. 2001. A Salmonella inositol phosphatase acts in conjunction with other bacterial effectors to promote host cell actin cytoskeleton rearrangements and bacterial internalization. Mol. Microbiol. 39: 248 259.

This is a required field
Please enter a valid email address
Please check the format of the address you have entered.
Approval was a Success
Invalid data
An Error Occurred
Approval was partially successful, following selected items could not be processed due to error