1887

Chapter 8 : Urinary Tract Infection as a Model for Innate Mucosal Immunity

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

Preview this chapter:
Zoom in
Zoomout

Urinary Tract Infection as a Model for Innate Mucosal Immunity, Page 1 of 2

| /docserver/preview/fulltext/10.1128/9781555817671/9781555812911_Chap08-1.gif /docserver/preview/fulltext/10.1128/9781555817671/9781555812911_Chap08-2.gif

Abstract:

Most studies on innate immunity have focused on macrophages, as these cells are crucial defenders against infection of the systemic compartments. This chapter talks about (i) the molecular mechanisms used by bacteria to trigger the innate host response, (ii) neutrophils as effectors of the antimicrobial defense of the urinary tract, and (iii) genetic defects in innate host defense pathways that explain the susceptibility to urinary tract infections (UTIs). P-fimbriated is used to examine the role of recognition receptors and toll-like receptor-4 (TLR4) coreceptors in epithelial cell activation. Cell activation can proceed in two steps, involving a primary ligand-binding receptor and a second receptor responsible for transmembrane signaling, which in this model is TLR4. The authors have speculated that epithelial unresponsiveness to lipopolysaccharide (LPS) may be essential to maintain mucosal integrity, and have used the murine IL-8 receptor homologue (mIL-8Rh) mouse to study chemokines and chemokine receptors in the defense against UTI. Inactivation of a single gene encoding mIL-8Rh is sufficient to convert the mice from a resistant to a susceptible phenotype, as defined both by acute disease susceptibility and by chronic disease development. The chemokine receptors must be functional to avoid the trapping of neutrophils that results in tissue destruction.

Citation: Samuelsson M, Bergsten G, Fischer H, Leijonhufvud I, Lundstedt A, Samuelsson P, Svensson M, Wullt B, Svanborg C, Karpman D, Wullt B. 2004. Urinary Tract Infection as a Model for Innate Mucosal Immunity, p 157-170. In Kaufmann S, Medzhitov R, Gordon S (ed), The Innate Immune Response to Infection. ASM Press, Washington, DC. doi: 10.1128/9781555817671.ch8

Key Concept Ranking

Innate Immune System
0.6096864
Infection and Immunity
0.51934534
Urinary Tract Infections
0.51202637
0.6096864
Highlighted Text: Show | Hide
Loading full text...

Full text loading...

Figures

Image of FIGURE 1
FIGURE 1

Innate responses at mucosal surfaces. (A) The epithelial barrier is breached by pathogenic bacteria. Following the initial adherence, the bacteria activate the epithelial cells to release of mediators of inflammation, immunity, and cell differentiation. (B) In our model, attachment is mediated through P fimbriae. Cell surface GSLs serve as recognition receptors and signaling is via TLR4. (C) The two-step model of the innate host response in the human urinary tract. Step 1: the adhering bacteria break the inertia of the mucosal barrier by triggering a cellular cytokine response. Step 2: the IL-8 chemokine family and the CXCR1 receptor support neutrophil migration across the epithelium and into the urine and, in the process, infection is cleared.

Citation: Samuelsson M, Bergsten G, Fischer H, Leijonhufvud I, Lundstedt A, Samuelsson P, Svensson M, Wullt B, Svanborg C, Karpman D, Wullt B. 2004. Urinary Tract Infection as a Model for Innate Mucosal Immunity, p 157-170. In Kaufmann S, Medzhitov R, Gordon S (ed), The Innate Immune Response to Infection. ASM Press, Washington, DC. doi: 10.1128/9781555817671.ch8
Permissions and Reprints Request Permissions
Download as Powerpoint
Image of FIGURE 2
FIGURE 2

Bacterial clearance is independent of specific immunity. (A) Kinetics of bacterial clearance. The initial reduction in bacterial numbers and activation of the mucosal response are followed by the neutrophil-dependent phase of bacterial clearance. There is no preexisting specific immune response, and infection is cleared before such a response can be activated. (B) Bacterial clearance is efficient in immunodeficient mice, but deficient in TLR4 mutant mice ( ).These experiments have been repeated in TCR KO and RAG KO mice ( ).The results show that bacterial clearance from the urinary tract depends on the innate immune system. n.s., not significant.

Citation: Samuelsson M, Bergsten G, Fischer H, Leijonhufvud I, Lundstedt A, Samuelsson P, Svensson M, Wullt B, Svanborg C, Karpman D, Wullt B. 2004. Urinary Tract Infection as a Model for Innate Mucosal Immunity, p 157-170. In Kaufmann S, Medzhitov R, Gordon S (ed), The Innate Immune Response to Infection. ASM Press, Washington, DC. doi: 10.1128/9781555817671.ch8
Permissions and Reprints Request Permissions
Download as Powerpoint
Image of FIGURE 3
FIGURE 3

Specific adherence as a mechanism of tissue targeting. (A) P-fimbriated adhering to a human urinary tract epithelial cell (bright-field microscopy; enlargement, ×1,000). (B) Fimbriae are adhesive organelles. Fimbrial expression (platinum-shadowed electron microscopy; enlargement, ×15,000). (C) Mechanism of adherence.The PapG adhesin at the fimbrial tip recognizes receptor epitopes defined by the Galα1-4Galβ disaccharide in cell surface GSLs. This interaction initiates the mucosal response. (D) Disease association of P-fimbrial expression. P fimbriae are expressed by >95% of strains causing acute pyelonephritis but <20% of asymptomatic carrier strains and commensal fecal strains.

Citation: Samuelsson M, Bergsten G, Fischer H, Leijonhufvud I, Lundstedt A, Samuelsson P, Svensson M, Wullt B, Svanborg C, Karpman D, Wullt B. 2004. Urinary Tract Infection as a Model for Innate Mucosal Immunity, p 157-170. In Kaufmann S, Medzhitov R, Gordon S (ed), The Innate Immune Response to Infection. ASM Press, Washington, DC. doi: 10.1128/9781555817671.ch8
Permissions and Reprints Request Permissions
Download as Powerpoint
Image of FIGURE 4
FIGURE 4

Consequences of TLR4 and CXCR1 deficiencies. Step 1: the bacteria bind to the primary targeting receptors and trigger inflammation.The specificity is determined by the PapG protein on the fimbrial tip and the Galα1-4Galβ receptor motif. Activation is through TLR4. Inactivation of the TLR4 signal aborts the inflammatory cascade. This results in asymptomatic bacterial carriage of the bacteria. Step 2: if TLR4 is functional and the response is activated, the epithelium will secrete inflammatory mediators. Neutrophils will be recruited to the site to deal with the infection. In the presence of the human IL-8 receptor, CXCR1, the neutrophils can squeeze through the tight junctions and enter the lumen with their cargo of phagocytosed bacteria.This will eventually result in a clearance of the infection and pyuria, one of the classic signs of an ongoing UTI. In the absence of CXCR1, the neutrophils are trapped under the epithelial barrier.This will inevitably result in tissue damage as the neutrophils release their contents in the tissues.

Citation: Samuelsson M, Bergsten G, Fischer H, Leijonhufvud I, Lundstedt A, Samuelsson P, Svensson M, Wullt B, Svanborg C, Karpman D, Wullt B. 2004. Urinary Tract Infection as a Model for Innate Mucosal Immunity, p 157-170. In Kaufmann S, Medzhitov R, Gordon S (ed), The Innate Immune Response to Infection. ASM Press, Washington, DC. doi: 10.1128/9781555817671.ch8
Permissions and Reprints Request Permissions
Download as Powerpoint

References

/content/book/10.1128/9781555817671.chap8
1. Agace, W. W.,, S. R. Hedges,, M. Ceska,, and C. Svanborg. 1993a. Interleukin-8 and the neutrophil response to mucosal gram-negative infection. J. Clin. Invest. 92: 780 781.
2. Agace, W.,, S. Hedges,, U. Andersson,, J. Andersson,, M. Ceska,, and C. Svanborg. 1993b. Selective cytokine production by epithelial cells following exposure to Escherichia coli. Infect. Immun. 61: 602 609.
3. Ahuja, S. K.,, T. Ozcelik,, A. Milatovitch,, U. Francke,, and P. M. Murphy. 1992. Molecular evolution of the human interleukin-8 receptor gene cluster. Nat. Genet. 2: 31 36.
4. Bergstén, G.,, M. Samuelsson,, B. Wullt,, I. Leijonhofvud,, H. Fischer,, and C. Svanborg. PapG-dependent adhesion breaks mucosal inertia and triggers the innate response. J. Infect. Dis., in press.
5. Beutler, B. 2000. Tlr4: central component of the sole mammalian LPS sensor. Curr. Opin. Immunol. 12: 20 26.
6. Bonecchi, R.,, G. Bianchi,, P. P. Bordignon,, D. D'Ambrosio,, R. Lang,, A. Borsatti,, S. Sozzani,, P. Allavena,, P. A. Gray,, A. Mantovani,, and F. Sinigaglia. 1998. Differential expression of chemokine receptors and chemotactic responsiveness of type 1 T helper cells (Th1s) and Th2s. J. Exp. Med. 187: 129 134.
7. Cacalano, G.,, J. Lee,, K. Kikly,, A. M. Ryan,, S. Pitts-Meek,, B. Hultgren,, W. I. Wood,, and M.W. Moore. 1994. Neutrophil and B cell expansion in mice that lack the murine IL-8 receptor homolog. Science 265: 682 684.
8. Eden, C. S.,, and H. Leffler. 1980. Glycosphingolipids of human urinary tract epithelial cells as possible receptors for adhering Escherichia coli bacteria. Scand. J. Infect. Dis. 24(Suppl.): 144 147.
9. Frendeus, B.,, G. Godaly,, L. Hang,, D. Karpman,, A. C. Lundstedt,, and C. Svanborg. 2000. Interleukin 8 receptor deficiency confers susceptibility to acute experimental pyelonephritis and may have a human counterpart. J. Exp. Med. 192: 881 890.
10. Frendeus, B.,, C. Wachtler,, M. Hedlund,, H. Fischer,, P. Samuelsson,, M. Svensson,, and C. Svanborg. 2001a. Escherichia coli P fimbriae utilize the Toll-like receptor 4 pathway for cell activation. Mol. Microbiol. 40: 37 51.
11. Frendeus, B.,, G. Godaly,, L. Hang,, D. Karpman,, and C. Svanborg. 2001b. Interleukin-8 receptor deficiency confers susceptibility to acute pyelonephritis. J. Infect. Dis. 183( Suppl.): S56 S60.
12. Freter, R. 1972. Parameters affecting the association of vibrios with the intestinal surface in experimental cholera. Infect. Immun. 6: 134 141.
13. Ganz, T. 2001. Defensins in the urinary tract and other tissues. J. Infect. Dis. 183( Suppl.): S41 S42.
14. Godaly, G.,, A. E. Proudfoot,, R. E. Offord,, C. Svanborg,, and W.W. Agace. 1997. Role of epithelial interleukin-8 (IL-8) and neutrophil IL-8 receptor A in Escherichia coli-induced transuroepithelial neutrophil migration. Infect. Immun. 65: 3451 3456.
15. Godaly, G.,, B. Frendeus,, A. Proudfoot,, M. Svensson,, P. Klemm,, and C. Svanborg. 1998. Role of fimbriae-mediated adherence for neutrophil migration across Escherichia coli-infected epithelial cell layers. Mol. Microbiol. 30: 725 735.
16. Godaly, G.,, L. Hang,, B. Frendeus,, and C. Svanborg. 2000. Transepithelial neutrophil migration is CXCR1 dependent in vitro and is defective in IL-8 receptor knockout mice. J. Immunol. 165: 5287 5294.
17. Godaly, G.,, G. Bergsten,, L. Hang,, H. Fischer,, B. Frendeus,, A. C. Lundstedt,, M. Samuelsson,, P. Samuelsson,, and C. Svanborg. 2001. Neutrophil recruitment, chemokine receptors, and resistance to mucosal infection. J. Leukoc. Biol. 69: 899 906.
18. Green, S. P.,, A. Chuntharapai,, and J.T. Curnutte. 1996. Interleukin-8 (IL-8), melanoma growth-stimulatory activity, and neutrophil-activating peptide selectively mediate priming of the neutrophil NADPH oxidase through the type A or type B IL-8 receptor. J. Biol. Chem. 271: 25400 25405.
19. Hagberg, L.,, U. Jodal,, T. K. Korhonen,, G. Lidin-Janson,, U. Lindberg,, and C. Svanborg-Eden. 1981. Adhesion, hemagglutination, and virulence of Escherichia coli causing urinary tract infections. Infect. Immun. 31: 564 570.
20. Hagberg, L.,, I. Engberg,, R. Freter,, J. Lam,, S. Olling,, and C. Svanborg-Eden. 1983. Ascending, unobstructed urinary tract infection in mice caused by pyelonephritogenic Escherichia coli of human origin. Infect. Immun. 40: 273 283.
21. Hagberg, L.,, R. Hull,, S. Hull,, J. R. McGhee,, S. M. Michalek,, and C. Svanborg-Eden. 1984. Difference in susceptibility to gram-negative urinary tract infection between C3H/HeJ and C3H/HeN mice. Infect. Immun. 46: 839 844.
22. Hammond, M. E.,, G. R. Lapointe,, P. H. Feucht,, S. Hilt,, C. A. Gallegos,, C. A. Gordon,, M. A. Giedlin,, G. Mullenbach,, and P. Tekamp-Olson. 1995. IL-8 induces neutrophil chemotaxis predominantly via type I IL-8 receptors. J. Immunol. 155: 1428 1433.
23. Hang, L.,, B. Wullt,, Z. Shen,, D. Karpman,, and C. Svanborg. 1998. Cytokine repertoire of epithelial cells lining the human urinary tract. J. Urol. 159: 2185 2192.
24. Hang, L.,, B. Frendeus,, G. Godaly,, and C. Svanborg. 2000. Interleukin-8 receptor knockout mice have subepithelial neutrophil entrapment and renal scarring following acute pyelonephritis. J. Infect. Dis. 182: 1738 1748.
25. Haraoka, M.,, L. Hang,, B. Frendeus,, G. Godaly,, M. Burdick,, R. Strieter,, and C. Svanborg. 1999. Neutrophil recruitment and resistance to urinary tract infection. J. Infect. Dis. 180: 1220 1229.
26. Hedges, S.,, M. Svensson,, and C. Svanborg. 1992. Interleukin-6 response of epithelial cell lines to bacterial stimulation in vitro. Infect. Immun. 60: 1295 1301.
27. Hedlund, M.,, M. Svensson,, A. Nilsson,, R. D. Duan,, and C. Svanborg. 1996. Role of the ceramide-signaling pathway in cytokine responses to P-fimbriated Escherichia coli. J. Exp. Med. 183: 1037 1044.
28. Hedlund, M.,, R. D. Duan,, A. Nilsson,, and C. Svanborg. 1998. Sphingomyelin, glycosphingolipids and ceramide signalling in cells exposed to P-fimbriated Escherichia coli. Mol. Microbiol. 29: 1297 1306.
29. Hedlund, M.,, C. Wachtler,, E. Johansson,, L. Hang,, J. E. Somerville,, R. P. Darveau,, and C. Svanborg. 1999. P fimbriae-dependent, lipopolysaccharide-independent activation of epithelial cytokine responses. Mol. Microbiol. 33: 693 703.
30. Hedlund, M.,, B. Frendeus,, C. Wachtler,, L. Hang,, H. Fischer,, and C. Svanborg. 2001. Type 1 fimbriae deliver an LPS- and TLR4-dependent activation signal to CD14-negative cells. Mol. Microbiol. 39: 542 552.
31. Kunin, C. 1987. Detection, Prevention and Management of Urinary Tract Infections. Lea and Febiger, Philadelphia, Pa..
32. Kunin, C. M.,, Q. F. Chin,, and S. Chambers. 1987. Morbidity and morality associated with indwelling urinary catheters in elderly patients in a nursing home—confounding due to the presence of associated diseases. J.Am. Geriatr. Soc. 35: 1001 1006.
33. Lamm, M. E.,, J. G. Nedrud,, C. S. Kaetzel,, and M. B. Mazanec. 1995. IgA and mucosal defense. APMIS 103: 241 246.
34. Lee, J.,, G. Cacalano,, T. Camerato,, K. Toy,, M.W. Moore,, and W. I. Wood. 1995. Chemokine binding and activities mediated by the mouse IL-8 receptor. J. Immunol. 155: 2158 2164.
35. Leffler, H.,, and C. Svanborg-Eden. 1980. Chemical identification of a glycosphingolipid receptor for Escherichia coli attaching to human urinary tract epithelial cells and agglutinating human erythrocytes. FEMS Microbiol. Lett. 24: 144 147.
36. Leffler, H.,, and C. Svanborg-Eden. 1981. Glycolipid receptors for uropathogenic Escherichia coli on human erythrocytes and uroepithelial cells. Infect. Immun. 34: 920 929.
37. Lindberg, F.,, B. Lund,, L. Johansson,, and S. Normark. 1987. Localization of the receptor-binding protein adhesin at the tip of the bacterial pilus. Nature 328: 84 87.
38. Linder, H.,, I. Engberg,, I. M. Baltzer,, K. Jann,, and C. Svanborg-Eden. 1988. Induction of inflammation by Escherichia coli on the mucosal level: requirement for adherence and endotoxin. Infect. Immun. 56: 1309 1313.
39. Lippert, U.,, M. Artuc,, A. Grutzkau,, A. Moller,, A. Kenderessy-Szabo,, D. Schadendorf,, J. Norgauer,, K. Hartmann,, R. Schweitzer-Stenner,, T. Zuberbier,, B. M. Henz,, and S. Kruger-Krasagakes. 1998. Expression and functional activity of the IL-8 receptor type CXCR1 and CXCR2 on human mast cells. J. Immunol. 161: 2600 2608.
40. Lloyd, A.,, W. Modi,, H. Sprenger,, S. Cevario,, J. Oppenheim,, and D. Kelvin. 1993. Assignment of genes for interleukin-8 receptors (IL8R) A and B to human chromosome band 2q35. Cytogenet. Cell Genet. 63: 238 240.
41. Middendorf, B.,, G. Blum-Oehler,, U. Dobrindt,, I. Muhldorfer,, S. Salge,, and J. Hacker. 2001. The pathogenicity islands (PAIs) of the uropathogenic Escherichia coli strain 536: island probing of PAI II536. J. Infect. Dis. 183( Suppl.): S17 S20.
42. Middleton, J.,, S. Neil,, J. Wintle,, I. Clark-Lewis,, H. Moore,, C. Lam,, M. Auer,, E. Hub,, and A. Rot. 1997. Transcytosis and surface presentation of IL-8 by venular endothelial cells. Cell 91: 385 395.
43. Ochensberger, B.,, L. Tassera,, D. Bifrare,, S. Rihs,, and C. A. Dahinden. 1999. Regulation of cytokine expression and leukotriene formation in human basophils by growth factors, chemokines and chemotactic agonists. Eur. J. Immunol. 29: 11 22.
44. Ogra, P.,, L. M., Bienenstock,, J. Mestecky,, W. Strober,, and J. McGhee. 2003. Mucosal Immunology, 3rd ed. Academic Press, San Diego, Calif..
45. Petering, H.,, O. Gotze,, D. Kimmig,, R. Smolarski,, A. Kapp,, and J. Elsner. 1999. The biologic role of interleukin-8: functional analysis and expression of CXCR1 and CXCR2 on human eosinophils. Blood 93: 694 702.
46. Plos, K.,, H. Connell,, U. Jodal,, B. I. Marklund,, S. Marild,, B. Wettergren,, and C. Svanborg. 1995. Intestinal carriage of P. fimbriated Escherichia coli and the susceptibility to urinary tract infection in young children. J. Infect. Dis. 171: 625 631.
47. Poltorak, A.,, X. He,, I. Smirnova,, M.Y. Liu,, C. Van Huffel,, X. Du,, D. Birdwell,, E. Alejos,, M. Silva,, C. Galanos,, M. Freudenberg,, P. Ricciardi-Castagnoli,, B. Layton,, and B. Beutler. 1998. Defective LPS signaling in C3H/HeJ and C57BL/10ScCr mice: mutations in Tlr4 gene. Science 282: 2085 2088.
48. Quan, J. M.,, T. R. Martin,, G. B. Rosenberg,, D. C. Foster,, T. Whitmore,, and R. B. Goodman. 1996. Antibodies against the N-terminus of IL-8 receptor A inhibit neutrophil chemotaxis. Biochem. Biophys. Res. Commun. 219: 405 411.
49. Sallusto, F.,, P. Schaerli,, P. Loetscher,, C. Schaniel,, D. Lenig,, C. R. Mackay,, S. Qin,, and A. Lanzavecchia. 1998. Rapid and coordinated switch in chemokine receptor expression during dendritic cell maturation. Eur. J. Immunol. 28: 2760 2769.
50. Sansonetti, P. J. 2001. Rupture, invasion and inflammatory destruction of the intestinal barrier by Shigella, making sense of prokaryote-eukaryote crosstalks. FEMS Microbiol. Rev. 25: 3 14.
51. Shahin, R. D.,, I. Engberg,, L. Hagberg,, and C. Svanborg Eden. 1987. Neutrophil recruitment and bacterial clearance correlated with LPS responsiveness in local gram-negative infection. J. Immunol. 138: 3475 3480.
52. Svanborg, C.,, et al. 1985. P. 385 398. In E. Skamene (ed.), Genetic Control of Host Resistance to Infection and Malignancy. Wiley-Liss, New York, N.Y..
53. Sung, M. A.,, K. Fleming,, H. A. Chen,, and S. Matthews. 2001. The solution structure of PapGII from uropathogenic Escherichia coli and its recognition of glycolipid receptors. EMBO Rep. 2: 621 627.
54. Svanborg, C.,, G. Godaly,, and M. Hedlund. 1999. Cytokine responses during mucosal infections: role in disease pathogenesis and host defence. Curr. Opin. Microbiol. 2: 99 105.
55. Svanborg, C.,, G. Bergsten,, H. Fischer,, B. Frendéus,, G. Godaly,, E. Gustafsson,, L. Hang,, M. Hedlund,, A. C. Lundstedt,, M. Samuelsson,, P. Samuelsson,, M. Svensson,, and B. Wullt. 2002. Adhesion, signal transduction and mucosal inflammation, p. 223 246. In M.Wilson (ed.), Bacterial Adhesion to Host Tissues—Mechanisms and Consequences, vol. 1. Cambridge University Press, Cambridge, United Kingdom.
56. Svanborg-Eden, C.,, L. A. Hanson,, U. Jodal,, U. Lindberg,, and A. S. Akerlund. 1976. Variable adherence to normal human urinary-tract epithelial cells of Escherichia coli strains associated with various forms of urinary-tract infection. Lancet 1: 490 492.
57. Svensson, M.,, R. Lindstedt,, N. S. Radin,, and C. Svanborg. 1994. Epithelial glucosphingolipid expression as a determinant of bacterial adherence and cytokine production. Infect. Immun. 62: 4404 4410.
58. Svensson, M.,, B. Frendeus,, T. Butters,, F. Platt,, R. Dwek,, and C. Svanborg. 2003. Glycolipid depletion in antimicrobial therapy. Mol. Microbiol. 47: 453 461.
59. Warren, J.W.,, H. L. Mobley,, and A. L. Trifillis. 1988. Internalization of Escherichia coli into human renal tubular epithelial cells. J. Infect. Dis. 158: 221 223.
60. Wold, A. E.,, M. Thorssen,, S. Hull,, and C. S. Eden. 1988. Attachment of Escherichia coli via mannose- or Gal alpha 1→Gal-beta-containing receptors to human colonic epithelial cells. Infect. Immun. 56: 2531 2537.
61. Wullt, B.,, G. Bergsten,, M. Samuelsson,, N. Gebretsadik,, R. Hull,, and C. Svanborg. 2001. The role of P fimbriae for colonization and host response induction in the human urinary tract. J. Infect. Dis. 183( Suppl. 1): S43 S46

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