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Genetics of innate immunity and UTI susceptibility

Abstract

A functional and well-balanced immune response is required to resist most infections. Slight dysfunctions in innate immunity can turn the 'friendly' host defense into an unpleasant foe and give rise to disease. Beneficial and destructive forces of innate immunity have been discovered in the urinary tract and mechanisms by which they influence the severity of urinary tract infections (UTIs) have been elucidated. By modifying specific aspects of the innate immune response to UTI, genetic variation either exaggerates the severity of acute pyelonephritis to include urosepsis and renal scarring or protects against symptomatic disease by suppressing innate immune signaling, as in asymptomatic bacteriuria (ABU). Different genes are polymorphic in patients prone to acute pyelonephritis or ABU, respectively, and yet discussions of UTI susceptibility in clinical practice still focus mainly on social and behavioral factors or dysfunctional voiding. Is it not time for UTIs to enter the era of molecular medicine? Defining why certain individuals are protected from UTI while others have severe, recurrent infections has long been difficult, but progress is now being made, encouraging new approaches to risk assessment and therapy in this large and important patient group, as well as revealing promising facets of 'good' versus 'bad' inflammation.

Key Points

  • Host resistance to urinary tract infections (UTIs) is controlled by the innate immune system and immune variants can exacerbate acute and chronic infection or be protective

  • Genetic variation influences susceptibility to infectious disease and specific genetic variants distinguish patients with different forms of UTI

  • Susceptibility to acute pyelonephritis, urosepsis-associated mortality and renal tissue damage in mice is caused by single-gene deletions that dysregulate innate immune effector functions; the same genes are polymorphic in patients who are prone to acute pyelonephritis

  • Changes to Toll-like receptor 4 expression and signaling can inhibit many aspects of the innate immune response and reduce inflammation and tissue damage, resulting in asymptomatic bacteriuria

  • Integrating molecular information on bacterial virulence and host immune genetics into diagnosis and therapy is of great interest and could identify patients prone to UTIs or those in need of aggressive therapy

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Figure 1: Interactions between mucosal surfaces and pathogens and commensals during symptomatic UTI or asymptomatic bacterial carriage.
Figure 2: Uroepithelial receptors for P or type 1 fimbriae.
Figure 3: Activation of TLR4 signaling by fimbriated UPEC.
Figure 4: Signaling pathways activated by type-1-fimbriated E. coli.
Figure 5: Contribution of genetics to UTI susceptibility in the murine UTI model.
Figure 6: Human polymorphisms in TLR4, CXCR1 and IRF3.

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References

  1. Hagberg, L. et al. Difference in susceptibility to Gram-negative urinary tract infection between C3H/HeJ and C3H/HeN mice. Infect. Immun. 46, 839–844 (1984).

    CAS  PubMed  PubMed Central  Google Scholar 

  2. Frendeus, B. et al. Interleukin 8 receptor deficiency confers susceptibility to acute experimental pyelonephritis and may have a human counterpart. J. Exp. Med. 192, 881–890 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Hagberg, L., Briles, D. E. & Eden, C. S. Evidence for separate genetic defects in C3H/HeJ and C3HeB/FeJ mice, that affect susceptibility to Gram-negative infections. J. Immunol. 134, 4118–4122 (1985).

    CAS  PubMed  Google Scholar 

  4. Poltorak, A. et al. Defective LPS signaling in C3H/HeJ and C57BL/10ScCr mice: mutations in Tlr4 gene. Science 282, 2085–2088 (1998).

    Article  CAS  PubMed  Google Scholar 

  5. Fischer, H., Yamamoto, M., Akira, S., Beutler, B. & Svanborg, C. Mechanism of pathogen-specific TLR4 activation in the mucosa: fimbriae, recognition receptors and adaptor protein selection. Eur. J. Immunol. 36, 267–277 (2006).

    Article  CAS  PubMed  Google Scholar 

  6. Lundstedt, A. C. et al. A genetic basis of susceptibility to acute pyelonephritis. PLoS ONE 2, e825 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Ragnarsdottir, B. et al. Toll-like receptor 4 promoter polymorphisms: common TLR4 variants may protect against severe urinary tract infection. PLoS ONE 5, e10734 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Picard, C. et al. Clinical features and outcome of patients with IRAK-4 and MyD88 deficiency. Medicine (Baltimore) 89, 403–425 (2010).

    Article  CAS  Google Scholar 

  9. Picard, C. et al. Pyogenic bacterial infections in humans with IRAK-4 deficiency. Science 299, 2076–2079 (2003).

    Article  CAS  PubMed  Google Scholar 

  10. von Bernuth, H. et al. Pyogenic bacterial infections in humans with MyD88 deficiency. Science 321, 691–696 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Doffinger, R. et al. X-linked anhidrotic ectodermal dysplasia with immunodeficiency is caused by impaired NF-κB signaling. Nat. Genet. 27, 277–285 (2001).

    Article  CAS  PubMed  Google Scholar 

  12. Stamm, W. E. & Norrby, S. R. Urinary tract infections: disease panorama and challenges. J. Infect. Dis. 183 (Suppl. 1), S1–S4 (2001).

    Article  PubMed  Google Scholar 

  13. Foxman, B. Epidemiology of urinary tract infections: incidence, morbidity, and economic costs. Am. J. Med. 113 (Suppl. 1A), 5S–13S (2002).

    Article  PubMed  Google Scholar 

  14. Tenke, P. et al. European and Asian guidelines on management and prevention of catheter-associated urinary tract infections. Int. J. Antimicrob. Agents 31 (Suppl. 1), S68–S78 (2008).

    Article  CAS  PubMed  Google Scholar 

  15. Svanborg, C. et al. The 'innate' host response protects and damages the infected urinary tract. Ann. Med. 33, 563–570 (2001).

    Article  CAS  PubMed  Google Scholar 

  16. Stenquist, K. et al. Bacteriuria in pregnancy: frequency and risk of acquisition. Am. J. Epidemiol. 129, 372–379 (1989).

    Article  Google Scholar 

  17. Wettergren, B., Jodal, U. & Jonasson, G. Epidemiology of bacteriuria during the first year of life. Acta Pediatr. Scand. 74, 925–933 (1985).

    Article  CAS  Google Scholar 

  18. Lindberg, U., Claesson, I., Hanson, L. A. & Jodal, U. Asymptomatic bacteriuria in schoolgirls. I. Clinical and laboratory findings. Acta Paediatr. Scand. 64, 425–431 (1975).

    Article  CAS  PubMed  Google Scholar 

  19. Nordenstam, G., Branberg, Å., Odén, A., Svanborg-Edén, C. & Svanborg, A. Bacteriuria and mortality in an elderly population. N. Engl. J. Med. 314, 1152–1156 (1986).

    Article  CAS  PubMed  Google Scholar 

  20. Grio, R. et al. Asymptomatic bacteriuria in pregnancy: maternal and fetal complications. Panminerva Med. 36, 198–200 (1994).

    CAS  PubMed  Google Scholar 

  21. Grio, R. et al. Asymptomatic bacteriuria in pregnancy: a diagnostic and therapeutic approach. Panminerva Med. 36, 195–197 (1994).

    CAS  PubMed  Google Scholar 

  22. Hansson, S. et al. Follicular cystitis in girls with untreated asymtomatic bacteriuria. J. Urol. 143, 330–332 (1990).

    Article  CAS  PubMed  Google Scholar 

  23. Anderson, P. et al. Persistence of Escherichia coli bacteriuria is not determined by bacterial adherence. Infect. Immun. 59, 2915–2921 (1991).

    Google Scholar 

  24. Hagberg, L. et al. Adhesion, hemagglutination, and virulence of Escherichia coli causing urinary tract infections. Infect. Immun. 31, 564–570 (1981).

    CAS  PubMed  PubMed Central  Google Scholar 

  25. Wullt, B. et al. Urodynamic factors influence the duration of Escherichia coli bacteriuria in deliberately colonized cases. J. Urol. 159, 2057–2062 (1998).

    Article  CAS  PubMed  Google Scholar 

  26. Hull, R. et al. Urinary tract infection prophylaxis using Escherichia coli 83972 in spinal cord injured patients. J. Urol. 163, 872–877 (2000).

    Article  CAS  PubMed  Google Scholar 

  27. Sunden, F., Hakansson, L., Ljunggren, E. & Wullt, B. Escherichia coli 83972 bacteriuria protects against recurrent lower urinary tract infections in patients with incomplete bladder emptying. J. Urol. 184, 179–185 (2010).

    Article  PubMed  Google Scholar 

  28. Wullt, B. et al. P fimbriae enhance the early establishment of Escherichia coli in the human urinary tract. Mol. Microbiol. 38, 456–464 (2000).

    Article  CAS  PubMed  Google Scholar 

  29. Ragnarsdottir, B. et al. Reduced toll-like receptor 4 expression in children with asymptomatic bacteriuria. J. Infect. Dis. 196, 475–484 (2007).

    Article  CAS  PubMed  Google Scholar 

  30. Zdziarski, J. et al. Host imprints on bacterial genomes--rapid, divergent evolution in individual patients. PLoS Pathog. 6, e1001078 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Lidin, J. G. et al. Comparison of Escherichia coli from bacteriuric patients with those from feces of healthy schoolchildren. J. Infect. Dis. 136, 346–353 (1977).

    Article  Google Scholar 

  32. Svanborg, C., Hanson, L. A., Jodal, U., Lindberg, U. & Akerlund, A. S. 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 (1976).

    Article  Google Scholar 

  33. Cirl, C. et al. Subversion of Toll-like receptor signaling by a unique family of bacterial Toll/interleukin-1 receptor domain-containing proteins. Nat. Med. 14, 399–406 (2008).

    Article  CAS  PubMed  Google Scholar 

  34. Oelschlaeger, T. A., Dobrindt, U. & Hacker, J. Virulence factors of uropathogens. Curr. Opin. Urol. 12, 33–38 (2002).

    Article  PubMed  Google Scholar 

  35. Nielubowicz, G. R. & Mobley, H. L. Host-pathogen interactions in urinary tract infection. Nat. Rev. Urol. 7, 430–441 (2010).

    Article  CAS  PubMed  Google Scholar 

  36. Anderson, G. G. et al. Intracellular bacterial biofilm-like pods in urinary tract infections. Science 301, 105–107 (2003).

    Article  CAS  PubMed  Google Scholar 

  37. Justice, S. S., Hunstad, D. A., Seed, P. C. & Hultgren, S. J. Filamentation by Escherichia coli subverts innate defenses during urinary tract infection. Proc. Natl Acad. Sci. USA 103, 19884–19889 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Mysorekar, I. U. & Hultgren, S. J. Mechanisms of uropathogenic Escherichia coli persistence and eradication from the urinary tract. Proc. Natl Acad. Sci. USA 103, 14170–14175 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Zdziarski, J., Svanborg, C., Wullt, B., Hacker, J. & Dobrindt, U. Molecular basis of commensalism in the urinary tract: low virulence or virulence attenuation? Infect. Immun. 76, 695–703 (2008).

    Article  CAS  PubMed  Google Scholar 

  40. Roos, V., Schembri, M. A., Ulett, G. C. & Klemm, P. Asymptomatic bacteriuria Escherichia coli strain 83972 carries mutations in the foc locus and is unable to express F1C fimbriae. Microbiology 152, 1799–1806 (2006).

    Article  CAS  PubMed  Google Scholar 

  41. Hedlund, M. et al. P fimbriae-dependent, lipopolysaccharide-independent activation of epithelial cytokine responses. Mol. Microbiol. 33, 693–703 (1999).

    Article  CAS  PubMed  Google Scholar 

  42. Samuelsson, P., Hang, L., Wullt, B., Irjala, H. & Svanborg, C. Toll-like receptor 4 expression and cytokine responses in the human urinary tract mucosa. Infect. Immun. 72, 3179–3186 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Garmendia, J., Frankel, G. & Crepin, V. F. Enteropathogenic and enterohemorrhagic Escherichia coli infections: translocation, translocation, translocation. Infect. Immun. 73, 2573–2585 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Mellies, J. L., Barron, A. M. & Carmona, A. M. Enteropathogenic and enterohemorrhagic Escherichia coli virulence gene regulation. Infect. Immun. 75, 4199–4210 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Viswanathan, V. K., Hodges, K. & Hecht, G. Enteric infection meets intestinal function: how bacterial pathogens cause diarrhoea. Nat. Rev. Microbiol. 7, 110–119 (2009).

    Article  CAS  PubMed  Google Scholar 

  46. Leffler, H. & Svanborg-Edén, C. Chemical identification of a glycosphingolipid receptor for Escherichia coli attaching to human urinary tract epithelial cells and agglutinating human erythrocytes. FEMS Microbiol. Lett. 8, 127–134 (1980).

    Article  CAS  Google Scholar 

  47. Svanborg-Edén, C., Hanson, L., Jodal, U., Lindberg, U. & Sohl-Åkelund, A. Variable adherence to normal urinary tract epithelial cells of Escherichia coli strains associated with various forms of urinary tract infection. Lancet 1, 490–492 (1976).

    Article  Google Scholar 

  48. Leffler, H. & Svanborg-Edén, C. Glycolipid receptors for uropathogenic Escherichia coli on human erythrocytes and uroepithelial cells. Infect. Immun. 34, 920–929 (1981).

    CAS  PubMed  PubMed Central  Google Scholar 

  49. Plos, K. et al. Intestinal carriage of P fimbriated Escherichia coli and the susceptibility to urinary tract infection in young children. J. Infect. Dis. 171, 625–631 (1995).

    Article  CAS  PubMed  Google Scholar 

  50. Lindberg, F., Lund, B., Johansson, L. & Normark, S. Localization of the receptor-binding protein adhesin at the tip of the bacterial pilus. Nature 328, 84–87 (1987).

    Article  CAS  PubMed  Google Scholar 

  51. Linder, H., Engberg, I., Hoschültzky, H., Mattsby-Baltzer, I. & Svanborg, C. Adhesion-dependent activation of mucosal interleukin-6 production. Infect. Immun. 59, 4357–4362 (1991).

    CAS  PubMed  PubMed Central  Google Scholar 

  52. Bergsten, G. et al. PapG-dependent adherence breaks mucosal inertia and triggers the innate host response. J. Infect. Dis. 189, 1734–1742 (2004).

    Article  CAS  PubMed  Google Scholar 

  53. Hedlund, M., Nilsson, Å., Duan, R. D. & Svanborg, C. Sphingomyelin, glycosphingolipids and ceramide signalling in cells exposed to P fimbriated Escherichia coli. Mol. Microbiol. 29, 1297–1306 (1998).

    Article  CAS  PubMed  Google Scholar 

  54. Hedlund, M., Svensson, M., Nilsson, A., Duan, R. D. & Svanborg, C. Role of the ceramide-signaling pathway in cytokine responses to P-fimbriated Escherichia coli. J. Exp. Med. 183, 1037–1044 (1996).

    Article  CAS  PubMed  Google Scholar 

  55. Fischer, H. et al. Ceramide as a TLR4 agonist; a putative signalling intermediate between sphingolipid receptors for microbial ligands and TLR4. Cell. Microbiol. 9, 1239–1251 (2007).

    CAS  Google Scholar 

  56. Fischer, H. et al. Pathogen specific, IRF3-dependent signaling and innate resistance to human kidney infection. PLoS Pathog. 6, e1001109 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Godaly, G. et al. Neutrophil recruitment, chemokine receptors, and resistance to mucosal infection. J. Leukoc. Biol. 69, 899–906 (2001).

    CAS  PubMed  Google Scholar 

  58. Svanborg-Eden, C. et al. Bacterial virulence versus host resistance in the urinary tracts of mice. Infect. Immun. 55, 1224–1232 (1987).

    CAS  PubMed  PubMed Central  Google Scholar 

  59. Mobley, H. L., Chippendale, G. R., Tenney, J. H., Hull, R. A. & Warren, J. W. Expression of type 1 fimbriae may be required for persistence of Escherichia coli in the catheterized urinary tract. J. Clin. Microbiol. 25, 2253–2257 (1987).

    CAS  PubMed  PubMed Central  Google Scholar 

  60. Hultgren, S. J., Porter, T. N., Schaeffer, A. J. & Duncan, J. L. Role of type 1 pili and effects of phase variation on lower urinary tract infections produced by Escherichia coli. Infect. Immun. 50, 370–377 (1985).

    CAS  PubMed  PubMed Central  Google Scholar 

  61. Schaeffer, A. J., Schwan, W. R., Hultgren, S. J. & Duncan, J. L. Relationship of type 1 pilus expression in Escherichia coli to ascending urinary tract infections in mice. Infect. Immun. 55, 373–380 (1987).

    CAS  PubMed  PubMed Central  Google Scholar 

  62. Wold, A. et al. Secretory immunoglobulin-A carries oligosaccharide receptors for Escherichia coli type 1 fimbrial lectin. Infect. Immun. 58, 3073–3077 (1990).

    CAS  PubMed  PubMed Central  Google Scholar 

  63. Xie, B. et al. Distinct glycan structures of uroplakins Ia and Ib: structural basis for the selective binding of FimH adhesin to uroplakin Ia. J. Biol. Chem. 281, 14644–14653 (2006).

    Article  CAS  PubMed  Google Scholar 

  64. Malaviya, R., Gao, Z., Thankavel, K., van der Merwe, P. A. & Abraham, S. N. The mast cell tumor necrosis factor alpha response to FimH-expressing Escherichia coli is mediated by the glycosylphosphatidylinositol-anchored molecule CD48. Proc. Natl Acad. Sci. USA 96, 8110–8115 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. Eto, D. S., Jones, T. A., Sundsbak, J. L. & Mulvey, M. A. Integrin-mediated host cell invasion by type 1-piliated uropathogenic Escherichia coli. PLoS Pathog. 3, e100 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Pak, J., Pu, Y., Zhang, Z. T., Hasty, D. L. & Wu, X. R. Tamm-Horsfall protein binds to type 1 fimbriated Escherichia coli and prevents E. coli from binding to uroplakin Ia and Ib receptors. J. Biol. Chem. 276, 9924–9930 (2001).

    Article  CAS  PubMed  Google Scholar 

  67. Wright, K. J., Seed, P. C. & Hultgren, S. J. Development of intracellular bacterial communities of uropathogenic Escherichia coli depends on type 1 pili. Cell. Microbiol. 9, 2230–2241 (2007).

    Article  CAS  PubMed  Google Scholar 

  68. Mulvey, M. A., Schilling, J. D. & Hultgren, S. J. Establishment of a persistent Escherichia coli reservoir during the acute phase of a bladder infection. Infect. Immun. 69, 4572–4579 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Rosen, D. A., Hooton, T. M., Stamm, W. E., Humphrey, P. A. & Hultgren, S. J. Detection of intracellular bacterial communities in human urinary tract infection. PLoS Med. 4, e329 (2007).

    Article  PubMed  PubMed Central  Google Scholar 

  70. Shin, J. S., Gao, Z. & Abraham, S. N. Involvement of cellular caveolae in bacterial entry into mast cells. Science 289, 785–788 (2000).

    Article  CAS  PubMed  Google Scholar 

  71. Baorto, D. M. et al. Survival of FimH-expressing enterobacteria in macrophages relies on glycolipid traffic. Nature 389, 636–639 (1997).

    Article  CAS  PubMed  Google Scholar 

  72. Shin, J. S., Gao, Z. & Abraham, S. N. Bacteria-host cell interaction mediated by cellular cholesterol/glycolipid-enriched microdomains. Biosci. Rep. 19, 421–432 (1999).

    Article  CAS  PubMed  Google Scholar 

  73. McLean, G. W. et al. The role of focal-adhesion kinase in cancer—a new therapeutic opportunity. Nat. Rev. Cancer 5, 505–515 (2005).

    Article  CAS  PubMed  Google Scholar 

  74. Mulvey, M. A. et al. Induction and evasion of host defenses by type 1-piliated uropathogenic Escherichia coli. Science 282, 1494–1497 (1998).

    Article  CAS  PubMed  Google Scholar 

  75. Klumpp, D. J. et al. Uropathogenic Escherichia coli induces extrinsic and intrinsic cascades to initiate urothelial apoptosis. Infect. Immun. 74, 5106–5113 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  76. Thumbikat, P. et al. Bacteria-induced uroplakin signaling mediates bladder response to infection. PLoS Pathog. 5, e1000415 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. Bishop, B. L. et al. Cyclic AMP-regulated exocytosis of Escherichia coli from infected bladder epithelial cells. Nat. Med. 13, 625–630 (2007).

    Article  CAS  PubMed  Google Scholar 

  78. Backhed, F., Meijer, L., Normark, S. & Richter-Dahlfors, A. TLR4-dependent recognition of lipopolysaccharide by epithelial cells requires sCD14. Cell. Microbiol. 4, 493–501 (2002).

    Article  CAS  PubMed  Google Scholar 

  79. Hedlund, M. et al. Type 1 fimbriae deliver an LPS- and TLR4-dependent activation signal to CD14-negative cells. Mol. Microbiol. 39, 542–552 (2001).

    Article  CAS  PubMed  Google Scholar 

  80. Schilling, J. D., Mulvey, M. A., Vincent, C. D., Lorenz, R. G. & Hultgren, S. J. Bacterial invasion augments epithelial cytokine responses to Escherichia coli through a lipopolysaccharide-dependent mechanism. J. Immunol. 166, 1148–1155 (2001).

    Article  CAS  PubMed  Google Scholar 

  81. Song, J., Bishop, B. L., Li, G., Duncan, M. J. & Abraham, S. N. TLR4-initiated and cAMP-mediated abrogation of bacterial invasion of the bladder. Cell Host Microbe 1, 287–298 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  82. Bergsten, G., Wullt, B., Schembri, M. A., Leijonhufvud, I. & Svanborg, C. Do type 1 fimbriae promote inflammation in the human urinary tract? Cell. Microbiol. 9, 1766–1781 (2007).

    Article  CAS  PubMed  Google Scholar 

  83. Connell, H. et al. Type 1 fimbrial adhesion enhances Escherichia coli virulence for the urinary tract. Proc. Natl Acad. Sci. USA 93, 9827–9832 (1996).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  84. Frendeus, B., Godaly, G., Hang, L., Karpman, D. & Svanborg, C. Interleukin-8 receptor deficiency confers susceptibility to acute pyelonephritis. J. Infect. Dis. 183 (Suppl. 1), S56–S60 (2001).

    Article  CAS  PubMed  Google Scholar 

  85. Ragnarsdottir, B. et al. TLR- and CXCR1-dependent innate immunity: insights into the genetics of urinary tract infections. Eur. J. Clin. Invest. 38 (Suppl. 2), 12–20 (2008).

    Article  CAS  PubMed  Google Scholar 

  86. Justice, S. S. et al. Differentiation and developmental pathways of uropathogenic Escherichia coli in urinary tract pathogenesis. Proc. Natl Acad. Sci. USA 101, 1333–1338 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  87. Yadav, M. et al. Inhibition of TIR domain signaling by TcpC: MyD88-dependent and independent effects on Escherichia coli virulence. PLoS Pathog. 6, e1001120 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  88. Hang, L., Frendeus, B., Godaly, G. & Svanborg, C. Interleukin-8 receptor knockout mice have subepithelial neutrophil entrapment and renal scarring following acute pyelonephritis. J. Infect. Dis. 182, 1738–1748 (2000).

    Article  CAS  PubMed  Google Scholar 

  89. Svensson, M. et al. Natural history of renal scarring in susceptible mIL-8Rh−/− mice. Kidney Int. 67, 103–110 (2005).

    Article  PubMed  Google Scholar 

  90. Taniguchi, T., Ogasawara, K., Takaoka, A. & Tanaka, N. IRF family of transcription factors as regulators of host defense. Annu. Rev. Immunol. 19, 623–655 (2001).

    Article  CAS  PubMed  Google Scholar 

  91. Honda, K. & Taniguchi, T. IRFs: master regulators of signalling by Toll-like receptors and cytosolic pattern-recognition receptors. Nat. Rev. Immunol. 6, 644–658 (2006).

    Article  CAS  PubMed  Google Scholar 

  92. Godaly, G. et al. Role of fimbriae-mediated adherence for neutrophil migration across Escherichia coli-infected epithelial cell layers. Mol. Microbol. 30, 725–735 (1998).

    Article  CAS  Google Scholar 

  93. Otto, G., Burdick, M., Strieter, R. & Godaly, G. Chemokine response to febrile urinary tract infection. Kidney Int. 68, 62–70 (2005).

    Article  CAS  PubMed  Google Scholar 

  94. Agace, W. W., Hedges, S. R., Ceska, M. & Svanborg, C. Interleukin-8 and the neutrophil response to mucosal gram-negative infection. J. Clin. Invest. 92, 780–785 (1993).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  95. Svensson, M., Irjala, H., Svanborg, C. & Godaly, G. Effects of epithelial and neutrophil CXCR2 on innate immunity and resistance to kidney infection. Kidney Int. 74, 81–90 (2008).

    Article  CAS  PubMed  Google Scholar 

  96. Andersen-Nissen, E. et al. Cutting edge: Tlr5−/− mice are more susceptible to Escherichia coli urinary tract infection. J. Immunol. 178, 4717–4720 (2007).

    Article  CAS  PubMed  Google Scholar 

  97. Zhang, D. et al. A Toll-like receptor that prevents infection by uropathogenic bacteria. Science 303, 1522–1526 (2004).

    Article  CAS  PubMed  Google Scholar 

  98. Yarovinsky, F. et al. TLR11 activation of dendritic cells by a protozoan profilin-like protein. Science 308, 1626–1629 (2005).

    Article  CAS  PubMed  Google Scholar 

  99. Ørskov, F., Ørskov, I., Jann, B. & Jann, K. Tamm-Horsfall protein or uromucoid is the normal urinary slime that traps type 1 fimbriated Escherichia coli. Lancet 1, 887 (1980).

    Article  PubMed  Google Scholar 

  100. Cavallone, D., Malagolini, N. & Serafini-Cessi, F. Mechanism of release of urinary Tamm-Horsfall glycoprotein from the kidney GPI-anchored counterpart. Biochem. Biophys. Res. Commun. 280, 110–114 (2001).

    Article  CAS  PubMed  Google Scholar 

  101. Schmid, M. et al. Uromodulin facilitates neutrophil migration across renal epithelial monolayers. Cell. Physiol. Biochem. 26, 311–318 (2010).

    Article  CAS  PubMed  Google Scholar 

  102. Bates, J. M. et al. Tamm-Horsfall protein knockout mice are more prone to urinary tract infection: rapid communication. Kidney Int. 65, 791–797 (2004).

    Article  CAS  PubMed  Google Scholar 

  103. Raffi, H. S., Bates, J. M. Jr, Laszik, Z. & Kumar, S. Tamm-horsfall protein protects against urinary tract infection by proteus mirabilis. J. Urol. 181, 2332–2338 (2009).

    Article  PubMed  PubMed Central  Google Scholar 

  104. Dou, W. et al. Defective expression of Tamm-Horsfall protein/uromodulin in COX-2-deficient mice increases their susceptibility to urinary tract infections. Am. J. Physiol. Renal Physiol. 289, F49–F60 (2005).

    Article  CAS  PubMed  Google Scholar 

  105. El-Achkar, T. M., Plotkin, Z., Marcic, B. & Dagher, P. C. Sepsis induces an increase in thick ascending limb Cox-2 that is TLR4 dependent. Am. J. Physiol. Renal Physiol. 293, F1187–F1196 (2007).

    Article  CAS  PubMed  Google Scholar 

  106. Saemann, M. D. et al. Tamm-Horsfall glycoprotein links innate immune cell activation with adaptive immunity via a Toll-like receptor-4-dependent mechanism. J. Clin. Invest. 115, 468–475 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  107. Boman, H. Antibacterial peptides: key components needed in immunity. Cell 65, 205–207 (1991).

    Article  CAS  PubMed  Google Scholar 

  108. Chromek, M. et al. The antimicrobial peptide cathelicidin protects the urinary tract against invasive bacterial infection. Nat. Med. 12, 636–641 (2006).

    Article  CAS  PubMed  Google Scholar 

  109. Hawn, T. R. et al. A common dominant TLR5 stop codon polymorphism abolishes flagellin signaling and is associated with susceptibility to legionnaires' disease. J. Exp. Med. 198, 1563–1572 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  110. Hawn, T. R. et al. Toll-like receptor polymorphisms and susceptibility to urinary tract infections in adult women. PLoS ONE 4, e5990 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  111. Rehli, M. et al. PU.1 and interferon consensus sequence-binding protein regulate the myeloid expression of the human Toll-like receptor 4 gene. J. Biol. Chem. 275, 9773–9781 (2000).

    Article  CAS  PubMed  Google Scholar 

  112. Arbour, N. C. et al. TLR4 mutations are associated with endotoxin hyporesponsiveness in humans. Nat. Genet. 25, 187–191 (2000).

    Article  CAS  PubMed  Google Scholar 

  113. Allen, A. et al. Variation in Toll-like receptor 4 and susceptibility to group A meningococcal meningitis in Gambian children. Pediatr. Infect. Dis. J. 22, 1018–1019 (2003).

    Article  PubMed  Google Scholar 

  114. Read, R. C. et al. A functional polymorphism of toll-like receptor 4 is not associated with likelihood or severity of meningococcal disease. J. Infect. Dis. 184, 640–642 (2001).

    Article  CAS  PubMed  Google Scholar 

  115. Karoly, E. et al. Heat shock protein 72 (HSPA1B) gene polymorphism and Toll-like receptor (TLR) 4 mutation are associated with increased risk of urinary tract infection in children. Pediatr. Res. 61, 371–374 (2007).

    Article  CAS  PubMed  Google Scholar 

  116. Yin, X. et al. Association of Toll-like receptor 4 gene polymorphism and expression with urinary tract infection types in adults. PLoS ONE 5, e14223 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  117. Calvano, J. E. et al. Response to systemic endotoxemia among humans bearing polymorphisms of the Toll-like receptor 4 (hTLR4). Clin. Immunol. 121, 186–190 (2006).

    Article  CAS  PubMed  Google Scholar 

  118. Marsik, C. et al. The Toll-like receptor 4 Asp299Gly and Thr399Ile polymorphisms influence the late inflammatory response in human endotoxemia. Clin. Chem. 51, 2178–2180 (2005).

    Article  CAS  PubMed  Google Scholar 

  119. Ferwerda, B. et al. TLR4 polymorphisms, infectious diseases, and evolutionary pressure during migration of modern humans. Proc. Natl Acad. Sci. USA 104, 16645–16650 (2007).

    Article  PubMed  PubMed Central  Google Scholar 

  120. Lichtinger, M., Ingram, R., Hornef, M., Bonifer, C. & Rehli, M. Transcription factor PU.1 controls transcription start site positioning and alternative TLR4 promoter usage. J. Biol. Chem. 282, 26874–26883 (2007).

    Article  CAS  PubMed  Google Scholar 

  121. Roger, T. et al. Critical role for Ets, AP-1 and GATA-like transcription factors in regulating mouse Toll-like receptor 4 (Tlr4) gene expression. Biochem. J. 387, 355–365 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  122. Roger, T., David, J., Glauser, M. P. & Calandra, T. MIF regulates innate immune responses through modulation of Toll-like receptor 4. Nature 414, 920–924 (2001).

    Article  CAS  PubMed  Google Scholar 

  123. Hawn, T. R. et al. Genetic variation of the human urinary tract innate immune response and asymptomatic bacteriuria in women. PLoS ONE 4, e8300 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  124. Schroder, N. W. et al. Heterozygous Arg753Gln polymorphism of human TLR-2 impairs immune activation by Borrelia burgdorferi and protects from late stage Lyme disease. J. Immunol. 175, 2534–2540 (2005).

    Article  PubMed  Google Scholar 

  125. Holmes, W. E., Lee, J., Kuang, W. J., Rice, G. C. & Wood, W. I. Structure and functional expression of a human interleukin-8 receptor. Science 253, 1278–1280 (1991).

    Article  CAS  PubMed  Google Scholar 

  126. Murphy, P. M. & Tiffany, H. L. Cloning of complementary DNA encoding a functional human interleukin-8 receptor. Science 253, 1280–1283 (1991).

    Article  CAS  PubMed  Google Scholar 

  127. Murdoch, C. & Finn, A. Chemokine receptors and their role in inflammation and infectious diseases. Blood 95, 3032–3043 (2000).

    CAS  PubMed  Google Scholar 

  128. Artifoni, L. et al. Interleukin-8 and CXCR1 receptor functional polymorphisms and susceptibility to acute pyelonephritis. J. Urol. 177, 1102–1106 (2007).

    Article  CAS  PubMed  Google Scholar 

  129. Smithson., A. et al. Expression of interleukin-8 receptors (CXCR1 and CXCR2) in premenopausal women with recurrent urinary tract infections. Clin. Diagn. Lab. Immunol. 12, 1358–1363 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  130. Centi, S. et al. Upper urinary tract infections are associated with RANTES promoter polymorphism. J. Pediatr. 157, 1038–1040 e1 (2010).

    Article  CAS  PubMed  Google Scholar 

  131. Hussein, A., Askar, E., Elsaeid, M. & Schaefer, F. Functional polymorphisms in transforming growth factor-beta-1 (TGFβ1) and vascular endothelial growth factor (VEGF) genes modify risk of renal parenchymal scarring following childhood urinary tract infection. Nephrol. Dial. Transplant. 25, 779–785 (2010).

    Article  CAS  PubMed  Google Scholar 

  132. Grainger, D. J. et al. Genetic control of the circulating concentration of transforming growth factor type β1. Hum. Mol. Gen. 8, 93–97 (1999).

    Article  CAS  PubMed  Google Scholar 

  133. Cotton, S. A., Gbadegesin, R. A., Williams, S., Brenchley, P. E. & Webb, N. J. Role of TGF-β1 in renal parenchymal scarring following childhood urinary tract infection. Kidney Int. 61, 61–67 (2002).

    Article  CAS  PubMed  Google Scholar 

  134. Solari, V., Owen, D. & Puri, P. Association of transforming growth factor-β1 gene polymorphism with reflux nephropathy. J. Urol. 174, 1609–1611 (2005).

    Article  CAS  PubMed  Google Scholar 

  135. Yim, H. E., Bae, I. S., Yoo, K. H., Hong, Y. S. & Lee, J. W. Genetic control of VEGF and TGF-β1 gene polymorphisms in childhood urinary tract infection and vesicoureteral reflux. Pediatr. Res. 62, 183–187 (2007).

    Article  CAS  PubMed  Google Scholar 

  136. Hughes, L. B. et al. Genetic risk factors for infection in patients with early rheumatoid arthritis. Genes Immun. 5, 641–647 (2004).

    Article  CAS  PubMed  Google Scholar 

  137. Lundstedt, A. C. et al. Inherited susceptibility to acute pyelonephritis: a family study of urinary tract infection. J. Infect. Dis. 195, 1227–1234 (2007).

    Article  PubMed  Google Scholar 

  138. Scholes, D. et al. Risk factors for recurrent urinary tract infection in young women. J. Infect. Dis. 182, 1177–1182 (2000).

    Article  CAS  PubMed  Google Scholar 

  139. Stauffer, C. M. et al. Family history and behavioral abnormalities in girls with recurrent urinary tract infections: a controlled study. J. Urol. 171, 1663–1665 (2004).

    Article  PubMed  Google Scholar 

  140. Scholes, D. et al. Family history and risk of recurrent cystitis and pyelonephritis in women. J. Urol. 184, 564–569 (2010).

    Article  PubMed  PubMed Central  Google Scholar 

  141. Svenson, S. B. et al. P-fimbriae of pyelonephritogenic Escherichia coli: identification and chemical characterization of receptors. Infection 11, 61–67 (1983).

    Article  CAS  PubMed  Google Scholar 

  142. Lomberg, H., Jodal, U., Svanborg-Edén, C., Leffler, H. & Samuelsson, B. P1 blood group and urinary tract infection. Lancet 1, 551–552 (1981).

    Article  CAS  PubMed  Google Scholar 

  143. Lomberg, H. et al. Correlation of P blood group phenotype, vesicoureteral reflux and bacterial attachment in patients with recurrent pyelonephritis. N. Engl. J. Med. 308, 1189–1192 (1983).

    Article  CAS  PubMed  Google Scholar 

  144. Stapleton, A., Nudelman, E., Clausen, H., Hakomori, S. & Stamm, W. E. Binding of uropathogenic Escherichia coli R45 to glycolipids extracted from vaginal epithelial cells is dependent on histo-blood group secretor status. J. Clin. Invest. 90, 965–972 (1992).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  145. Lindstedt, R. et al. The receptor repertoire defines the host range for attaching Escherichia coli recognizing globo-A. Infect. Immun. 59, 1086–1092 (1991).

    CAS  PubMed  PubMed Central  Google Scholar 

  146. Svensson, M. et al. Carbohydrate receptor depletion as an antimicrobial strategy for prevention of urinary tract infection. J. Infect. Dis. 183 (Suppl. 1), S70–S73 (2001).

    Article  PubMed  Google Scholar 

  147. Svanborg Eden, C., Briles, D., Hagberg, L., McGhee, J. & Michalec, S. Genetic factors in host resistance to urinary tract infection. Infection 12, 118–123 (1984).

    Article  CAS  PubMed  Google Scholar 

  148. Hopkins, W. J., James, L. J., Balish, E. & Uehling, D. T. Congenital immunodeficiencies in mice increase susceptibility to urinary tract infection. J. Urol. 149, 922–925 (1993).

    Article  CAS  PubMed  Google Scholar 

  149. Jones-Carson, J., Balish, E. & Uehling, D. T. Susceptibility of immunodeficient gene-knockout mice to urinary tract infection. J. Urol. 161, 338–341 (1999).

    Article  CAS  PubMed  Google Scholar 

  150. Sivick, K. E., Schaller, M. A., Smith, S. N. & Mobley, H. L. The innate immune response to uropathogenic Escherichia coli involves IL-17A in a murine model of urinary tract infection. J. Immunol. 184, 2065–2075 (2010).

    Article  CAS  PubMed  Google Scholar 

  151. Hodson, C. J. & Edwards, D. Chronic pyelonephritis and vesico-ureteric reflex. Clin. Radiol. 11, 219–231 (1960).

    Article  CAS  PubMed  Google Scholar 

  152. Ransley, P. & Risdon, R. Reflux and renal scarring. Br. J. Radiol. 51, (Suppl. 14), 1–38 (1978).

    Google Scholar 

  153. Stokland, E., Hellstrom, M., Jacobsson, B., Jodal, U. & Sixt, R. Renal damage one year after first urinary tract infection: role of dimercaptosuccinic acid scintigraphy. J. Pediatr. 129, 815–820 (1996).

    Article  CAS  PubMed  Google Scholar 

  154. Stokland, E., Hellstrom, M., Jacobsson, B., Jodal, U. & Sixt, R. Evaluation of DMSA scintigraphy and urography in assessing both acute and permanent renal damage in children. Acta Radiologica 39, 447–452 (1998).

    Article  CAS  PubMed  Google Scholar 

  155. Kass, E. J., Kernen, K. M. & Carey, J. M. Paediatric urinary tract infection and the necessity of complete urological imaging. BJU Int. 86, 94–96 (2000).

    Article  CAS  PubMed  Google Scholar 

  156. Craig, J. C., Irwig, L. M., Knight, J. F. & Roy, L. P. Does treatment of vesicoureteric reflux in childhood prevent end-stage renal disease attributable to reflux nephropathy? Pediatrics 105, 1236–1241 (2000).

    Article  CAS  PubMed  Google Scholar 

  157. Lomberg, H., Hellström, M., Jodal, U. & Svanborg-Edén, C. Renal scarring and non-attaching bacteria. Lancet 2, 1341 (1986).

    Article  CAS  PubMed  Google Scholar 

  158. Hodson, C., Maling, T., McManamon, P. & Lewis, M. The pathogenesis of reflux nephropathy (chronic atrophic pyelonephritis). Br. J. Radiol. 48 (Suppl. 13), 1–26 (1975).

    Google Scholar 

  159. Mebust, W. K. & Foret, J. D. Vesicoureteral reflux in identical twins. J. Urol. 108, 635–636 (1972).

    Article  CAS  PubMed  Google Scholar 

  160. Nishimura, H. et al. Role of the angiotensin type 2 receptor gene in congenital anomalies of the kidney and urinary tract, CAKUT, of mice and men. Mol. Cell 3, 1–10 (1999).

    Article  CAS  PubMed  Google Scholar 

  161. Oshima, K. et al. Angiotensin type II receptor expression and ureteral budding. J. Urol. 166, 1848–1852 (2001).

    Article  CAS  PubMed  Google Scholar 

  162. Yu, O. H., Murawski, I. J., Myburgh, D. B. & Gupta, I. R. Overexpression of RET leads to vesicoureteric reflux in mice. Am. J. Physiol. Renal Physiol. 287, F1123–F1130 (2004).

    Article  CAS  PubMed  Google Scholar 

  163. Hu, P. et al. Ablation of uroplakin III gene results in small urothelial plaques, urothelial leakage, and vesicoureteral reflux. J. Cell Biol. 151, 961–972 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  164. Kong, X. T. et al. Roles of uroplakins in plaque formation, umbrella cell enlargement, and urinary tract diseases. J. Cell Biol. 167, 1195–1204 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  165. Yoneda, A., Cascio, S., Oue, T., Chertin, B. & Puri, P. Risk factors for the development of renal parenchymal damage in familial vesicoureteral reflux. J. Urol. 168, 1704–1707 (2002).

    Article  CAS  PubMed  Google Scholar 

  166. Savvidou, A. et al. Polymorphisms of the TNF-α and ACE genes, and renal scarring in infants with urinary tract infection. J. Urol. 183, 684–687 (2010).

    Article  CAS  PubMed  Google Scholar 

  167. Ozen, S. et al. Implications of certain genetic polymorphisms in scarring in vesicoureteric reflux: importance of ACE polymorphism. Am. J. Kidney Dis. 34, 140–145 (1999).

    Article  CAS  PubMed  Google Scholar 

  168. Haszon, I. et al. ACE gene polymorphism and renal scarring in primary vesicoureteric reflux. Pediatr. Nephrol. 17, 1027–1031 (2002).

    Article  PubMed  Google Scholar 

  169. Ohtomo, Y. et al. Angiotensin converting enzyme gene polymorphism in primary vesicoureteral reflux. Pediatr. Nephrol. 16, 648–652 (2001).

    Article  CAS  PubMed  Google Scholar 

  170. Rigoli, L. et al. Angiotensin-converting enzyme and angiotensin type 2 receptor gene genotype distributions in Italian children with congenital uropathies. Pediatr. Res. 56, 988–993 (2004).

    Article  CAS  PubMed  Google Scholar 

  171. Park, H. W. et al. Association of angiotensin I converting enzyme gene polymorphism with reflux nephropathy in children. Nephron 86, 52–55 (2000).

    Article  CAS  PubMed  Google Scholar 

  172. Ece, A., Tekes, S., Gurkan, F., Bilici, M. & Budak, T. Polymorphisms of the angiotensin converting enzyme and angiotensin II type 1 receptor genes and renal scarring in non-uropathic children with recurrent urinary tract infection. Nephrology (Carlton) 10, 377–381 (2005).

    Article  CAS  Google Scholar 

  173. Sekerli, E., Katsanidis, D., Vavatsi, N., Makedou, A. & Gatzola, M. ACE gene insertion/deletion polymorphism and renal scarring in children with urinary tract infections. Pediatr. Nephrol. 24, 1975–1980 (2009).

    Article  PubMed  Google Scholar 

  174. Liu, K. P., Lin, C. Y., Chen, H. J., Wei, C. F. & Lee-Chen, G. J. Renin-angiotensin system polymorphisms in Taiwanese primary vesicoureteral reflux. Pediatr. Nephrol. 19, 594–601 (2004).

    Article  PubMed  Google Scholar 

  175. Cho, S. J. & Lee, S. J. ACE gene polymorphism and renal scar in children with acute pyelonephritis. Pediatr. Nephrol. 17, 491–495 (2002).

    Article  PubMed  Google Scholar 

  176. Conte, M. L. et al. A genome search for primary vesicoureteral reflux shows further evidence for genetic heterogeneity. Pediatr. Nephrol. 23, 587–595 (2008).

    Article  PubMed  PubMed Central  Google Scholar 

  177. Cordell, H. J. et al. Whole-genome linkage and association scan in primary, nonsyndromic vesicoureteric reflux. J. Am. Soc. Nephrol. 21, 113–123 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  178. Lore, F., Talidis, F., Di Cairano, G. & Renieri, A. Multiple endocrine neoplasia type 2 syndromes may be associated with renal malformations. J. Int. Med. 250, 37–42 (2001).

    Article  CAS  Google Scholar 

  179. Yang, Y., Houle, A. M., Letendre, J. & Richter, A. RET Gly691Ser mutation is associated with primary vesicoureteral reflux in the French-Canadian population from Quebec. Hum. Mutat. 29, 695–702 (2008).

    Article  CAS  PubMed  Google Scholar 

  180. Darlow, J. M., Molloy, N. H., Green, A. J., Puri, P. & Barton, D. E. The increased incidence of the RET p.Gly691Ser variant in French-Canadian vesicoureteric reflux patients is not replicated by a larger study in Ireland. Hum. Mutat. 30, E612–E617 (2009).

    Article  PubMed  Google Scholar 

  181. Jenkins, D. et al. Mutation analyses of uroplakin II in children with renal tract malformations. Nephrol. Dial. Transplant. 21, 3415–3421 (2006).

    Article  CAS  PubMed  Google Scholar 

  182. Jenkins, D. et al. De novo uroplakin IIIa heterozygous mutations cause human renal adysplasia leading to severe kidney failure. J. Am. Soc. Nephrol. 16, 2141–2149 (2005).

    Article  CAS  PubMed  Google Scholar 

  183. Kelly, H. et al. Uroplakin III is not a major candidate gene for primary vesicoureteral reflux. Eur. J. Hum. Genet. 13, 500–502 (2005).

    Article  CAS  PubMed  Google Scholar 

  184. Haraoka, M. et al. Neutrophil recruitment and resistance to urinary tract infection. J. Infect. Dis. 180, 1220–1229 (1999).

    Article  CAS  PubMed  Google Scholar 

  185. Hopkins, W., Gendron-Fitzpatrick, A., McCarthy, D. O., Haine, J. E. & Uehling, D. T. Lipopolysaccharide-responder and nonresponder C3H mouse strains are equally susceptible to an induced Escherichia coli urinary tract infection. Infect. Immun. 64, 1369–1372 (1996).

    CAS  PubMed  PubMed Central  Google Scholar 

  186. Mo, L. et al. Ablation of the Tamm-Horsfall protein gene increases susceptibility of mice to bladder colonization by type 1-fimbriated Escherichia coli. Am. J. Physiol. Renal Physiol. 286, F795–F802 (2004).

    Article  CAS  PubMed  Google Scholar 

  187. Tabel, Y., Berdeli, A. & Mir, S. Association of TLR2 gene Arg753Gln polymorphism with urinary tract infection in children. Int. J. Immunogenet. 34, 399–405 (2007).

    Article  CAS  PubMed  Google Scholar 

  188. Yim, H. E. et al. Genetic polymorphism of the renin-angiotensin system on the development of primary vesicoureteral reflux. Am. J. Nephrol. 24, 178–187 (2004).

    Article  CAS  PubMed  Google Scholar 

  189. Spasojevic-Dimitrijeva, B., Zivkovic, M., Stankovic, A., Stojkovic, L. & Kostic, M. The IL-6 −174G/C polymorphism and renal scarring in children with first acute pyelonephritis. Pediatr. Nephrol. 25, 2099–2106 (2010).

    Article  PubMed  Google Scholar 

  190. Lee-Chen, G. J. et al. Significance of the tissue kallikrein promoter and transforming growth factor-β1 polymorphisms with renal progression in children with vesicoureteral reflux. Kidney Int. 65, 1467–1472 (2004).

    Article  CAS  PubMed  Google Scholar 

  191. Kowalewska-Pietrzak, M., Klich, I. & Mlynarski, W. TGF-β1 gene polymorphisms and primary vesicoureteral reflux in childhood. Pediatr. Nephrol. 23, 2195–2200 (2008).

    Article  PubMed  Google Scholar 

  192. Kuroda, S., Solari, V. & Puri, P. Association of transforming growth factor-β1 gene polymorphism with familial vesicoureteral reflux. J. Urol. 178, 1650–1653 (2007).

    Article  CAS  PubMed  Google Scholar 

  193. Jiang, S. et al. Lack of major involvement of human uroplakin genes in vesicoureteral reflux: implications for disease heterogeneity. Kidney Int. 66, 10–19 (2004).

    Article  CAS  PubMed  Google Scholar 

  194. Kuroda, S. & Puri, P. Lack of association of IL8 gene polymorphisms with familial vesico-ureteral reflux. Pediatr. Surg. Int. 23, 441–445 (2007).

    Article  PubMed  Google Scholar 

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All authors researched data for the article. B. Ragnarsdóttir and C. Svanborg made equal contributions to discussions of the article. B. Ragnarsdóttir, N. Lutay, and B. Köves and C. Svanborg wrote the article. B. Ragnarsdóttir, N. Lutay and C. Svanborg reviewed and edited the manuscript.

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Ragnarsdóttir, B., Lutay, N., Grönberg-Hernandez, J. et al. Genetics of innate immunity and UTI susceptibility. Nat Rev Urol 8, 449–468 (2011). https://doi.org/10.1038/nrurol.2011.100

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