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.

References

  1. 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. 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).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  3. 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  Google Scholar 

  4. 4

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

    CAS  Article  Google Scholar 

  5. 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).

    CAS  Article  Google Scholar 

  6. 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. 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. 8

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

    CAS  Article  Google Scholar 

  9. 9

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

    CAS  Article  Google Scholar 

  10. 10

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

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  11. 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).

    CAS  Article  Google Scholar 

  12. 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. 13

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

    Article  Google Scholar 

  14. 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).

    CAS  Article  PubMed  Google Scholar 

  15. 15

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

    CAS  Article  Google Scholar 

  16. 16

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

    Article  Google Scholar 

  17. 17

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

    CAS  Article  Google Scholar 

  18. 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).

    CAS  Article  Google Scholar 

  19. 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).

    CAS  Article  Google Scholar 

  20. 20

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

    CAS  PubMed  Google Scholar 

  21. 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. 22

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

    CAS  Article  Google Scholar 

  23. 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. 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. 25

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

    CAS  Article  Google Scholar 

  26. 26

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

    CAS  Article  Google Scholar 

  27. 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  Google Scholar 

  28. 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).

    CAS  Article  Google Scholar 

  29. 29

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

    CAS  Article  Google Scholar 

  30. 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. 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. 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. 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).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  34. 34

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

    Article  Google Scholar 

  35. 35

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

    CAS  Article  PubMed  Google Scholar 

  36. 36

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

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  37. 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).

    CAS  Article  Google Scholar 

  38. 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).

    CAS  Article  Google Scholar 

  39. 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).

    CAS  Article  Google Scholar 

  40. 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).

    CAS  Article  Google Scholar 

  41. 41

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

    CAS  Article  Google Scholar 

  42. 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).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  43. 43

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

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  44. 44

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

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  45. 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).

    CAS  Article  Google Scholar 

  46. 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).

    CAS  Article  Google Scholar 

  47. 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. 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. 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).

    CAS  Article  Google Scholar 

  50. 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).

    CAS  Article  Google Scholar 

  51. 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. 52

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

    CAS  Article  Google Scholar 

  53. 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).

    CAS  Article  Google Scholar 

  54. 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).

    CAS  Article  Google Scholar 

  55. 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. 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. 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. 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. 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. 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. 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. 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. 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).

    CAS  Article  Google Scholar 

  64. 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).

    CAS  Article  Google Scholar 

  65. 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. 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).

    CAS  Article  Google Scholar 

  67. 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).

    CAS  Article  Google Scholar 

  68. 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).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  69. 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. 70

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

    CAS  Article  Google Scholar 

  71. 71

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

    CAS  Article  Google Scholar 

  72. 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).

    CAS  Article  Google Scholar 

  73. 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).

    CAS  Article  Google Scholar 

  74. 74

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

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  75. 75

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

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  76. 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. 77

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

    CAS  Article  Google Scholar 

  78. 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).

    CAS  Article  Google Scholar 

  79. 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).

    CAS  Article  Google Scholar 

  80. 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).

    CAS  Article  Google Scholar 

  81. 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).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  82. 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).

    CAS  Article  Google Scholar 

  83. 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).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  84. 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).

    CAS  Article  Google Scholar 

  85. 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).

    CAS  Article  Google Scholar 

  86. 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).

    CAS  Article  Google Scholar 

  87. 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. 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).

    CAS  Article  Google Scholar 

  89. 89

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

    Article  Google Scholar 

  90. 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).

    CAS  Article  Google Scholar 

  91. 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).

    CAS  Article  Google Scholar 

  92. 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).

    CAS  Article  Google Scholar 

  93. 93

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

    CAS  Article  Google Scholar 

  94. 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).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  95. 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).

    CAS  Article  Google Scholar 

  96. 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).

    CAS  Article  Google Scholar 

  97. 97

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

    CAS  Article  Google Scholar 

  98. 98

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

    CAS  Article  Google Scholar 

  99. 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  Google Scholar 

  100. 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).

    CAS  Article  Google Scholar 

  101. 101

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

    CAS  Article  Google Scholar 

  102. 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).

    CAS  Article  Google Scholar 

  103. 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. 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).

    CAS  Article  Google Scholar 

  105. 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).

    CAS  Article  Google Scholar 

  106. 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. 107

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

    CAS  Article  Google Scholar 

  108. 108

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

    CAS  Article  Google Scholar 

  109. 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).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  110. 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. 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).

    CAS  Article  Google Scholar 

  112. 112

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

    CAS  Article  PubMed  Google Scholar 

  113. 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  Google Scholar 

  114. 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).

    CAS  Article  Google Scholar 

  115. 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).

    CAS  Article  Google Scholar 

  116. 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).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  117. 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).

    CAS  Article  Google Scholar 

  118. 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).

    CAS  Article  Google Scholar 

  119. 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  Google Scholar 

  120. 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).

    CAS  Article  Google Scholar 

  121. 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).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  122. 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).

    CAS  Article  Google Scholar 

  123. 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. 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  Google Scholar 

  125. 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).

    CAS  Article  Google Scholar 

  126. 126

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

    CAS  Article  Google Scholar 

  127. 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. 128

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

    CAS  Article  Google Scholar 

  129. 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. 130

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

    CAS  Article  Google Scholar 

  131. 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).

    CAS  Article  Google Scholar 

  132. 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).

    CAS  Article  Google Scholar 

  133. 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).

    CAS  Article  Google Scholar 

  134. 134

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

    CAS  Article  Google Scholar 

  135. 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).

    CAS  Article  Google Scholar 

  136. 136

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

    CAS  Article  Google Scholar 

  137. 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  Google Scholar 

  138. 138

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

    CAS  Article  Google Scholar 

  139. 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  Google Scholar 

  140. 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. 141

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

    CAS  Article  Google Scholar 

  142. 142

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

    CAS  Article  Google Scholar 

  143. 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).

    CAS  Article  Google Scholar 

  144. 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).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  145. 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. 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  Google Scholar 

  147. 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).

    CAS  Article  Google Scholar 

  148. 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).

    CAS  Article  Google Scholar 

  149. 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).

    CAS  Article  Google Scholar 

  150. 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).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  151. 151

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

    CAS  Article  Google Scholar 

  152. 152

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

    Google Scholar 

  153. 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).

    CAS  Article  Google Scholar 

  154. 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).

    CAS  Article  Google Scholar 

  155. 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).

    CAS  Article  Google Scholar 

  156. 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).

    CAS  Article  Google Scholar 

  157. 157

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

    CAS  Article  Google Scholar 

  158. 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. 159

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

    CAS  Article  Google Scholar 

  160. 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).

    CAS  Article  Google Scholar 

  161. 161

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

    CAS  Article  Google Scholar 

  162. 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).

    CAS  Article  Google Scholar 

  163. 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).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  164. 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).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  165. 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).

    CAS  Article  Google Scholar 

  166. 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).

    CAS  Article  Google Scholar 

  167. 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).

    CAS  Article  Google Scholar 

  168. 168

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

    Article  Google Scholar 

  169. 169

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

    CAS  Article  Google Scholar 

  170. 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).

    CAS  Article  Google Scholar 

  171. 171

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

    CAS  Article  Google Scholar 

  172. 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).

    CAS  Article  Google Scholar 

  173. 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  Google Scholar 

  174. 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  Google Scholar 

  175. 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  Google Scholar 

  176. 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. 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).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  178. 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).

    CAS  Article  Google Scholar 

  179. 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).

    CAS  Article  Google Scholar 

  180. 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  Google Scholar 

  181. 181

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

    CAS  Article  Google Scholar 

  182. 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).

    CAS  Article  Google Scholar 

  183. 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).

    CAS  Article  Google Scholar 

  184. 184

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

    CAS  Article  Google Scholar 

  185. 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. 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).

    CAS  Article  Google Scholar 

  187. 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).

    CAS  Article  Google Scholar 

  188. 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).

    CAS  Article  Google Scholar 

  189. 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  Google Scholar 

  190. 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).

    CAS  Article  Google Scholar 

  191. 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  Google Scholar 

  192. 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).

    CAS  Article  Google Scholar 

  193. 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).

    CAS  Article  Google Scholar 

  194. 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  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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