Innate immunity and urinary tract infection

  • Christina Ching
  • Laura Schwartz
  • John David Spencer
  • Brian BecknellEmail author
Educational Review


Urinary tract infections are a severe public health problem. The emergence and spread of antimicrobial resistance among uropathogens threaten to further compromise the quality of life and health of people who develop acute and recurrent upper and lower urinary tract infections. The host defense mechanisms that prevent invasive bacterial infection are not entirely delineated. However, recent evidence suggests that versatile innate immune defenses play a key role in shielding the urinary tract from invading uropathogens. Over the last decade, considerable advances have been made in defining the innate mechanisms that maintain immune homeostasis in the kidney and urinary tract. When these innate defenses are compromised or dysregulated, pathogen susceptibility increases. The objective of this review is to provide an overview of how basic science discoveries are elucidating essential innate host defenses in the kidney and urinary tract. In doing so, we highlight how these findings may ultimately translate into the clinic as new biomarkers or therapies for urinary tract infection.


Urinary tract infection Innate immunity Pyelonephritis Pattern recognition receptors Cytokines Antimicrobial peptides 


Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflict of interest.


  1. 1.
    Shaikh N, Morone NE, Bost JE, Farrell MH (2008) Prevalence of urinary tract infection in childhood: a meta-analysis. Pediatr Infect Dis J 27:302–308CrossRefGoogle Scholar
  2. 2.
    Zasloff M (2007) Antimicrobial peptides, innate immunity, and the normally sterile urinary tract. J Am Soc Nephrol 18:2810–2816CrossRefGoogle Scholar
  3. 3.
    Spencer JD, Schwaderer AL, Becknell B, Watson J, Hains DS (2014) The innate immune response during urinary tract infection and pyelonephritis. Pediatr Nephrol 29:1139–1149CrossRefGoogle Scholar
  4. 4.
    Hato T, Dagher PC (2015) How the innate immune system senses trouble and causes trouble. Clin J Am Soc Nephrol 10:1459–1469CrossRefGoogle Scholar
  5. 5.
    Becknell B, Schwaderer A, Hains DS, Spencer JD (2015) Amplifying renal immunity: the role of antimicrobial peptides in pyelonephritis. Nat Rev Nephrol 11:642–655CrossRefGoogle Scholar
  6. 6.
    Bogdan C, Rollinghoff M, Diefenbach A (2000) Reactive oxygen and reactive nitrogen intermediates in innate and specific immunity. Curr Opin Immunol 12:64–76CrossRefGoogle Scholar
  7. 7.
    Stapleton AE (2014) Urinary tract infection pathogenesis: host factors. Infect Dis Clin N Am 28:149–159CrossRefGoogle Scholar
  8. 8.
    Takeuchi O, Akira S (2010) Pattern recognition receptors and inflammation. Cell 140:805–820CrossRefGoogle Scholar
  9. 9.
    Chowdhury P, Sacks SH, Sheerin NS (2004) Minireview: functions of the renal tract epithelium in coordinating the innate immune response to infection. Kidney Int 66:1334–1344CrossRefGoogle Scholar
  10. 10.
    Song J, Abraham SN (2008) TLR-mediated immune responses in the urinary tract. Curr Opin Microbiol 11:66–73CrossRefGoogle Scholar
  11. 11.
    Behzadi E, Behzadi P (2016) The role of toll-like receptors (TLRs) in urinary tract infections (UTIs). Cent European J Urol 69:404–410Google Scholar
  12. 12.
    Poltorak A, He X, Smirnova I, Liu MY, Van Huffel C, Du X, Birdwell D, Alejos E, Silva M, Galanos C, Freudenberg M, Ricciardi-Castagnoli P, Layton B, Beutler B (1998) Defective LPS signaling in C3H/HeJ and C57BL/10ScCr mice: mutations in Tlr4 gene. Science 282:2085–2088CrossRefGoogle Scholar
  13. 13.
    Weichhart T, Haidinger M, Horl WH, Saemann MD (2008) Current concepts of molecular defence mechanisms operative during urinary tract infection. Eur J Clin Investig 38(Suppl 2):29–38CrossRefGoogle Scholar
  14. 14.
    Schilling JD, Martin SM, Hunstad DA, Patel KP, Mulvey MA, Justice SS, Lorenz RG, Hultgren SJ (2003) CD14- and Toll-like receptor-dependent activation of bladder epithelial cells by lipopolysaccharide and type 1 piliated Escherichia coli. Infect Immun 71:1470–1480CrossRefGoogle Scholar
  15. 15.
    Schilling JD, Martin SM, Hung CS, Lorenz RG, Hultgren SJ (2003) Toll-like receptor 4 on stromal and hematopoietic cells mediates innate resistance to uropathogenic Escherichia coli. Proc Natl Acad Sci U S A 100:4203–4208CrossRefGoogle Scholar
  16. 16.
    Bens M, Vimont S, Ben Mkaddem S, Chassin C, Goujon JM, Balloy V, Chignard M, Werts C, Vandewalle A (2014) Flagellin/TLR5 signalling activates renal collecting duct cells and facilitates invasion and cellular translocation of uropathogenic Escherichia coli. Cell Microbiol 16:1503–1517CrossRefGoogle Scholar
  17. 17.
    Chassin C, Vimont S, Cluzeaud F, Bens M, Goujon JM, Fernandez B, Hertig A, Rondeau E, Arlet G, Hornef MW, Vandewalle A (2008) TLR4 facilitates translocation of bacteria across renal collecting duct cells. J Am Soc Nephrol 19:2364–2374CrossRefGoogle Scholar
  18. 18.
    Ragnarsdottir B, Fischer H, Godaly G, Gronberg-Hernandez J, Gustafsson M, Karpman D, Lundstedt AC, Lutay N, Ramisch S, Svensson ML, Wullt B, Yadav M, Svanborg C (2008) TLR- and CXCR1-dependent innate immunity: insights into the genetics of urinary tract infections. Eur J Clin Investig 38(Suppl 2):12–20CrossRefGoogle Scholar
  19. 19.
    Leifer CA, Medvedev AE (2016) Molecular mechanisms of regulation of Toll-like receptor signaling. J Leukoc Biol 100:927–941CrossRefGoogle Scholar
  20. 20.
    Castro-Alarcon N, Rodriguez-Garcia R, Ruiz-Rosas M, Munoz-Valle JF, Guzman-Guzman IP, Parra-Rojas I, Vazquez-Villamar M (2019) Association between TLR4 polymorphisms (896 A>G, 1196 C>T, - 2570 A>G, - 2081 G>A) and virulence factors in uropathogenic Escherichia coli. Clin Exp Med 19:105–113CrossRefGoogle Scholar
  21. 21.
    Karoly E, Fekete A, Banki NF, Szebeni B, Vannay A, Szabo AJ, Tulassay T, Reusz GS (2007) 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 61:371–374CrossRefGoogle Scholar
  22. 22.
    Cirl C, Wieser A, Yadav M, Duerr S, Schubert S, Fischer H, Stappert D, Wantia N, Rodriguez N, Wagner H, Svanborg C, Miethke T (2008) Subversion of Toll-like receptor signaling by a unique family of bacterial Toll/interleukin-1 receptor domain-containing proteins. Nat Med 14:399–406CrossRefGoogle Scholar
  23. 23.
    Fischer H, Lutay N, Ragnarsdottir B, Yadav M, Jonsson K, Urbano A, Al Hadad A, Ramisch S, Storm P, Dobrindt U, Salvador E, Karpman D, Jodal U, Svanborg C (2010) Pathogen specific, IRF3-dependent signaling and innate resistance to human kidney infection. PLoS Pathog 6:e1001109CrossRefGoogle Scholar
  24. 24.
    Puthia M, Ambite I, Cafaro C, Butler D, Huang Y, Lutay N, Rydstrom G, Gullstrand B, Swaminathan B, Nadeem A, Nilsson B, Svanborg C (2016) IRF7 inhibition prevents destructive innate immunity-a target for nonantibiotic therapy of bacterial infections. Sci Transl Med 8:336ra59CrossRefGoogle Scholar
  25. 25.
    Abraham SN, Miao Y (2015) The nature of immune responses to urinary tract infections. Nat Rev Immunol 15:655–663CrossRefGoogle Scholar
  26. 26.
    Hannan TJ, Mysorekar IU, Hung CS, Isaacson-Schmid ML, Hultgren SJ (2010) Early severe inflammatory responses to uropathogenic E. coli predispose to chronic and recurrent urinary tract infection. PLoS Pathog 6:e1001042CrossRefGoogle Scholar
  27. 27.
    Schilling JD, Mulvey MA, Vincent CD, Lorenz RG, Hultgren SJ (2001) Bacterial invasion augments epithelial cytokine responses to Escherichia coli through a lipopolysaccharide-dependent mechanism. J Immunol 166:1148–1155CrossRefGoogle Scholar
  28. 28.
    Ragnarsdottir B, Svanborg C (2012) Susceptibility to acute pyelonephritis or asymptomatic bacteriuria: host-pathogen interaction in urinary tract infections. Pediatr Nephrol 27:2017–2029CrossRefGoogle Scholar
  29. 29.
    Ching CB, Gupta S, Li B, Cortado H, Mayne N, Jackson AR, McHugh KM, Becknell (2018) Interleukin-6/Stat3 signaling has an essential role in the host antimicrobial response to urinary tract infection. Kidney Int 93:1320–1329CrossRefGoogle Scholar
  30. 30.
    Khalil A, Tullus K, Bartfai T, Bakhiet M, Jaremko G, Brauner A (2000) Renal cytokine responses in acute Escherichia coli pyelonephritis in IL-6-deficient mice. Clin Exp Immunol 122:200–206CrossRefGoogle Scholar
  31. 31.
    Dixit A, Bottek J, Beerlage AL, Schuettpelz J, Thiebes S, Brenzel A, Garbers C, Rose-John S, Mittrucker HW, Squire A, Engel DR (2018) Frontline Science: Proliferation of Ly6C(+) monocytes during urinary tract infections is regulated by IL-6 trans-signaling. J Leukoc Biol 103:13–22Google Scholar
  32. 32.
    Owusu-Boaitey N, Bauckman KA, Zhang T, Mysorekar IU (2016) Macrophagic control of the response to uropathogenic E. coli infection by regulation of iron retention in an IL-6-dependent manner. Immun Inflamm Dis 4:413–426CrossRefGoogle Scholar
  33. 33.
    Agace W, Hedges S, Svanborg C (1992) Lps genotype in the C57 black mouse background and its influence on the interleukin-6 response to E. coli urinary tract infection. Scand J Immunol 35:531–538CrossRefGoogle Scholar
  34. 34.
    Rodriguez LM, Robles B, Marugan JM, Suarez A, Santos F (2008) Urinary interleukin-6 is useful in distinguishing between upper and lower urinary tract infections. Pediatr Nephrol 23:429–433CrossRefGoogle Scholar
  35. 35.
    Sheu JN, Chen MC, Chen SM, Chen SL, Chiou SY, Lue KH (2009) Relationship between serum and urine interleukin-6 elevations and renal scarring in children with acute pyelonephritis. Scand J Urol Nephrol 43:133–137CrossRefGoogle Scholar
  36. 36.
    Mizutani M, Hasegawa S, Matsushige T, Ohta N, Kittaka S, Hoshide M, Kusuda T, Takahashi K, Ichihara K, Ohga S (2017) Distinctive inflammatory profile between acute focal bacterial nephritis and acute pyelonephritis in children. Cytokine 99:24–29CrossRefGoogle Scholar
  37. 37.
    Godaly G, Hang L, Frendeus B, Svanborg C (2000) Transepithelial neutrophil migration is CXCR1 dependent in vitro and is defective in IL-8 receptor knockout mice. J Immunol 165:5287–5294CrossRefGoogle Scholar
  38. 38.
    Frendeus B, Godaly G, Hang L, Karpman D, Lundstedt AC, Svanborg C (2000) Interleukin 8 receptor deficiency confers susceptibility to acute experimental pyelonephritis and may have a human counterpart. J Exp Med 192:881–890CrossRefGoogle Scholar
  39. 39.
    Hang L, Frendeus B, Godaly G, Svanborg C (2000) Interleukin-8 receptor knockout mice have subepithelial neutrophil entrapment and renal scarring following acute pyelonephritis. J Infect Dis 182:1738–1748CrossRefGoogle Scholar
  40. 40.
    Han SS, Lu Y, Chen M, Xu YQ, Wang Y (2019) Association between interleukin 8-receptor gene (CXCR1 and CXCR2) polymorphisms and urinary tract infection: evidence from 4097 subjects. Nephrology (Carlton) 24:464–471CrossRefGoogle Scholar
  41. 41.
    Mahlapuu M, Hakansson J, Ringstad L, Bjorn C (2016) Antimicrobial peptides: an emerging category of therapeutic agents. Front Cell Infect Microbiol 6:194CrossRefGoogle Scholar
  42. 42.
    Morrison G, Kilanowski F, Davidson D, Dorin J (2003) Characterization of the mouse beta defensin 1, Defb1, mutant mouse model. Infect Immun 70:3053–3060CrossRefGoogle Scholar
  43. 43.
    Chromek M, Slamova Z, Bergman P, Kovacs L, Podracka L, Ehren I, Hokfelt T, Gudmundsson GH, Gallo RL, Agerberth B, Brauner A (2006) The antimicrobial peptide cathelicidin protects the urinary tract against invasive bacterial infection. Nat Med 12:636–641CrossRefGoogle Scholar
  44. 44.
    Murtha MJ, Eichler T, Bender K, Metheny J, Li B, Schwaderer AL, Mosquera C, James C, Schwartz L, Becknell B, Spencer JD (2018) Insulin receptor signaling regulates renal collecting duct and intercalated cell antibacterial defenses. J Clin Invest 128:5634–5646CrossRefGoogle Scholar
  45. 45.
    Spencer JD, Schwaderer AL, Dirosario JD, McHugh KM, McGillivary G, Justice SS, Carpenter AR, Baker PB, Harder J, Hains DS (2011) Ribonuclease 7 is a potent antimicrobial peptide within the human urinary tract. Kidney Int 80:174–180CrossRefGoogle Scholar
  46. 46.
    Paragas N, Kulkarni R, Werth M, Schmidt-Ott KM, Forster C, Deng R, Zhang Q, Singer E, Klose AD, Shen TH, Francis KP, Ray S, Vijayakumar S, Seward S, Bovino ME, Xu K, Takabe Y, Amaral FE, Mohan S, Wax R, Corbin K, Sanna-Cherchi S, Mori K, Johnson L, Nickolas T, D’Agati V, Lin CS, Qiu A, Al-Awgati Q, Ratner AJ, Barasch J (2014) alpha-Intercalated cells defend the urinary system from bacterial infection. J Clin Invest 124:2963–2976CrossRefGoogle Scholar
  47. 47.
    Steigedal M, Marstad A, Haug M, Damas JK, Strong RK, Roberts PL, Himpsl SD, Stapleton A, Hooton TM, Mobley HL, Hawn TR, Flo TH (2014) Lipocalin 2 imparts selective pressure on bacterial growth in the bladder and is elevated in women with urinary tract infection. J Immunol 193:6081–6089CrossRefGoogle Scholar
  48. 48.
    Houamel D, Ducrot N, Lefebvre T, Daher R, Moulouel B, Sari MA, Letteron P, Lyoumi S, Millot S, Tourret J, Bouvet O, Vaulont S, Vandewalle A, Denamur E, Puy H, Beaumont C, Gouya L, Karim Z (2016) Hepcidin as a major component of renal antibacterial defenses against uropathogenic Escherichia coli. J Am Soc Nephrol 27:835–846CrossRefGoogle Scholar
  49. 49.
    Kulaksiz H, Theilig F, Bachmann S, Gehrke SG, Rost D, Janetzko A, Cetin Y, Stremmel W (2005) The iron-regulatory peptide hormone hepcidin: expression and cellular localization in the mammalian kidney. J Endocrinol 184:361–370CrossRefGoogle Scholar
  50. 50.
    Bates JM, Raffi HM, Prasadan K, Mascarenhas R, Laszik Z, Maeda N, Hultgren SJ, Kumar S (2004) Tamm-Horsfall protein knockout mice are more prone to urinary tract infection: rapid communication. Kidney Int 65:791–797CrossRefGoogle Scholar
  51. 51.
    Raqib R, Sarker P, Bergman P, Ara G, Lindh M, Sack DA, Nasirul Islam KM, Gudmundsson GH, Andersson J, Agerberth B (2006) Improved outcome in shigellosis associated with butyrate induction of an endogenous peptide antibiotic. Proc Natl Acad Sci U S A 103:9178–9183CrossRefGoogle Scholar
  52. 52.
    Steinmann J, Halldorsson S, Agerberth B, Gudmundsson GH (2009) Phenylbutyrate induces antimicrobial peptide expression. Antimicrob Agents Chemother 53:5127–5133CrossRefGoogle Scholar
  53. 53.
    Park K, Kim YI, Shin KO, Seo HS, Kim JY, Mann T, Oda Y, Lee YM, Holleran WM, Elias PM, Uchida Y (2014) The dietary ingredient, genistein, stimulates cathelicidin antimicrobial peptide expression through a novel S1P-dependent mechanism. J Nutr Biochem 25:734–740CrossRefGoogle Scholar
  54. 54.
    Schwaderer AL, Wang H, Kim S, Kline JM, Liang D, Brophy PD, McHugh KM, Tseng GC, Saxena V, Barr-Beare E, Pierce KR, Shaikh N, Manak JR, Cohen DM, Becknell B, Spencer JD, Baker PB, Yu CY, Hains DS (2016) Polymorphisms in alpha-defensin-encoding DEFA1A3 associate with urinary tract infection risk in children with vesicoureteral reflux. J Am Soc Nephrol 27:3175–3186CrossRefGoogle Scholar
  55. 55.
    Watson JR, Hains DS, Cohen DM, Spencer JD, Kline JM, Yin H, Schwaderer AL (2016) Evaluation of novel urinary tract infection biomarkers in children. Pediatr Res 79:934–939CrossRefGoogle Scholar
  56. 56.
    Forster CS, Johnson K, Patel V, Wax R, Rodig N, Barasch J, Bachur R, Lee RS (2017) Urinary NGAL deficiency in recurrent urinary tract infections. Pediatr Nephrol 32:1077–1080CrossRefGoogle Scholar
  57. 57.
    Lubell TR, Barasch JM, Xu K, Ieni M, Cabrera KI, Dayan PS (2017) Urinary neutrophil gelatinase-associated Lipocalin for the diagnosis of urinary tract infections. Pediatrics 140:e20171090CrossRefGoogle Scholar
  58. 58.
    Liu Y, Memet S, Saban R, Kong X, Aprikian P, Sokurenko E, Sun TT, Wu XR (2015) Dual ligand/receptor interactions activate urothelial defenses against uropathogenic E. coli. Sci Rep 5:16234CrossRefGoogle Scholar
  59. 59.
    Song J, Bishop BL, Li G, Grady R, Stapleton A, Abraham SN (2009) TLR4-mediated expulsion of bacteria from infected bladder epithelial cells. Proc Natl Acad Sci U S A 106:14966–14971CrossRefGoogle Scholar
  60. 60.
    Choi HW, Bowen SE, Miao Y, Chan CY, Miao EA, Abrink M, Moeser AJ, Abraham SN (2016) Loss of bladder epithelium induced by cytolytic mast cell granules. Immunity 45:1258–1269CrossRefGoogle Scholar
  61. 61.
    Mysorekar IU, Isaacson-Schmid M, Walker JN, Mills JC, Hultgren SJ (2009) Bone morphogenetic protein 4 signaling regulates epithelial renewal in the urinary tract in response to uropathogenic infection. Cell Host Microbe 5:463–475CrossRefGoogle Scholar
  62. 62.
    Berry MR, Mathews RJ, Ferdinand JR, Jing C, Loudon KW, Wlodek E, Dennison TW, Kuper C, Neuhofer W, Clatworthy MR (2017) Renal sodium gradient orchestrates a dynamic antibacterial defense zone. Cell 170:860–874 e19CrossRefGoogle Scholar
  63. 63.
    Haraoka M, Hang L, Frendeus B, Godaly G, Burdick M, Strieter R, Svanborg C (1999) Neutrophil recruitment and resistance to urinary tract infection. J Infect Dis 180:1220–1229CrossRefGoogle Scholar
  64. 64.
    Hannan TJ, Roberts PL, Riehl TE, van der Post S, Binkley JM, Schwartz DJ, Miyoshi H, Mack M, Schwendener RA, Hooton TM, Stappenbeck TS, Hansson GC, Stenson WF, Colonna M, Stapleton AE, Hultgren SJ (2014) Inhibition of cyclooxygenase-2 prevents chronic and recurrent cystitis. EBioMedicine 1:46–57CrossRefGoogle Scholar
  65. 65.
    Schiwon M, Weisheit C, Franken L, Gutweiler S, Dixit A, Meyer-Schwesinger C, Pohl JM, Maurice NJ, Thiebes S, Lorenz K, Quast T, Fuhrmann M, Baumgarten G, Lohse MJ, Opdenakker G, Bernhagen J, Bucala R, Panzer U, Kolanus W, Grone HJ, Garbi N, Kastenmuller W, Knolle PA, Kurts C, Engel DR (2014) Crosstalk between sentinel and helper macrophages permits neutrophil migration into infected uroepithelium. Cell 156:456–468CrossRefGoogle Scholar
  66. 66.
    Gur C, Coppenhagen-Glazer S, Rosenberg S, Yamin R, Enk J, Glasner A, Bar-On Y, Fleissig O, Naor R, Abed J, Mevorach D, Granot Z, Bachrach G, Mandelboim O (2013) Natural killer cell-mediated host defense against uropathogenic E. coli is counteracted by bacterial hemolysinA-dependent killing of NK cells. Cell Host Microbe 14:664–674CrossRefGoogle Scholar
  67. 67.
    Minagawa S, Ohyama C, Hatakeyama S, Tsuchiya N, Kato T, Habuchi T (2005) Activation of natural killer T cells by alpha-galactosylceramide mediates clearance of bacteria in murine urinary tract infection. J Urol 173:2171–2174CrossRefGoogle Scholar
  68. 68.
    Malaviya R, Ikeda T, Ross E, Abraham SN (1996) Mast cell modulation of neutrophil influx and bacterial clearance at sites of infection through TNF-alpha. Nature 381:77–80CrossRefGoogle Scholar
  69. 69.
    Malaviya R, Ikeda T, Abraham SN, Malaviya R (2004) Contribution of mast cells to bacterial clearance and their proliferation during experimental cystitis induced by type 1 fimbriated E. coli. Immunol Lett 91:103–111CrossRefGoogle Scholar
  70. 70.
    Hains DS, Chen X, Saxena V, Barr-Beare E, Flemming W, Easterling R, Becknell B, Schwartz GJ, Schwaderer AL (2014) Carbonic anhydrase 2 deficiency leads to increased pyelonephritis susceptibility. Am J Physiol Renal Physiol 307:F869–F880CrossRefGoogle Scholar
  71. 71.
    Eichler TE, Becknell B, Easterling RS, Ingraham SE, Cohen DM, Schwaderer AL, Hains DS, Li B, Cohen A, Metheny J, Tridandapani S, Spencer JD (2016) Insulin and the phosphatidylinositol 3-kinase signaling pathway regulate Ribonuclease 7 expression in the human urinary tract. Kidney Int 90:568–579CrossRefGoogle Scholar
  72. 72.
    Isaacson B, Hadad T, Glasner A, Gur C, Granot Z, Bachrach G, Mandelboim O (2017) Stromal cell-derived factor 1 mediates immune cell attraction upon urinary tract infection. Cell Rep 20:40–47CrossRefGoogle Scholar

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© IPNA 2019

Authors and Affiliations

  1. 1.Nephrology and Urology Research Affinity GroupNationwide Children’s HospitalColumbusUSA
  2. 2.Center of Clinical and Translational ResearchThe Research Institute at Nationwide Children’s HospitalColumbusUSA
  3. 3.Division of UrologyNationwide Children’s HospitalColumbusUSA
  4. 4.Division of Pediatric NephrologyNationwide Children’s HospitalColumbusUSA

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