The bladder is continuously protected by passive defences such as a mucus layer, antimicrobial peptides and secretory immunoglobulins; however, these defences are occasionally overcome by invading bacteria that can induce a strong host inflammatory response in the bladder. The urothelium and resident immune cells produce additional defence molecules, cytokines and chemokines, which recruit inflammatory cells to the infected tissue. Resident and recruited immune cells act together to eradicate bacteria from the bladder and to develop lasting immune memory against infection. However, urinary tract infection (UTI) is commonly recurrent, suggesting that the induction of a memory response in the bladder is inadequate to prevent reinfection. Additionally, infection seems to induce long-lasting changes in the urothelium, which can render the tissue more susceptible to future infection. The innate immune response is well-studied in the field of UTI, but considerably less is known about how adaptive immunity develops and how repair mechanisms restore bladder homeostasis following infection. Furthermore, data demonstrate that sex-based differences in immunity affect resolution and infection can lead to tissue remodelling in the bladder following resolution of UTI. To combat the rise in antimicrobial resistance, innovative therapeutic approaches to bladder infection are currently in development. Improving our understanding of how the bladder responds to infection will support the development of improved treatments for UTI, particularly for those at risk of recurrent infection.
The bladder contains constitutive passive defences, such as mucus and immunoglobulins, to protect it against colonization.
Robust cytokine expression and inflammatory cell infiltration into the bladder during urinary tract infection are dependent on bacterial species and sex.
Uropathogenic Escherichia coli induces a non-sterilizing adaptive immune response in the bladder.
Uropathogenic Escherichia coli causes long-lasting changes in the bladder urothelium, conferring resistance or increased susceptibility to subsequent infections depending on the outcomes of the first infection.
Vaccines and other non-antibiotic-based therapies in development might provide therapeutic relief to those suffering from recurrent or chronic urinary tract infection.
Subscribe to Journal
Get full journal access for 1 year
only $17.42 per issue
All prices are NET prices.
VAT will be added later in the checkout.
Rent or Buy article
Get time limited or full article access on ReadCube.
All prices are NET prices.
Ozturk, R. & Murt, A. Epidemiology of urological infections: a global burden. World J. Urol. https://doi.org/10.1007/s00345-019-03071-4 (2020).
Flores-Mireles, A. L., Walker, J. N., Caparon, M. & Hultgren, S. J. Urinary tract infections: epidemiology, mechanisms of infection and treatment options. Nat. Rev. Microbiol. 13, 269–284 (2015).
Odegaard, J. I. & Hsieh, M. H. Immune responses to Schistosoma haematobium infection. Parasite Immunol. 36, 428–438 (2014).
Sobel, J. D., Fisher, J. F., Kauffman, C. A. & Newman, C. A. Candida urinary tract infections — epidemiology. Clin. Infect. Dis. 52, S433–S436 (2011).
Foxman, B. The epidemiology of urinary tract infection. Nat. Rev. Urol. 7, 653–660 (2010).
Wagenlehner, F. et al. The global prevalence of infections in urology study: a long-term, worldwide surveillance study on urological infections. Pathogens 5, 10 (2016).
Bryce, A. et al. Global prevalence of antibiotic resistance in paediatric urinary tract infections caused by Escherichia coli and association with routine use of antibiotics in primary care: systematic review and meta-analysis. BMJ 352, i939 (2016).
Johnson, J. R., Johnston, B., Clabots, C., Kuskowski, M. A. & Castanheira, M. Escherichia coli sequence type ST131 as the major cause of serious multidrug-resistant E. coli infections in the United States. Clin. Infect. Dis. 51, 286–294 (2010).
Rijavec, M. et al. High prevalence of multidrug resistance and random distribution of mobile genetic elements among uropathogenic Escherichia coli (UPEC) of the four major phylogenetic groups. Curr. Microbiol. 53, 158–162 (2006).
Hickling, D. R., Sun, T. T. & Wu, X. R. Anatomy and physiology of the urinary tract: relation to host defense and microbial infection. Microbiol. Spectr. 3, 10 (2015).
Katouli, M. Population structure of gut Escherichia coli and its role in development of extra-intestinal infections. Iran. J. Microbiol. 2, 59–72 (2010).
Hooton, T. M. Recurrent urinary tract infection in women. Int. J. Antimicrob. Agents 17, 259–268 (2001).
Russo, T. A., Stapleton, A., Wenderoth, S., Hooton, T. M. & Stamm, W. E. Chromosomal restriction fragment length polymorphism analysis of Escherichia coli strains causing recurrent urinary tract infections in young women. J. Infect. Dis. 172, 440–445 (1995).
Wold, A. E., Caugant, D. A., Lidin-Janson, G., de Man, P. & Svanborg, C. Resident colonic Escherichia coli strains frequently display uropathogenic characteristics. J. Infect. Dis. 165, 46–52 (1992).
Chen, S. L. et al. Genomic diversity and fitness of E. coli strains recovered from the intestinal and urinary tracts of women with recurrent urinary tract infection. Sci. Transl Med. 5, 184ra160 (2013).
Ingersoll, M. A. & Albert, M. L. From infection to immunotherapy: host immune responses to bacteria at the bladder mucosa. Mucosal Immunol. 6, 1041–1053 (2013).
Geerlings, S. E. Clinical presentations and epidemiology of urinary tract infections. Microbiol. Spectr. 4, 1–11 (2016).
Foxman, B. Urinary tract infection syndromes: occurrence, recurrence, bacteriology, risk factors, and disease burden. Infect. Dis. Clin. North. Am. 28, 1–13 (2014).
Scholes, D. et al. Family history and risk of recurrent cystitis and pyelonephritis in women. J. Urol. 184, 564–569 (2010).
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).
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).
Lundstedt, A. C. et al. A genetic basis of susceptibility to acute pyelonephritis. PLoS One 2, e825 (2007).
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).
Ramakrishnan, K. & Scheid, D. C. Diagnosis and management of acute pyelonephritis in adults. Am. Fam. Physician 71, 933–942 (2005).
Wagenlehner, F. M., Pilatz, A., Naber, K. G. & Weidner, W. Therapeutic challenges of urosepsis. Eur. J. Clin. Invest. 38, 45–49 (2008).
Armbruster, C. E. & Mobley, H. L. Merging mythology and morphology: the multifaceted lifestyle of Proteus mirabilis. Nat. Rev. Microbiol. 10, 743–754 (2012).
Nielubowicz, G. R. & Mobley, H. L. Host–pathogen interactions in urinary tract infection. Nat. Rev. Urol. 7, 430–441 (2010).
Delzell, J. E. Jr & Lefevre, M. L. Urinary tract infections during pregnancy. Am. Fam. Physician 61, 713–721 (2000).
Stenqvist, K. et al. Bacteriuria in pregnancy. Frequency and risk of acquisition. Am. J. Epidemiol. 129, 372–379 (1989).
Goswami, R. et al. Prevalence of urinary tract infection and renal scars in patients with diabetes mellitus. Diabetes Res. Clin. Pract. 53, 181–186 (2001).
Jacobsen, S. M., Stickler, D. J., Mobley, H. L. & Shirtliff, M. E. Complicated catheter-associated urinary tract infections due to Escherichia coli and Proteus mirabilis. Clin. Microbiol. Rev. 21, 26–59 (2008).
Rousseau, M. et al. Bladder catheterization increases susceptibility to infection that can be prevented by prophylactic antibiotic treatment. JCI Insight 1, e88178 (2016).
Flores-Mireles, A. L., Pinkner, J. S., Caparon, M. G. & Hultgren, S. J. EbpA vaccine antibodies block binding of Enterococcus faecalis to fibrinogen to prevent catheter-associated bladder infection in mice. Sci. Transl Med. 6, 254ra127 (2014).
Al-Hazmi, H. Role of duration of catheterization and length of hospital stay on the rate of catheter-related hospital-acquired urinary tract infections. Res. Rep. Urol. 7, 41–47 (2015).
Hooton, T. M. et al. Diagnosis, prevention, and treatment of catheter-associated urinary tract infection in adults: 2009 international clinical practice guidelines from the Infectious Diseases Society of America. Clin. Infect. Dis. 50, 625–663 (2010).
Maharjan, G., Khadka, P., Siddhi Shilpakar, G., Chapagain, G. & Dhungana, G. R. Catheter-associated urinary tract infection and obstinate biofilm producers. Can. J. Infect. Dis. Med. Microbiol. 2018, 7624857 (2018).
Maki, D. G. & Tambyah, P. A. Engineering out the risk for infection with urinary catheters. Emerg. Infect. Dis. 7, 342–347 (2001).
Schelling, K. et al. Reducing catheter-associated urinary tract infections in a neuro-spine intensive care unit. Am. J. Infect. Control. 43, 892–894 (2015).
Lipsky, B. A. Urinary tract infections in men. Epidemiology, pathophysiology, diagnosis, and treatment. Ann. Intern. Med. 110, 138–150 (1989).
Harper, M. & Fowlis, G. 3. Management of urinary tract infections in men. Trends Urol. Gynaecol. Sex. Health 12, 30–35 (2007).
Price, T. K. et al. The clinical urine culture: enhanced techniques improve detection of clinically relevant microorganisms. J. Clin. Microbiol. 54, 1216–1222 (2016).
Brecher, S. M. Complicated urinary tract infections: what’s a Lab To Do? J. Clin. Microbiol. 54, 1189–1190 (2016).
Franz, M. & Horl, W. H. Common errors in diagnosis and management of urinary tract infection. I. Pathophysiology and diagnostic techniques. Nephrol. Dial. Transpl. 14, 2746–2753 (1999).
Bartoletti, R. et al. European Association of Urology guidelines - urological infections. EAU https://uroweb.org/guideline/urological-infections/ (2016).
Tandan, M., Duane, S., Cormican, M., Murphy, A. W. & Vellinga, A. Reconsultation and antimicrobial treatment of urinary tract infection in male and female patients in general practice. Antibiotics 5, 31 (2016).
Drekonja, D. M., Rector, T. S., Cutting, A. & Johnson, J. R. Urinary tract infection in male veterans: treatment patterns and outcomes. JAMA Intern. Med. 173, 62–68 (2013).
Trautner, B. W. New perspectives on urinary tract infection in men. JAMA Intern. Med. 173, 68–70 (2013).
Germanos, G. J. et al. No clinical benefit to treating male urinary tract infection longer than seven days: an outpatient database study. Open Forum Infect. Dis. 6, ofz216 (2019).
Ruben, F. L. et al. Clinical infections in the noninstitutionalized geriatric age group: methods utilized and incidence of infections. The Pittsburgh Good Health Study. Am. J. Epidemiol. 141, 145–157 (1995).
Krieger, J. N. et al. Epidemiology of prostatitis. Int. J. Antimicrob. Agents 31, S85–S90 (2008).
Schaeffer, A. J. Epidemiology and demographics of prostatitis. Andrologia 35, 252–257 (2003).
Wagenlehner, F. M., Weidner, W., Pilatz, A. & Naber, K. G. Urinary tract infections and bacterial prostatitis in men. Curr. Opin. Infect. Dis. 27, 97–101 (2014).
Meares, E. M. Jr. & Stamey, T. A. The diagnosis and management of bacterial prostatitis. Br. J. Urol. 44, 175–179 (1972).
Lupo, F. & Ingersoll, M. A. Is bacterial prostatitis a urinary tract infection? Nat. Rev. Urol. 16, 203–204 (2019).
Trautner, B. W. Asymptomatic bacteriuria: when the treatment is worse than the disease. Nat. Rev. Urol. 9, 85–93 (2012).
Cai, T. et al. The role of asymptomatic bacteriuria in young women with recurrent urinary tract infections: to treat or not to treat? Clin. Infect. Dis. 55, 771–777 (2012).
Werner, N. L., Hecker, M. T., Sethi, A. K. & Donskey, C. J. Unnecessary use of fluoroquinolone antibiotics in hospitalized patients. BMC Infect. Dis. 11, 187 (2011).
Mora-Bau, G. et al. Macrophages subvert adaptive immunity to urinary tract infection. PLoS Pathog. 11, e1005044 (2015).
Hu, P. et al. Role of membrane proteins in permeability barrier function: uroplakin ablation elevates urothelial permeability. Am. J. Physiol. Renal Physiol 283, F1200–F1207 (2002).
Liang, F. X. et al. Organization of uroplakin subunits: transmembrane topology, pair formation and plaque composition. Biochem. J. 355, 13–18 (2001).
Negrete, H. O., Lavelle, J. P., Berg, J., Lewis, S. A. & Zeidel, M. L. Permeability properties of the intact mammalian bladder epithelium. Am. J. Physiol. 271, F886–F894 (1996).
Hurst, R. E. Structure, function, and pathology of proteoglycans and glycosaminoglycans in the urinary tract. World J. Urol. 12, 3–10 (1994).
Sihra, N., Goodman, A., Zakri, R., Sahai, A. & Malde, S. Nonantibiotic prevention and management of recurrent urinary tract infection. Nat. Rev. Urol. 15, 750–776 (2018).
Wu, X. R., Sun, T. T. & Medina, J. J. In vitro binding of type 1-fimbriated Escherichia coli to uroplakins Ia and Ib: relation to urinary tract infections. Proc. Natl Acad. Sci. USA 93, 9630–9635 (1996).
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).
Mulvey, M. A. et al. Induction and evasion of host defenses by type 1-piliated uropathogenic Escherichia coli. Science 282, 1494–1497 (1998).
Cornish, J., Lecamwasam, J. P., Harrison, G., Vanderwee, M. A. & Miller, T. E. Host defence mechanisms in the bladder. II. Disruption of the layer of mucus. Br. J. Exp. Pathol. 69, 759–770 (1988).
Parsons, C. L. The role of the urinary epithelium in the pathogenesis of interstitial cystitis/prostatitis/urethritis. Urology 69, 9–16 (2007).
Parsons, C. L., Mulholland, S. G. & Anwar, H. Antibacterial activity of bladder surface mucin duplicated by exogenous glycosaminoglycan (heparin). Infect. Immun. 24, 552–557 (1979).
Parsons, C. L., Pollen, J. J., Anwar, H., Stauffer, C. & Schmidt, J. D. Antibacterial activity of bladder surface mucin duplicated in the rabbit bladder by exogenous glycosaminoglycan (sodium pentosanpolysulfate). Infect. Immun. 27, 876–881 (1980).
Ruggieri, M. R., Hanno, P. M. & Levin, R. M. The effects of heparin on the adherence of five species of urinary tract pathogens to urinary bladder mucosa. Urol. Res. 12, 199–203 (1984).
Serafini-Cessi, F., Malagolini, N. & Cavallone, D. Tamm-horsfall glycoprotein: biology and clinical relevance. Am. J. Kidney Dis. 42, 658–676 (2003).
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).
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).
Lanne, B. et al. Glycoconjugate receptors for P-fimbriated Escherichia coli in the mouse. An animal model of urinary tract infection. J. Biol. Chem. 270, 9017–9025 (1995).
James-Ellison, M. Y., Roberts, R., Verrier-Jones, K., Williams, J. D. & Topley, N. Mucosal immunity in the urinary tract: changes in sIgA, FSC and total IgA with age and in urinary tract infection. Clin. Nephrol. 48, 69–78 (1997).
Mestecky, J. & McGhee, J. R. Immunoglobulin A (IgA): molecular and cellular interactions involved in IgA biosynthesis and immune response. Adv. Immunol. 40, 153–245 (1987).
Corthesy, B. Role of secretory IgA in infection and maintenance of homeostasis. Autoimmun. Rev. 12, 661–665 (2013).
Mathias, A., Pais, B., Favre, L., Benyacoub, J. & Corthesy, B. Role of secretory IgA in the mucosal sensing of commensal bacteria. Gut Microbes 5, 688–695 (2014).
Mantis, N. J., Rol, N. & Corthesy, B. Secretory IgA’s complex roles in immunity and mucosal homeostasis in the gut. Mucosal Immunol. 4, 603–611 (2011).
Pastorello, I. et al. EsiB, a novel pathogenic Escherichia coli secretory immunoglobulin A-binding protein impairing neutrophil activation. MBio 4, e00206–13 (2013).
Zychlinsky Scharff, A. et al. Sex differences in IL-17 contribute to chronicity in male versus female urinary tract infection. JCI Insight 5, e122998 (2019).
Artis, D. & Spits, H. The biology of innate lymphoid cells. Nature 517, 293–301 (2015).
Klose, C. S. & Artis, D. Innate lymphoid cells as regulators of immunity, inflammation and tissue homeostasis. Nat. Immunol. 17, 765–774 (2016).
Gagliani, N. & Huber, S. Basic aspects of T helper cell differentiation. Methods Mol. Biol. 1514, 19–30 (2017).
Chevalier, M. F. et al. ILC2-modulated T cell-to-MDSC balance is associated with bladder cancer recurrence. J. Clin. Invest. 127, 2916–2929 (2017).
Gardiner, R. A. et al. Immunohistochemical analysis of the human bladder. Br. J. Urol. 58, 19–25 (1986).
el-Demiry, M. I., Hargreave, T. B., Busuttil, A., James, K. & Chisholm, G. D. Immunohistochemical identification of lymphocyte subsets and macrophages in normal human urothelium using monoclonal antibodies. Br. J. Urol. 58, 436–442 (1986).
Hart, D. N. & Fabre, J. W. Major histocompatibility complex antigens in rat kidney, ureter, and bladder. Localization with monoclonal antibodies and demonstration of Ia-positive dendritic cells. Transplantation 31, 318–325 (1981).
Hjelm, E., Forsum, U. & Klareskog, L. Anti-Ia-reactive cells in the urinary tract of man, guinea-pig, rat and mouse. Scand. J. Immunol. 16, 531–538 (1982).
Hung, C. S., Dodson, K. W. & Hultgren, S. J. A murine model of urinary tract infection. Nat. Protoc. 4, 1230–1243 (2009).
Zychlinsky Scharff, A., Albert, M. L. & Ingersoll, M. A. Urinary tract infection in a small animal model: transurethral catheterization of male and female mice. J. Vis. Exp. https://doi.org/10.3791/54432 (2017).
Olson, P. D., Hruska, K. A. & Hunstad, D. A. Androgens enhance male urinary tract infection severity in a new model. J. Am. Soc. Nephrol. 27, 1625–1634 (2016).
Ingersoll, M. A. Sex differences shape the response to infectious diseases. PLoS Pathog. 13, e1006688 (2017).
Rosen, D. A. et al. Molecular variations in Klebsiella pneumoniae and Escherichia coli FimH affect function and pathogenesis in the urinary tract. Infect. Immun. 76, 3346–3356 (2008).
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).
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).
Anderson, G. G. et al. Intracellular bacterial biofilm-like pods in urinary tract infections. Science 301, 105–107 (2003).
Thumbikat, P. et al. Bacteria-induced uroplakin signaling mediates bladder response to infection. PLoS Pathog. 5, e1000415 (2009).
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).
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).
Bishop, B. L. et al. Cyclic AMP-regulated exocytosis of Escherichia coli from infected bladder epithelial cells. Nat. Med. 13, 625–630 (2007).
Apodaca, G. Stretch-regulated exocytosis of discoidal vesicles in urinary bladder epithelium. Urology 57, 103–104 (2001).
Song, J. et al. A novel TLR4-mediated signaling pathway leading to IL-6 responses in human bladder epithelial cells. PLoS Pathog. 3, e60 (2007).
Song, J. et al. TLR4-mediated expulsion of bacteria from infected bladder epithelial cells. Proc. Natl Acad. Sci. USA 106, 14966–14971 (2009).
Miao, Y., Li, G., Zhang, X., Xu, H. & Abraham, S. N. A TRP channel senses lysosome neutralization by pathogens to trigger their expulsion. Cell 161, 1306–1319 (2015).
Cadwell, K. et al. Virus-plus-susceptibility gene interaction determines Crohn’s disease gene Atg16L1 phenotypes in intestine. Cell 141, 1135–1145 (2010).
Cadwell, K. et al. A key role for autophagy and the autophagy gene Atg16l1 in mouse and human intestinal Paneth cells. Nature 456, 259–263 (2008).
Wang, C. et al. Atg16L1 deficiency confers protection from uropathogenic Escherichia coli infection in vivo. Proc. Natl Acad. Sci. USA 109, 11008–11013 (2012).
Hampe, J. et al. A genome-wide association scan of nonsynonymous SNPs identifies a susceptibility variant for Crohn disease in ATG16L1. Nat. Genet. 39, 207–211 (2007).
Wang, C. et al. A non-canonical autophagy-dependent role of the ATG16L1(T300A) variant in urothelial vesicular trafficking and uropathogenic Escherichia coli persistence. Autophagy 15, 527–542 (2019).
Martin-Sanchez, D. et al. Cell death-based approaches in treatment of the urinary tract-associated diseases: a fight for survival in the killing fields. Cell Death Dis. 9, 118 (2018).
Lauzier, A. et al. Colorectal cancer cells respond differentially to autophagy inhibition in vivo. Sci. Rep. 9, 11316 (2019).
Valore, E. V. et al. Human beta-defensin-1: an antimicrobial peptide of urogenital tissues. J. Clin. Invest. 101, 1633–1642 (1998).
Zasloff, M. The antibacterial shield of the human urinary tract. Kidney Int. 83, 548–550 (2013).
Jaillon, S. et al. The humoral pattern recognition molecule PTX3 is a key component of innate immunity against urinary tract infection. Immunity 40, 621–632 (2014).
Becknell, B. et al. Ribonucleases 6 and 7 have antimicrobial function in the human and murine urinary tract. Kidney Int. 87, 151–161 (2015).
Spencer, J. D. et al. Ribonuclease 7, an antimicrobial peptide upregulated during infection, contributes to microbial defense of the human urinary tract. Kidney Int. 83, 615–625 (2013).
Spencer, J. D. et al. An endogenous ribonuclease inhibitor regulates the antimicrobial activity of ribonuclease 7 in the human urinary tract. Kidney Int. 85, 1179–1191 (2014).
Boix, E. & Nogues, M. V. Mammalian antimicrobial proteins and peptides: overview on the RNase A superfamily members involved in innate host defence. Mol. Biosyst. 3, 317–335 (2007).
Huang, Y. C. et al. The flexible and clustered lysine residues of human ribonuclease 7 are critical for membrane permeability and antimicrobial activity. J. Biol. Chem. 282, 4626–4633 (2007).
Spencer, J. D. et al. Ribonuclease 7 is a potent antimicrobial peptide within the human urinary tract. Kidney Int. 80, 174–180 (2011).
Durr, U. H., Sudheendra, U. S. & Ramamoorthy, A. LL-37, the only human member of the cathelicidin family of antimicrobial peptides. Biochim. Biophys. Acta 1758, 1408–1425 (2006).
Gallo, R. L. et al. Identification of CRAMP, a cathelin-related antimicrobial peptide expressed in the embryonic and adult mouse. J. Biol. Chem. 272, 13088–13093 (1997).
Chromek, M. et al. The antimicrobial peptide cathelicidin protects the urinary tract against invasive bacterial infection. Nat. Med. 12, 636–641 (2006).
Nielsen, K. L. et al. Role of urinary cathelicidin LL-37 and human beta-defensin 1 in uncomplicated Escherichia coli urinary tract infections. Infect. Immun. 82, 1572–1578 (2014).
Spencer, J. D., Schwaderer, A. L., Becknell, B., Watson, J. & Hains, D. S. The innate immune response during urinary tract infection and pyelonephritis. Pediatr. Nephrol. 29, 1139–1149 (2014).
Ihi, T., Nakazato, M., Mukae, H. & Matsukura, S. Elevated concentrations of human neutrophil peptides in plasma, blood, and body fluids from patients with infections. Clin. Infect. Dis. 25, 1134–1140 (1997).
Spencer, J. D. et al. Human alpha defensin 5 expression in the human kidney and urinary tract. PLoS One 7, e31712 (2012).
Becknell, B. et al. Expression and antimicrobial function of beta-defensin 1 in the lower urinary tract. PLoS One 8, e77714 (2013).
Zhao, J., Wang, Z., Chen, X., Wang, J. & Li, J. Effects of intravesical liposome-mediated human beta-defensin-2 gene transfection in a mouse urinary tract infection model. Microbiol. Immunol. 55, 217–223 (2011).
Gomes, A. C., Moreira, A. C., Mesquita, G. & Gomes, M. S. Modulation of iron metabolism in response to infection: twists for all tastes. Pharmaceuticals 11, 84 (2018).
Robinson, A. E., Heffernan, J. R. & Henderson, J. P. The iron hand of uropathogenic Escherichia coli: the role of transition metal control in virulence. Future Microbiol. 13, 745–756 (2018).
Garcia, E. C., Brumbaugh, A. R. & Mobley, H. L. Redundancy and specificity of Escherichia coli iron acquisition systems during urinary tract infection. Infect. Immun. 79, 1225–1235 (2011).
Henderson, J. P. et al. Quantitative metabolomics reveals an epigenetic blueprint for iron acquisition in uropathogenic Escherichia coli. PLoS Pathog. 5, e1000305 (2009).
Hagan, E. C. & Mobley, H. L. Haem acquisition is facilitated by a novel receptor Hma and required by uropathogenic Escherichia coli for kidney infection. Mol. Microbiol. 71, 79–91 (2009).
Flo, T. H. et al. Lipocalin 2 mediates an innate immune response to bacterial infection by sequestrating iron. Nature 432, 917–921 (2004).
Patras, K. A. et al. Augmentation of urinary lactoferrin enhances host innate immune clearance of uropathogenic Escherichia coli. J. Innate Immun. 11, 481–495 (2019).
Arao, S. et al. Measurement of urinary lactoferrin as a marker of urinary tract infection. J. Clin. Microbiol. 37, 553–557 (1999).
Johnson, E. E. & Wessling-Resnick, M. Iron metabolism and the innate immune response to infection. Microbes Infect. 14, 207–216 (2012).
Steigedal, M. et al. Lipocalin 2 imparts selective pressure on bacterial growth in the bladder and is elevated in women with urinary tract infection. J. Immunol. 193, 6081–6089 (2014).
Cassat, J. E. & Skaar, E. P. Iron in infection and immunity. Cell Host Microbe 13, 509–519 (2013).
Bauckman, K. A. et al. Dietary restriction of iron availability attenuates UPEC pathogenesis in a mouse model of urinary tract infection. Am. J. Physiol. Renal Physiol. 316, F814–F822 (2019).
Houamel, D. et al. Hepcidin as a major component of renal antibacterial defenses against uropathogenic Escherichia coli. J. Am. Soc. Nephrol. 27, 835–846 (2016).
Lu, Y. C., Yeh, W. C. & Ohashi, P. S. LPS/TLR4 signal transduction pathway. Cytokine 42, 145–151 (2008).
Aderem, A. & Ulevitch, R. J. Toll-like receptors in the induction of the innate immune response. Nature 406, 782–787 (2000).
Schilling, J. D. et al. CD14- and Toll-like receptor-dependent activation of bladder epithelial cells by lipopolysaccharide and type 1 piliated Escherichia coli. Infect. Immun. 71, 1470–1480 (2003).
Schilling, J. D., Martin, S. M., Hung, C. S., Lorenz, R. G. & Hultgren, S. J. Toll-like receptor 4 on stromal and hematopoietic cells mediates innate resistance to uropathogenic Escherichia coli. Proc. Natl Acad. Sci. USA 100, 4203–4208 (2003).
Shahin, R. D., Engberg, I., Hagberg, L. & Svanborg Eden, C. Neutrophil recruitment and bacterial clearance correlated with LPS responsiveness in local gram-negative infection. J. Immunol. 138, 3475–3480 (1987).
Ragnarsdottir, B. et al. Reduced toll-like receptor 4 expression in children with asymptomatic bacteriuria. J. Infect. Dis. 196, 475–484 (2007).
Eden, C. S., Shahin, R. & Briles, D. Host resistance to mucosal gram-negative infection. Susceptibility of lipopolysaccharide nonresponder mice. J. Immunol. 140, 3180–3185 (1988).
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).
Andersen-Nissen, E. et al. Cutting edge: Tlr5−/− mice are more susceptible to Escherichia coli urinary tract infection. J. Immunol. 178, 4717–4720 (2007).
Zhang, D. et al. A toll-like receptor that prevents infection by uropathogenic bacteria. Science 303, 1522–1526 (2004).
Klumpp, D. J. et al. Uropathogenic Escherichia coli potentiates type 1 pilus-induced apoptosis by suppressing NF-κB. Infect. Immun. 69, 6689–6695 (2001).
Ingersoll, M. A., Kline, K. A., Nielsen, H. V. & Hultgren, S. J. G-CSF induction early in uropathogenic Escherichia coli infection of the urinary tract modulates host immunity. Cell Microbiol. 10, 2568–2578 (2008).
Schiwon, M. et al. Crosstalk between sentinel and helper macrophages permits neutrophil migration into infected uroepithelium. Cell 156, 456–468 (2014).
Malaviya, R., Ikeda, T., Ross, E. & Abraham, S. N. Mast cell modulation of neutrophil influx and bacterial clearance at sites of infection through TNF-α. Nature 381, 77–80 (1996).
Isaacson, B. et al. Stromal cell-derived factor 1 mediates immune cell attraction upon urinary tract infection. Cell Rep. 20, 40–47 (2017).
Hang, L. et al. Macrophage inflammatory protein-2 is required for neutrophil passage across the epithelial barrier of the infected urinary tract. J. Immunol. 162, 3037–3044 (1999).
Waldhuber, A. et al. Uropathogenic Escherichia coli strain CFT073 disrupts NLRP3 inflammasome activation. J. Clin. Invest. 126, 2425–2436 (2016).
Armbruster, C. E., Smith, S. N., Mody, L. & Mobley, H. L. T. Urine cytokine and chemokine levels predict urinary tract infection severity independent of uropathogen, urine bacterial burden, host genetics, and host age. Infect. Immun. (2018).
Lin, A. E. et al. Role of hypoxia inducible factor-1alpha (HIF-1alpha) in innate defense against uropathogenic Escherichia coli infection. PLoS Pathog. 11, e1004818 (2015).
Sundac, L. et al. Protein-based profiling of the immune response to uropathogenic Escherichia coli in adult patients immediately following hospital admission for acute cystitis. Pathog. Dis. 74, ftw062 (2016).
Ambite, I. et al. Molecular basis of acute cystitis reveals susceptibility genes and immunotherapeutic targets. PLoS Pathog. 12, e1005848 (2016).
He, Y., Hara, H. & Nunez, G. Mechanism and regulation of NLRP3 inflammasome activation. Trends Biochem. Sci. 41, 1012–1021 (2016).
Kline, K. A., Schwartz, D. J., Lewis, W. G., Hultgren, S. J. & Lewis, A. L. Immune activation and suppression by group B streptococcus in a murine model of urinary tract infection. Infect. Immun. 79, 3588–3595 (2011).
Kline, K. A. et al. Characterization of a novel murine model of Staphylococcus saprophyticus urinary tract infection reveals roles for Ssp and SdrI in virulence. Infect. Immun. 78, 1943–1951 (2010).
Ulett, G. C. et al. Group B Streptococcus (GBS) urinary tract infection involves binding of GBS to bladder uroepithelium and potent but GBS-specific induction of interleukin 1α. J. Infect. Dis. 201, 866–870 (2010).
Megyeri, K., Mandi, Y., Degre, M. & Rosztoczy, I. Induction of cytokine production by different Staphylococcal strains. Cytokine 19, 206–212 (2002).
Conway, L. J., Carter, E. J. & Larson, E. L. Risk factors for nosocomial bacteremia secondary to urinary catheter-associated bacteriuria: a systematic review. Urol. Nurs. 35, 191–203 (2015).
Fabbian, F. et al. Is female gender as harmful as bacteria? Analysis of hospital admissions for urinary tract infections in elderly patients. J. Womens Health 24, 587–592 (2015).
Oliveira, P. A. et al. Technical Report: technique of bladder catheterization in female mice and rats for intravesical instillation in models of bladder cancer. Scand. J. Lab. Anim. Sci. 36, 5–9 (2009).
Seager, C. M. et al. Intravesical delivery of rapamycin suppresses tumorigenesis in a mouse model of progressive bladder cancer. Cancer Prev. Res. 2, 1008–1014 (2009).
El Behi, M. et al. An essential role for decorin in bladder cancer invasiveness. EMBO Mol. Med. 5, 1835–1851 (2013).
Hagberg, L. et al. Ascending, unobstructed urinary tract infection in mice caused by pyelonephritogenic Escherichia coli of human origin. Infect. Immun. 40, 273–283 (1983).
Olson, P. D., Hruska, K. A. & Hunstad, D. A. Androgens enhance male urinary tract infection severity in a new model. J. Am. Soc. Nephrol. 27, 1625–1634 (2015).
Boehm, B. J., Colopy, S. A., Jerde, T. J., Loftus, C. J. & Bushman, W. Acute bacterial inflammation of the mouse prostate. Prostate 72, 307–317 (2012).
Olson, P. D. et al. Androgen exposure potentiates formation of intratubular communities and renal abscesses by Escherichia coli. Kidney Int. 94, 502–513 (2018).
Ahmadikia, K. et al. Increased urine interleukin-17 and interleukin-22 levels in patients with candidal urinary tract infection. Iran. J. Kidney Dis. 12, 33–39 (2018).
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).
Abraham, S. N. & Miao, Y. The nature of immune responses to urinary tract infections. Nat. Rev. Immunol. 15, 655–663 (2015).
Haraoka, M. et al. Neutrophil recruitment and resistance to urinary tract infection. J. Infect. Dis. 180, 1220–1229 (1999).
Horvath, D. J. Jr. et al. Morphological plasticity promotes resistance to phagocyte killing of uropathogenic Escherichia coli. Microbes Infect. 13, 426–437 (2011).
Engel, D. et al. Tumor necrosis factor alpha- and inducible nitric oxide synthase-producing dendritic cells are rapidly recruited to the bladder in urinary tract infection but are dispensable for bacterial clearance. Infect. Immun. 74, 6100–6107 (2006).
Cheong, C. et al. Microbial stimulation fully differentiates monocytes to DC-SIGN/CD209+ dendritic cells for immune T cell areas. Cell 143, 416–429 (2010).
Carey, A. J. et al. Uropathogenic escherichia coli engages CD14-dependent signaling to enable bladder-macrophage-dependent control of acute urinary tract infection. J. Infect. Dis. 213, 659–668 (2016).
Symington, J. W. et al. ATG16L1 deficiency in macrophages drives clearance of uropathogenic E. coli in an IL-1beta-dependent manner. Mucosal Immunol. 8, 1388–1399 (2015).
Daley, J. M., Thomay, A. A., Connolly, M. D., Reichner, J. S. & Albina, J. E. Use of Ly6G-specific monoclonal antibody to deplete neutrophils in mice. J. Leukoc. Biol. 83, 64–70 (2008).
Marshall, J. C. The effects of granulocyte colony-stimulating factor in preclinical models of infection and acute inflammation. Shock 24, 120–129 (2005).
Yu, L. et al. Mucosal infection rewires TNFa signaling dynamics to skew susceptibility to recurrence. Elife 8, e46677 (2019).
Kau, A. L. et al. Enterococcus faecalis tropism for the kidneys in the urinary tract of C57BL/6J mice. Infect. Immun. 73, 2461–2468 (2005).
Kline, K. A. & Lewis, A. L. Gram-positive uropathogens, polymicrobial urinary tract infection, and the emerging microbiota of the urinary tract. Microbiol. Spectr. 4, 10 (2016).
Lacerda Mariano, L. & Ingersoll, M. A. Bladder resident macrophages: mucosal sentinels. Cell Immunol. 330, 136–141 (2018).
Aurora, A. B. et al. Macrophages are required for neonatal heart regeneration. J. Clin. Invest. 124, 1382–1392 (2014).
Duffield, J. S. et al. Selective depletion of macrophages reveals distinct, opposing roles during liver injury and repair. J. Clin. Invest. 115, 56–65 (2005).
Goren, I. et al. A transgenic mouse model of inducible macrophage depletion: effects of diphtheria toxin-driven lysozyme M-specific cell lineage ablation on wound inflammatory, angiogenic, and contractive processes. Am. J. Pathol. 175, 132–147 (2009).
Summan, M. et al. Macrophages and skeletal muscle regeneration: a clodronate-containing liposome depletion study. Am. J. Physiol. Regul. Integr. Comp. Physiol. 290, R1488–R1495 (2006).
van Amerongen, M. J., Harmsen, M. C., van Rooijen, N., Petersen, A. H. & van Luyn, M. J. Macrophage depletion impairs wound healing and increases left ventricular remodeling after myocardial injury in mice. Am. J. Pathol. 170, 818–829 (2007).
Gur, C. et al. Natural killer cell-mediated host defense against uropathogenic E. coli is counteracted by bacterial hemolysinA-dependent killing of NK cells. Cell Host Microbe 14, 664–674 (2013).
Cui, Y. et al. Mucosal-associated invariant T cell-rich congenic mouse strain allows functional evaluation. J. Clin. Invest. 125, 4171–4185 (2015).
Siegfried, L., Kmetova, M., Puzova, H., Molokacova, M. & Filka, J. Virulence-associated factors in Escherichia coli strains isolated from children with urinary tract infections. J. Med. Microbiol. 41, 127–132 (1994).
Nagamatsu, K. et al. Dysregulation of Escherichia coli alpha-hemolysin expression alters the course of acute and persistent urinary tract infection. Proc. Natl Acad. Sci. USA 112, E871–E880 (2015).
Jones-Carson, J., Balish, E. & Uehling, D. T. Susceptibility of immunodeficient gene-knockout mice to urinary tract infection. J. Urol. 161, 338–341 (1999).
Papotto, P. H., Ribot, J. C. & Silva-Santos, B. IL-17+ γδ T cells as kick-starters of inflammation. Nat. Immunol. 18, 604–611 (2017).
Treiner, E. et al. Selection of evolutionarily conserved mucosal-associated invariant T cells by MR1. Nature 422, 164–169 (2003).
Tilloy, F. et al. An invariant T cell receptor α chain defines a novel TAP-independent major histocompatibility complex class Ib-restricted α/β T cell subpopulation in mammals. J. Exp. Med. 189, 1907–1921 (1999).
Porcelli, S., Yockey, C. E., Brenner, M. B. & Balk, S. P. Analysis of T cell antigen receptor (TCR) expression by human peripheral blood CD4-8- alpha/beta T cells demonstrates preferential use of several V beta genes and an invariant TCR alpha chain. J. Exp. Med. 178, 1–16 (1993).
Le Bourhis, L. et al. Antimicrobial activity of mucosal-associated invariant T cells. Nat. Immunol. 11, 701–708 (2010).
Skjot-Rasmussen, L. et al. Persisting clones of Escherichia coli isolates from recurrent urinary tract infection in men and women. J. Med. Microbiol. 60, 550–554 (2011).
Czaja, C. A. et al. Prospective cohort study of microbial and inflammatory events immediately preceding Escherichia coli recurrent urinary tract infection in women. J. Infect. Dis. 200, 528–536 (2009).
Silverman, J. A., Schreiber, H. L. T., Hooton, T. M. & Hultgren, S. J. From physiology to pharmacy: developments in the pathogenesis and treatment of recurrent urinary tract infections. Curr. Urol. Rep. 14, 448–456 (2013).
Thumbikat, P., Waltenbaugh, C., Schaeffer, A. J. & Klumpp, D. J. Antigen-specific responses accelerate bacterial clearance in the bladder. J. Immunol. 176, 3080–3086 (2006).
Jodal, U. et al. Local antibodies in childhood urinary tract infection: a preliminary study. Int. Arch. Allergy Appl. Immunol. 47, 537–546 (1974).
Ethel, S., Bhat, G. K. & Hegde, B. M. Bacterial adherence and humoral immune response in women with symptomatic and asymptomatic urinary tract infection. Indian. J. Med. Microbiol. 24, 30–33 (2006).
Floege, J., Boddeker, M., Stolte, H. & Koch, K. M. Urinary IgA, secretory IgA and secretory component in women with recurrent urinary tract infections. Nephron 56, 50–55 (1990).
Chan, C. Y., St John, A. L. & Abraham, S. N. Mast cell interleukin-10 drives localized tolerance in chronic bladder infection. Immunity 38, 349–359 (2013).
Svanborg-Eden, C. & Svennerholm, A. M. Secretory immunoglobulin A and G antibodies prevent adhesion of Escherichia coli to human urinary tract epithelial cells. Infect. Immun. 22, 790–797 (1978).
Brumbaugh, A. R. & Mobley, H. L. Preventing urinary tract infection: progress toward an effective Escherichia coli vaccine. Expert. Rev. Vaccines 11, 663–676 (2012).
Mike, L. A., Smith, S. N., Sumner, C. A., Eaton, K. A. & Mobley, H. L. Siderophore vaccine conjugates protect against uropathogenic Escherichia coli urinary tract infection. Proc. Natl Acad. Sci. USA 113, 13468–13473 (2016).
Langermann, S. et al. Prevention of mucosal Escherichia coli infection by FimH-adhesin-based systemic vaccination. Science 276, 607–611 (1997).
Habibi, M. et al. Intranasal immunization with fusion protein MrpH.FimH and MPL adjuvant confers protection against urinary tract infections caused by uropathogenic Escherichia coli and Proteus mirabilis. Mol. Immunol. 64, 285–294 (2015).
Asadi Karam, M. R., Oloomi, M., Mahdavi, M., Habibi, M. & Bouzari, S. Vaccination with recombinant FimH fused with flagellin enhances cellular and humoral immunity against urinary tract infection in mice. Vaccine 31, 1210–1216 (2013).
Billips, B. K., Yaggie, R. E., Cashy, J. P., Schaeffer, A. J. & Klumpp, D. J. A live-attenuated vaccine for the treatment of urinary tract infection by uropathogenic Escherichia coli. J. Infect. Dis. 200, 263–272 (2009).
Langermann, S. et al. Vaccination with FimH adhesin protects cynomolgus monkeys from colonization and infection by uropathogenic Escherichia coli. J. Infect. Dis. 181, 774–778 (2000).
Lutay, N. et al. Bacterial control of host gene expression through RNA polymerase II. J. Clin. Invest. 123, 2366–2379 (2013).
O’Brien, V. P. et al. A mucosal imprint left by prior Escherichia coli bladder infection sensitizes to recurrent disease. Nat. Microbiol. 2, 16196 (2016).
Wang, J. Neutrophils in tissue injury and repair. Cell Tissue Res. 371, 531–539 (2018).
Ambite, I. et al. Bacterial suppression of RNA polymerase II-dependent host gene expression. Pathogens 5, 49 (2016).
Hannan, T. J. et al. Inhibition of cyclooxygenase-2 prevents chronic and recurrent cystitis. EBioMedicine 1, 46–57 (2014).
Shin, K. et al. Hedgehog/Wnt feedback supports regenerative proliferation of epithelial stem cells in bladder. Nature 472, 110–114 (2011).
Mysorekar, I. U., Isaacson-Schmid, M., Walker, J. N., Mills, J. C. & Hultgren, S. J. Bone morphogenetic protein 4 signaling regulates epithelial renewal in the urinary tract in response to uropathogenic infection. Cell Host Microbe 5, 463–475 (2009).
Liao, X. et al. Distinct roles of resident and nonresident macrophages in nonischemic cardiomyopathy. Proc. Natl Acad. Sci. USA 115, E4661–E4669 (2018).
Minutti, C. M. et al. A macrophage-pericyte axis directs tissue restoration via amphiregulin-induced transforming growth factor beta activation. Immunity 50, 645–654.e6 (2019).
Minutti, C. M., Knipper, J. A., Allen, J. E. & Zaiss, D. M. Tissue-specific contribution of macrophages to wound healing. Semin. Cell Dev. Biol. 61, 3–11 (2017).
Naber, K. G. Treatment options for acute uncomplicated cystitis in adults. J. Antimicrob. Chemother. 46, 23–27 (2000).
Bauer, H. W. et al. A long-term, multicenter, double-blind study of an Escherichia coli extract (OM-89) in female patients with recurrent urinary tract infections. Eur. Urol. 47, 542–548 (2005).
Grischke, E. M. & Ruttgers, H. Treatment of bacterial infections of the female urinary tract by immunization of the patients. Urol. Int. 42, 338–341 (1987).
Marinova, S. et al. Cellular and humoral systemic and mucosal immune responses stimulated by an oral polybacterial immunomodulator in patients with chronic urinary tract infections. Int. J. Immunopathol. Pharmacol. 18, 457–473 (2005).
Aziminia, N. et al. Vaccines for the prevention of recurrent urinary tract infections: a systematic review. BJU Int. 123, 753–768 (2019).
Inoue, M. et al. Safety, tolerability and immunogenicity of the ExPEC4V (JNJ-63871860) vaccine for prevention of invasive extraintestinal pathogenic Escherichia coli disease: a phase 1, randomized, double-blind, placebo-controlled study in healthy Japanese participants. Hum. Vaccin. Immunother. 14, 2150–2157 (2018).
Kruze, D., Holzbecher, K., Andrial, M. & Bossart, W. Urinary antibody response after immunisation with a vaccine against urinary tract infection. Urol. Res. 17, 361–366 (1989).
Huttner, A. & Gambillara, V. The development and early clinical testing of the ExPEC4V conjugate vaccine against uropathogenic Escherichia coli. Clin. Microbiol. Infect. 24, 1046–1050 (2018).
National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/show/NCT03500679 (2019).
Bleidorn, J., Gagyor, I., Kochen, M. M., Wegscheider, K. & Hummers-Pradier, E. Symptomatic treatment (ibuprofen) or antibiotics (ciprofloxacin) for uncomplicated urinary tract infection? — results of a randomized controlled pilot trial. BMC Med. 8, 30 (2010).
Kronenberg, A. et al. Symptomatic treatment of uncomplicated lower urinary tract infections in the ambulatory setting: randomised, double blind trial. BMJ 359, j4784 (2017).
Gagyor, I. et al. Ibuprofen versus fosfomycin for uncomplicated urinary tract infection in women: randomised controlled trial. BMJ 351, h6544 (2015).
Bleidorn, J., Hummers-Pradier, E., Schmiemann, G., Wiese, B. & Gagyor, I. Recurrent urinary tract infections and complications after symptomatic versus antibiotic treatment: follow-up of a randomised controlled trial. Ger. Med. Sci. 14, Doc01 (2016).
Vik, I. et al. Ibuprofen versus pivmecillinam for uncomplicated urinary tract infection in women — a double-blind, randomized non-inferiority trial. PLoS Med. 15, e1002569 (2018).
Tasdemir, S. et al. Intravesical hyaluronic acid and chondroitin sulfate alone and in combination for urinary tract infection: assessment of protective effects in a rat model. Int. J. Urol. 19, 1108–1112 (2012).
Constantinides, C. et al. Prevention of recurrent bacterial cystitis by intravesical administration of hyaluronic acid: a pilot study. BJU Int. 93, 1262–1266 (2004).
Damiano, R. et al. Prevention of recurrent urinary tract infections by intravesical administration of hyaluronic acid and chondroitin sulphate: a placebo-controlled randomised trial. Eur. Urol. 59, 645–651 (2011).
Kranjcec, B., Papes, D. & Altarac, S. D-mannose powder for prophylaxis of recurrent urinary tract infections in women: a randomized clinical trial. World J. Urol. 32, 79–84 (2014).
Cusumano, C. K. et al. Treatment and prevention of urinary tract infection with orally active FimH inhibitors. Sci. Transl Med. 3, 109ra115 (2011).
Yamamoto, S. et al. Genetic evidence supporting the fecal-perineal-urethral hypothesis in cystitis caused by Escherichia coli. J. Urol. 157, 1127–1129 (1997).
Spaulding, C. N. et al. Selective depletion of uropathogenic E. coli from the gut by a FimH antagonist. Nature 546, 528–532 (2017).
Zdziarski, J. et al. Host imprints on bacterial genomes — rapid, divergent evolution in individual patients. PLoS Pathog. 6, e1001078 (2010).
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).
Ambite, I. et al. Fimbriae reprogram host gene expression — divergent effects of P and type 1 fimbriae. PLoS Pathog. 15, e1007671 (2019).
Sunden, F., Hakansson, L., Ljunggren, E. & Wullt, B. Bacterial interference — is deliberate colonization with Escherichia coli 83972 an alternative treatment for patients with recurrent urinary tract infection? Int. J. Antimicrob. Agents 28, S26–S29 (2006).
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).
Prasad, A., Cevallos, M. E., Riosa, S., Darouiche, R. O. & Trautner, B. W. A bacterial interference strategy for prevention of UTI in persons practicing intermittent catheterization. Spinal Cord. 47, 565–569 (2009).
Wullt, B. & Svanborg, C. Deliberate establishment of asymptomatic bacteriuria — a novel strategy to prevent recurrent UTI. Pathogens 5, 52 (2016).
Sehgal, A. et al. The role of CSF1R-dependent macrophages in control of the intestinal stem-cell niche. Nat. Commun. 9, 1272 (2018).
Wynn, T. A. & Vannella, K. M. Macrophages in tissue repair, regeneration, and fibrosis. Immunity 44, 450–462 (2016).
Goplen, N. P. et al. Tissue-resident macrophages limit pulmonary CD8 resident memory T cell establishment. Front. Immunol. 10, 2332 (2019).
Klein, S. L. & Flanagan, K. L. Sex differences in immune responses. Nat. Rev. Immunol. 16, 626–638 (2016).
Whitacre, C. C. Sex differences in autoimmune disease. Nat. Immunol. 2, 777–780 (2001).
Raz, R. & Stamm, W. E. A controlled trial of intravaginal estriol in postmenopausal women with recurrent urinary tract infections. N. Engl. J. Med. 329, 753–756 (1993).
Eriksen, B. A randomized, open, parallel-group study on the preventive effect of an estradiol-releasing vaginal ring (Estring) on recurrent urinary tract infections in postmenopausal women. Am. J. Obstet. Gynecol. 180, 1072–1079 (1999).
Luthje, P. et al. Estrogen supports urothelial defense mechanisms. Sci. Transl Med. 5, 190ra180 (2013).
Shaikh, N., Morone, N. E., Bost, J. E. & Farrell, M. H. Prevalence of urinary tract infection in childhood: a meta-analysis. Pediatr. Infect. Dis. J. 27, 302–308 (2008).
Kohler, T. S., Yadven, M., Manvar, A., Liu, N. & Monga, M. The length of the male urethra. Int. Braz. J. Urol. 34, 451–454 (2008).
Babikir, I. H. et al. The impact of cathelicidin, the human antimicrobial peptide LL-37 in urinary tract infections. BMC Infect. Dis. 18, 17 (2018).
We thank M. Rousseau for critical reading of the manuscript. L.L.M. is part of the Pasteur-Paris University (PPU) International PhD Program, which received funding from the European Union’s Horizon 2020 research and innovation programme under the Marie Sklodowska-Curie grant agreement No. 665807 and from the Labex Milieu Intérieur (ANR-10-LABX-69-01). We would also like to acknowledge funding from the Agence Nationale de la Recherché (French National Research Agency) grant number ANR-17-CE17-0014 for supporting our work on urinary tract infection and host responses.
The authors declare no competing interests.
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
About this article
Cite this article
Lacerda Mariano, L., Ingersoll, M.A. The immune response to infection in the bladder. Nat Rev Urol 17, 439–458 (2020). https://doi.org/10.1038/s41585-020-0350-8