Key Points
-
An overarching theme of the immune system in the bladder seems to be balancing the need to respond promptly to microbial challenge with the need to rapidly curtail inflammatory responses, as the structural integrity of the epithelial barrier is disrupted during prolonged immune responses.
-
Bladder epithelial cells not only alert the immune system during infection but also directly mediate bacterial clearance by secreting antimicrobial compounds into the urine and by expelling invading bacteria back into the bladder lumen to reduce intracellular load.
-
Crosstalk between different subsets of macrophages in the bladder coordinates the precise recruitment and onset of neutrophil responses, and thereby reduces harmful inflammatory reactions.
-
Mast cells seem to have a dual role in immune regulation in the urinary tract. They promote early mobilization of immune cells into the bladder and are central to terminating these pro-inflammatory responses presumably when the bladder epithelial barrier is disrupted. However, this homeostatic action often results in blunted adaptive immune responses.
-
Although neutrophils are the predominant immune cells mediating bacterial clearance in the bladder, excessive neutrophil responses can cause damage to the bladder tissue and predispose this organ to persistent infections.
-
Several unconventional, but potentially effective, strategies have been described that can boost immune defences of the bladder to contain or prevent urinary tract infections.
Abstract
The urinary tract is constantly exposed to microorganisms that inhabit the gastrointestinal tract, but generally the urinary tract resists infection by gut microorganisms. This resistance to infection is mainly ascribed to the versatility of the innate immune defences in the urinary tract, as the adaptive immune responses are limited particularly when only the lower urinary tract is infected. In recent years, as the strengths and weaknesses of the immune system of the urinary tract have emerged and as the virulence attributes of uropathogens are recognized, several potentially effective and unconventional strategies to contain or prevent urinary tract infections have emerged.
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 12 print issues and online access
$209.00 per year
only $17.42 per issue
Buy this article
- Purchase on Springer Link
- Instant access to full article PDF
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
References
Wu, X. R., Kong, X. P., Pellicer, A., Kreibich, G. & Sun, T. T. Uroplakins in urothelial biology, function, and disease. Kidney Int. 75, 1153–1165 (2009).
Grist, M. & Chakraborty, J. Identification of a mucin layer in the urinary bladder. Urology 44, 26–33 (1994).
Ronald, A. The etiology of urinary tract infection: traditional and emerging pathogens. Am. J. Med. 113 (Suppl. 1A), 14S–19S (2002).
Foxman, B., Barlow, R., D'Arcy, H., Gillespie, B. & Sobel, J. D. Urinary tract infection: self-reported incidence and associated costs. Ann. Epidemiol. 10, 509–515 (2000).
Schaeffer, A. J. Recurrent urinary tract infections in women. Pathogenesis and management. Postgrad. Med. 81, 51–58 (1987).
Foxman, B. The epidemiology of urinary tract infection. Nat. Rev. Urol. 7, 653–660 (2010).
Nicolle, L. E. Urinary tract pathogens in complicated infection and in elderly individuals. J. Infect. Dis. 183 (Suppl. 1), S5–S8 (2001).
Kurts, C., Panzer, U., Anders, H. J. & Rees, A. J. The immune system and kidney disease: basic concepts and clinical implications. Nat. Rev. Immunol. 13, 738–753 (2013). This is a comprehensive review describing the immune system in the kidney.
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).
Akira, S. & Takeda, K. Toll-like receptor signalling. Nat. Rev. Immunol. 4, 499–511 (2004).
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).
Ragnarsdottir, B., Lutay, N., Gronberg-Hernandez, J., Koves, B. & Svanborg, C. Genetics of innate immunity and UTI susceptibility. Nat. Rev. Urol. 8, 449–468 (2011). This review provides valuable information on the genetics of UTI susceptibility and also describes virulence factors of UPEC and complementary innate signalling events that occur in the urinary tract following a UTI.
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).
Nagamatsu, K. et al. Dysregulation of Escherichia coli α-hemolysin expression alters the course of acute and persistent urinary tract infection. Proc. Natl Acad. Sci. USA 112, E871–E880 (2015).
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).
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).
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).
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).
Flo, T. H. et al. Lipocalin 2 mediates an innate immune response to bacterial infection by sequestrating iron. Nature 432, 917–921 (2004).
Goetz, D. H. et al. The neutrophil lipocalin NGAL is a bacteriostatic agent that interferes with siderophore-mediated iron acquisition. Mol. Cell 10, 1033–1043 (2002).
Paragas, N. et al. α-intercalated cells defend the urinary system from bacterial infection. J. Clin. Invest. 124, 2963–2976 (2014).
Chromek, M. et al. The antimicrobial peptide cathelicidin protects the urinary tract against invasive bacterial infection. Nat. Med. 12, 636–641 (2006).
Valore, E. V. et al. Human β-defensin-1: an antimicrobial peptide of urogenital tissues. J. Clin. Invest. 101, 1633–1642 (1998). References 22 and 23 show the important role of secreted AMPs in defence against UPEC infections.
Spencer, J. D. et al. Ribonuclease 7 is a potent antimicrobial peptide within the human urinary tract. Kidney Int. 80, 174–180 (2011).
Danka, E. S. & Hunstad, D. A. Cathelicidin augments epithelial receptivity and pathogenesis in experimental Escherichia coli cystitis. J. Infect. Dis. 211, 1164–1173 (2015).
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).
Bishop, B. L. et al. Cyclic AMP-regulated exocytosis of Escherichia coli from infected bladder epithelial cells. Nat. Med. 13, 625–630 (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). References 27–29 investigate the molecular aspects of the powerful exocytic activities of BECs following invasion of UPEC. This activity seems to be a component of the cell-autonomous defence system and is an effective strategy to reduce intracellular bacterial load.
Mulvey, M. A. et al. Induction and evasion of host defenses by type 1-piliated uropathogenic Escherichia coli. Science 282, 1494–1497 (1998). This study describes how superficial BECs reduce bacterial load following UPEC infection by spontaneous exfoliation into the urine.
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).
Shin, K. et al. Hedgehog/Wnt feedback supports regenerative proliferation of epithelial stem cells in bladder. Nature 472, 110–114 (2011). References 31 and 32 reveal the existence of a highly efficient programme within the bladder epithelium to rapidly restore its barrier function after shedding of the superficial epithelium.
Haraoka, M. et al. Neutrophil recruitment and resistance to urinary tract infection. J. Infect. Dis. 180, 1220–1229 (1999).
Agace, W. W., Patarroyo, M., Svensson, M., Carlemalm, E. & Svanborg, C. Escherichia coli induces transuroepithelial neutrophil migration by an intercellular adhesion molecule-1-dependent mechanism. Infect. Immun. 63, 4054–4062 (1995).
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).
Hannan, T. J. et al. Inhibition of cyclooxygenase-2 prevents chronic and recurrent cystitis. EBioMedicine 1, 46–57 (2014).
Engel, D. R. et al. CCR2 mediates homeostatic and inflammatory release of Gr1high monocytes from the bone marrow, but is dispensable for bladder infiltration in bacterial urinary tract infection. J. Immunol. 181, 5579–5586 (2008).
Duell, B. L., Carey, A. J., Dando, S. J., Schembri, M. A. & Ulett, G. C. Human bladder uroepithelial cells synergize with monocytes to promote IL-10 synthesis and other cytokine responses to uropathogenic Escherichia coli. PLoS ONE 8, e78013 (2013).
Symington, J. W. et al. ATG16L1 deficiency in macrophages drives clearance of uropathogenic E. coli in an IL-1β dependent manner. Mucosal Immunol. http://dx.doi.org/10.1038/mi.2015.7 (2015).
Schiwon, M. et al. Crosstalk between sentinel and helper macrophages permits neutrophil migration into infected uroepithelium. Cell 156, 456–468 (2014). This paper describes the crosstalk between different subsets of macrophages within the bladder mucosa that governs the recruitment and precise onset of neutrophil responses.
Nathan, C. Neutrophils and immunity: challenges and opportunities. Nat. Rev. Immunol. 6, 173–182 (2006).
Shelburne, C. P. et al. Mast cells augment adaptive immunity by orchestrating dendritic cell trafficking through infected tissues. Cell Host Microbe 6, 331–342 (2009).
Abraham, S. N. & St John, A. L. Mast cell-orchestrated immunity to pathogens. Nat. Rev. Immunol. 10, 440–452 (2010).
Abraham, S., Shin, J. & Malaviya, R. Type 1 fimbriated Escherichia coli-mast cell interactions in cystitis. J. Infect. Dis. 183 (Suppl. 1), S51–S55 (2001).
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). This study describes the homeostatic role of mast cells in terminating pro-inflammatory responses, presumably after the bladder epithelial barrier is disrupted. However, this premature termination of inflammation also negatively affects the development of memory responses to the uropathogen.
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).
Engel, D. et al. Tumor necrosis factor α- 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).
Jones-Carson, J., Balish, E. & Uehling, D. T. Susceptibility of immunodeficient gene-knockout mice to urinary tract infection. J. Urol. 161, 338–341 (1999).
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).
Deckmann, K. et al. Bitter triggers acetylcholine release from polymodal urethral chemosensory cells and bladder reflexes. Proc. Natl Acad. Sci. USA 111, 8287–8292 (2014).
Ratner, J. J., Thomas, V. L., Sanford, B. A. & Forland, M. Bacteria-specific antibody in the urine of patients with acute pyelonephritis and cystitis. J. Infect. Dis. 143, 404–412 (1981).
Wei, Y. et al. Activation of endogenous anti-inflammatory mediator cyclic AMP attenuates acute pyelonephritis in mice induced by uropathogenic Escherichia coli. Am. J. Pathol. 185, 472–484 (2014).
Langermann, S. et al. Prevention of mucosal Escherichia coli infection by FimH-adhesin-based systemic vaccination. Science 276, 607–611 (1997).
Brumbaugh, A. R. & Mobley, H. L. Preventing urinary tract infection: progress toward an effective Escherichia coli vaccine. Expert Rev. Vaccines 11, 663–676 (2012).
McLachlan, J. B. et al. Mast cell activators: a new class of highly effective vaccine adjuvants. Nat. Med. 14, 536–541 (2008).
Alteri, C. J., Hagan, E. C., Sivick, K. E., Smith, S. N. & Mobley, H. L. Mucosal immunization with iron receptor antigens protects against urinary tract infection. PLoS Pathog. 5, e1000586 (2009).
Thankavel, K. et al. Localization of a domain in the FimH adhesin of Escherichia coli type 1 fimbriae capable of receptor recognition and use of a domain-specific antibody to confer protection against experimental urinary tract infection. J. Clin. Invest. 100, 1123–1136 (1997).
Luthje, P. et al. Estrogen supports urothelial defense mechanisms. Sci. Transl Med. 5, 190ra80 (2013).
Chassin, C. et al. Hormonal control of the renal immune response and antibacterial host defense by arginine vasopressin. J. Exp. Med. 204, 2837–2852 (2007).
Schlager, T. A., Hendley, J. O., Wilson, R. A., Simon, V. & Whittam, T. S. Correlation of periurethral bacterial flora with bacteriuria and urinary tract infection in children with neurogenic bladder receiving intermittent catheterization. Clin. Infect. Dis. 28, 346–350 (1999).
Bollgren, I. & Winberg, J. The periurethral aerobic bacterial flora in healthy boys and girls. Acta Paediatr. Scand. 65, 74–80 (1976).
Reid, G. Probiotic agents to protect the urogenital tract against infection. Am. J. Clin. Nutr. 73, 437S–443S (2001).
Abraham, S. N. et al. Protection against Escherichia coli-induced urinary tract infections with hybridoma antibodies directed against type 1 fimbriae or complementary D-mannose receptors. Infect. Immun. 48, 625–628 (1985).
Ferrieres, L., Hancock, V. & Klemm, P. Biofilm exclusion of uropathogenic bacteria by selected asymptomatic bacteriuria Escherichia coli strains. Microbiology 153, 1711–1719 (2007).
Lutay, N. et al. Bacterial control of host gene expression through RNA polymerase II. J. Clin. Invest. 123, 2366–2379 (2013).
Hannan, T. J., Mysorekar, I. U., Hung, C. S., Isaacson-Schmid, M. L. & Hultgren, S. J. Early severe inflammatory responses to uropathogenic E. coli predispose to chronic and recurrent urinary tract infection. PLoS Pathog. 6, e1001042 (2010).
Nielubowicz, G. R. & Mobley, H. L. Host–pathogen interactions in urinary tract infection. Nat. Rev. Urol. 7, 430–441 (2010).
Ulett, G. C. et al. Uropathogenic Escherichia coli virulence and innate immune responses during urinary tract infection. Curr. Opin. Microbiol. 16, 100–107 (2013).
Henderson, J. P. et al. Quantitative metabolomics reveals an epigenetic blueprint for iron acquisition in uropathogenic Escherichia coli. PLoS Pathog. 5, e1000305 (2009).
Mulvey, M. A., Schilling, J. D., Martinez, J. J. & Hultgren, S. J. Bad bugs and beleaguered bladders: interplay between uropathogenic Escherichia coli and innate host defenses. Proc. Natl Acad. Sci. USA 97, 8829–8835 (2000).
Gupta, K. et al. International clinical practice guidelines for the treatment of acute uncomplicated cystitis and pyelonephritis in women: A 2010 update by the Infectious Diseases Society of America and the European Society for Microbiology and Infectious Diseases. Clin. Infect. Dis. 52, e103–e120 (2011).
Acknowledgements
The authors' work is supported by the US National Institutes of Health (grants R01 AI96305, R01 AI35678, R01 DK077159, R01 AI50021, R37 DK50814 and R21 AI056101) and a block grant from Duke–National University of Singapore Graduate Medical School.
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Competing interests
The authors declare no competing financial interests.
Glossary
- Uroplakins
-
Transmembranous tetraspanin-family proteins that form numerous plaques and cover the apical surface of the urothelium.
- Uromodulin
-
A highly mannosylated protein that integrates with mucin and, upon encountering bacteria, specifically adheres to the mannose-binding type 1 fimbriae on uropathogenic Escherichia coli.
- Neutrophil gelatinase-associated lipocalin
-
(NGAL). An iron-trafficking protein that binds to iron through its interaction with siderophores.
- Siderophores
-
Iron-chelating compounds secreted by microorganisms growing under low iron conditions.
- Enterochelin
-
A high-affinity siderophore that is mainly secreted by Gram-negative bacteria to acquire iron.
- α-intercalated cells
-
Specialized cells that are located in the collecting duct of the kidney medulla and are responsible for regulating the electrolyte balance.
- Antimicrobial peptides
-
(AMPs). Short peptides that preferentially bind and insert into the outer leaflet of the bacterial membrane and form pores to damage the microbial membrane integrity.
- Pentraxins
-
Soluble pattern recognition receptors that specifically detect the lipopolysaccharides and outer membrane proteins of bacteria and promote their uptake by phagocytes.
- Fusiform vesicles
-
Specialized membrane vesicles that are found near the apical surface of the superficial epithelium of the bladder and are responsible for providing extra membrane during bladder expansion.
- Autophagy
-
An evolutionarily conserved process in which acidic double-membraned vacuoles sequester intracellular contents (such as damaged organelles and intracellular pathogens) and target them for degradation through fusion to secondary lysosomes.
- Sonic hedgehog
-
(SHH). An essential intercellular signalling protein for pattern formation and tissue regeneration during development.
- Macrophage migration inhibitory factor
-
(MIF). A pro-inflammatory cytokine that regulates key functions of macrophages by inhibiting the anti-inflammatory effects of glucocorticoids.
- Matrix metalloproteinase 9
-
(MMP9). An endopeptidase involved in the cleavage of a variety of substrates, including collagen and extracellular matrix components.
- Detrusor muscle region
-
A layer of bladder wall that is composed of smooth muscle.
- Forskolin
-
A plant extract and adenylyl cyclase activator with a potent capacity to increase intracellular cAMP levels.
- Fimbrial adhesin FimH
-
A highly conserved protein that is expressed by common uropathogens; it mediates bacterial adhesion of type 1 fimbriae by binding to host D-mannose.
Rights and permissions
About this article
Cite this article
Abraham, S., Miao, Y. The nature of immune responses to urinary tract infections. Nat Rev Immunol 15, 655–663 (2015). https://doi.org/10.1038/nri3887
Published:
Issue Date:
DOI: https://doi.org/10.1038/nri3887
This article is cited by
-
Urine biomarkers individually and as a consensus model show high sensitivity and specificity for detecting UTIs
BMC Infectious Diseases (2024)
-
From mucosal infection to successful cancer immunotherapy
Nature Reviews Urology (2023)
-
Infection as an under-recognized precipitant of acute heart failure: prognostic and therapeutic implications
Heart Failure Reviews (2023)
-
The Potential Role of Persister Cells in Urinary Tract Infections
Current Urology Reports (2023)
-
Urinary tract infections trigger synucleinopathy via the innate immune response
Acta Neuropathologica (2023)