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The nature of immune responses to urinary tract infections

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.

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Figure 1: Organization of immune-competent cells along the urinary tract.
Figure 2: Scope of innate immune responses in the bladder.
Figure 3: Mechanisms to curtail inflammatory responses in the bladder following infection.

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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.

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Correspondence to Soman N. Abraham.

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PowerPoint slides

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.

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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

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