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Urinary tract infections: microbial pathogenesis, host–pathogen interactions and new treatment strategies

Abstract

Urinary tract infections (UTIs) are common, recurrent infections that can be mild to life-threatening. The continued emergence of antibiotic resistance, together with our increasing understanding of the detrimental effects conferred by broad-spectrum antibiotic use on the health of the beneficial microbiota of the host, has underscored the weaknesses in our current treatment paradigm for UTIs. In this Review, we discuss how recent microbiological, structural, genetic and immunological studies have expanded our understanding of host–pathogen interactions during UTI pathogenesis. These basic scientific findings have the potential to shift the strategy for UTI treatment away from broad-spectrum antibiotics targeting conserved aspects of bacterial replication towards pathogen-specific antibiotic-sparing therapeutics that target core determinants of bacterial virulence at the host–pathogen interface.

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Fig. 1: Overview of urinary tract infection pathogenesis by UPEC.
Fig. 2: Bacterial urovirulence factors.
Fig. 3: Pathogenesis of catheter-associated urinary tract infections.

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Acknowledgements

The authors thank K. W. Dodson and T. J. Hannan for their helpful suggestions and comments on the manuscript. Work in the authors’ laboratory was supported by grants AI099099, AI095542, AI029549 and AI048689 from the US National Institution of Allergy and Infectious Diseases, grants DK051406 and DK108840 from the US National Institute of Diabetes and Digestive and Kidney Diseases and Medical Scientist Training Program Grant T32GM07200 from the US National Institute of General Medical Sciences. The authors apologize to researchers whose work was not included in this Review due to space constraints.

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R.D.K and S.J.H. researched data for the article, discussed the content, wrote the article, and reviewed and edited the manuscript before submission.

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Correspondence to Scott J. Hultgren.

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S.J.H. has an ownership interest in Fimbrion Therapeutics, and may benefit if the company is successful in marketing mannosides. S.J.H. is also the chief scientific officer of QureTech Bio. R.D.K. declares no competing interests.

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Glossary

Urinary meatus

The opening of the urethra through which urine exits in males and females, sometimes referred to as the external urethral orifice.

Uncomplicated cystitis

An isolated infection of the bladder and/or lower urinary tract without signs or symptoms of upper urinary tract or systemic infection in a patient without significant comorbid conditions, such as pregnancy or structural urinary tract abnormalities.

Complicated cystitis

An infection of the upper urinary tract leading to upper urinary tract signs or systemic symptoms, or any urinary tract infection in pregnant women, immunocompromised patients or patients with functional urinary tract abnormalities.

Pyelonephritis

An infection of the renal pelvis, calices and/or cortex.

Fibrinogen

A glycoprotein released into the bladder lumen in response to inflammation and infection, and which can coat urinary catheters and serve as a nidus for bacterial binding.

Biofilms

Large collections of microbial organisms embedded within a complex extracellular matrix comprising polysaccharides, proteinaceous fibres and extracellular DNA.

Umbrella cells

Also known as facet cells, umbrella cells are large, polarized superficial cells that line the bladder lumen.

C3H/HeN mice

An inbred mouse strain commonly used for the study of a variety of disease processes, including urinary tract infections.

Lymphonodular hyperplasia

Enlargement of mucosal lymphoid nodules seen via histology.

Bacteriuria

The presence of bacteria in urine not attributable to contamination. Can be symptomatic or asymptomatic.

Nutritional immunity

Sequestration of nutrients by a host organism to prevent colonization by and proliferation of pathogens.

Siderophores

Low molecular weight compounds secreted by the host systems to bind metal ions and transport them across cellular membranes.

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Klein, R.D., Hultgren, S.J. Urinary tract infections: microbial pathogenesis, host–pathogen interactions and new treatment strategies. Nat Rev Microbiol 18, 211–226 (2020). https://doi.org/10.1038/s41579-020-0324-0

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