Infections in the lower urinary tract rarely migrate to the kidneys, but the precise mechanism that the human body employs to keep the twin organs disease-free has remained a medical mystery—until now.

A multidisciplinary team at Cambridge University in England solved the conundrum in an elegant series of experiments. Dr Andrew P. Stewart and colleagues found that highly specialised biological structures called neutrophil extracellular traps—NETs—are pivotal in protecting the kidneys from infection.

NETs are sticky webs of wispy strands that quite literally serve as traps. They ensnare bacteria that attempt to migrate northward to the kidneys from the lower urinary tract. NETs add to an array of antimicrobial activities mounted by the body to beat back infection.

Writing in Science Translational Medicine, Stewart and his team presented compelling evidence that sticky mesh-like immune NETs serve as a crucial antibacterial defence against infection. The team's study not only revealed the presence of NETs in the urinary tract but also answered a longstanding question in UTI research: What spares the kidneys from pathogens?

"These findings highlight the role of NETosis in preventing ascending infections in the urinary tract," Stewart, the study's lead author, wrote. He underscored that NETosis refers to the formation of NETs, which prevent any of the various species of bacteria—E. coli, Enterococcal faecalis, Proteus mirabilis, among others—from migrating upward from the bladder to the kidneys. The study focused on E. coli, the most common bacterial cause of UTIs.

The process of NETosis is another wonder of human biology. It reveals how the body, and more specifically, the immune system, creates structures to ensnare pathogens. The key entity in NETosis is the neutrophil, an immune cell, which is signalled to undergo a unique form of cell death.

As it succumbs, the neutrophil releases its DNA, histones, and granule proteins, leaving behind a mesh-like structure, a net. E. coli and other bacteria become entrapped just as insects are snared by a spider's web. The process of NETosis isn't rare because NETs are found in the urine of healthy people, Stewart and colleagues confirmed.

To get a mental image of a NET, picture a spider's web—not the lacy geometric kind ornamented with dew drops, but the thicker, more heavily woven type found in attics. NETs are created from neutrophils, critically important cells of the immune system. The main difference between a spider's web and a NET is scale. The arachnids' webs are large and visible to the naked eye; a NET is infinitesimal and requires powerful microscopy.

To be clear, NETs don't stop UTIs from occurring, but they do stop them from spreading and wreaking havoc elsewhere in the urinary tract, the Cambridge team's research demonstrated.

Indeed, bacterial invasion of the lower urinary tract is extraordinarily common, according to the World Health Organization, which estimates that hundreds of millions of people are impacted globally each year. Usually, UTIs are limited to the bladder, but on rare occasions, the invading microbes defy the body's immunological defences by migrating up the urinary tract and into one or both of the twin purplish-coloured organs, the kidneys.

Once infected, the kidneys are susceptible to serious complications. But the rarity of it, the Cambridge team found, demonstrates that the body has antimicrobial strategies, NETosis being key, which helps confine bacteria to the bladder, keeping the kidneys infection-free.

"Lower urinary tract infection is common but only rarely complicated by pyelonephritis," Stewart added. Pyelonephritis refers to an infection in one or both kidneys. The condition, which is marked by pain and potent inflammation, requires immediate medical care, doctors say, because, in some instances, pyelonephritis can be life-threatening.

As part of the study, the Cambridge team analysed urine samples from 15 healthy people. The scientists found that one biological entity stood out in each of the samples—the presence of NETs. These structures interacted with a protein called uromodulin, which aided in the formation of large webs that entrapped disease-causing bacteria.

The authors validated these findings in mouse models of UTI caused by E. coli. Stewart and colleagues found that interrupting NET formation allowed bacteria to invade the kidneys.

"We identified neutrophil extracellular traps in healthy human urine that provide an antibacterial defence strategy within the urinary tract," Stewart asserted.

Additionally, the Cambridge experiments showed that leukocyte esterase dipstick tests—one of the most common for UTI detection—work by highlighting neutrophils. It was long assumed that the test was detecting the overall neutrophil count. But Stewart and collaborators found that it actually was working by pinpointing neutrophils that had released NETs.

"Not only did this study highlight the role of NETosis … but it also revealed that the mechanistic underpinning of the decades-old and ubiquitous urine dipstick has been somewhat misunderstood," Stewart concluded.

More information: Andrew P. Stewart et al, Neutrophil extracellular traps protect the kidney from ascending infection and are required for a positive leukocyte dipstick test, Science Translational Medicine (2024). DOI: 10.1126/scitranslmed.adh5090

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