Critical Bacterial Protein Linked to Chronic Urinary Tract Infections (UTIs) Identified

Highlights:

• Urinary tract infections (UTIs) are one of the commonest reasons for hospital visits.
• Nearly 80 percent of UTIs are caused by E. coli
• Newprotein in E. coli identified, that may enable persistence of infection.
• Targeting this protein may help treat or prevent chronic infection.

A protein present in urinary tract infection (UTI) causing bacteria, primarily E. coli may be responsible for persistence of the bacteria in the urinary bladder, and causing chronic infections. Researchers have identified this protein, and also succeeded in vaccinating mice against this protein, finding that it reduced the incidence of severe UTIs. Why Many UTIs Become Chronic?

Once the bacteria gain entry into the bladder, the bacteria attach to the bladder wall by means of long hair like projections pili which serve as organs of attachment. This prevents their being swept away by the urinary stream, enabling them to establish infection in the urinary tract in its initial stages. A team of scientists have now identified a second pilus, called Fml, with genes that are remarkably similar to the type 1 pilus but whose function was not known.

This study focused on the role of these pili in causing severe or chronic infections, and whether this knowledge could be used for therapeutic purposes

Details of The Study

As part of the present study, Hultgren, postdoctoral researcher Matthew Conover, PhD, colleagues Ségolène Ruer, PhD, and Han Remaut, PhD, of Vrije Universiteit Brussel in Belgium, and others proceeded to find out the function of the Fml pilus. They focused their attention on a protein known as FmlH, which they thought was located at the tip of the pilus, since it would help bacteria attach easily to the bladder wall.

The scientists removed the gene for FmlH from some of the E. coli and then infected the urinary tracts of mice with bacteria having the FmlH gene, and others deficient in the gene. They discovered that E. coli deficient in FmlH were less likely to cause chronic infections in mice compared to E. coli with the protein intact.

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In the initial days of the infection, both the strains multiplied to similar levels. However, by the end of the fourth week, the bacteria lacking the FmlH were found to be 1,000 times less abundant in the bladder and 100 times less abundant in the kidneys than the bacteria with the protein.

“We found that the Fml pilus plays little to no role in acute bladder infection, but after the establishment of infection and the onset of inflammation, it contributes to the persistence of bacteria in the bladder,” said Conover, who led the study as a researcher in Hultgren’s lab.

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Vaccination Studies In Mice Using The FmlH Protein

The researchers administered one group of mice two doses of a vaccine made from a piece of the FmlH protein, four weeks apart. Another group of mice received mock vaccinations without the protein.

Both groups of mice were infected with E. coli and the amount of bacteria in their bladders and kidneys, one, two and three days after infection, were estimated. On day one, there was no difference in the number of bacteria between the mice that received the vaccine and those that didn’t. However, by the third day, the unvaccinated mice had over 1,000 times more number of bacteria in their bladders and 100 times more bacteria in their kidneys than the vaccinated mice.

“This is a proof of concept that we can interfere with the ability of the bacteria to adhere to the bladder and reduce chronic bladder infection and spread to other parts of the body,” Hultgren said. “We are continuing to work on developing vaccines and drugs that are effective in blocking the interaction between the bacteria and the body to prevent the establishment of disease.”

About Urinary Tract Infection

Infection of the urinary tract comprising the kidneys, ureters, bladder and urethra is referred to as UTI. It is most commonly due to E. coli, a bacteria that occurs in the bowel.

UTIs are very common and are responsible for nearly 10 million healthcare visits annually.

Women are more likely to develop UTIs compared to men, due to their shorter urethras and proximity of urethral opening to the anal and vaginal openings.

Signs and Symptoms of UTI

• Feeling an urgency to urinate, passing only a few drops of urine
• Burning feeling during urination
• Pressure, or pain in the lower part of the abdomen
• Cloudy or blood-stained urine
• Fever with chills

Scope Of This Study For Human Application

The researchers have showed that FmlH protein is capable of binding to human bladder cell lines, indicating that the results in mice may be applicable to humans too.

“Taking biopsies of human bladders during a UTI would be contraindicated because of the risk of spreading the bacteria, so the cell lines are the best model of human infection we have,” Conover said.

If further studies show that vaccination could reduce severe disease in models of human infection, it could well mean new therapeutic options for UTI, made more significant in the scenario of emerging antibiotic resistance among bacteria.

“Our findings reveal how bacteria have evolved a mechanism to colonize the bladder in order to persist and cause UTIs, and our vaccination study suggests that inhibiting this mechanism could be part of a viable approach to treating or preventing these infections,” said Scott Hultgren, PhD, the Helen L. Stoever Professor of Molecular Microbiology and one of the study’s senior authors.

References

1. Chronic Urinary Tract Infections - (https://www.bcm.edu/healthcare/care-centers/obstetrics-gynecology/conditions/chronic-urinary-tract-infections)
2. What Do I Need to Know About UTIs - (https://www.niddk.nih.gov/health-information/health-topics/urologic-disease/urinary-tract-infections-in-adults/Pages/ez.aspx)

Source-Medindia