Targeting Deficiencies in the TLR5 Mediated Vaginal Response to Treat Female Recurrent Urinary Tract Infection

Area of Science:

• Immunology
• Microbiology
• Urology

Background:

• Recurrent urinary tract infections (rUTIs) significantly impact women's health, with antibiotic treatments leading to resistance and re-infection.
• The innate immune system of the urogenital tract plays a vital role in combating these infections.
• Host defence peptides (HDPs) are key effectors in this innate defence mechanism.

Purpose of the Study:

• To investigate the role of HDPs, specifically beta-defensin 2 (BD2), in the innate defence against uropathogenic Escherichia coli (UPEC) in the urogenital tract.
• To explore the potential of immunomodulatory therapies targeting HDP induction for treating rUTIs.
• To examine the influence of genetic factors, such as TLR5 single nucleotide polymorphisms (SNPs), on HDP levels and rUTI susceptibility.

Main Methods:

• In vitro modeling of UTIs using human vaginal and bladder epithelial cells challenged with UPEC and microbial components.
• Analysis of flagellin's role via the TLR5/NFκB pathway in inducing BD2 production.
• Measurement of BD2 concentrations in urine and vaginal secretions from women with and without rUTIs, including those with TLR5 SNPs.
• Assessment of topical vaginal estrogen's effect on BD2 levels.

Main Results:

• Flagellin, acting through TLR5/NFκB, significantly increased BD2 production in epithelial cells.
• UPEC growth was enhanced in BD2-depleted urine from infected mice, highlighting BD2's protective role.
• Women with rUTIs showed reduced vaginal BD2 levels, particularly those with the TLR5^392Stop SNP.
• Vaginal estrogen treatment successfully increased BD2 concentrations in all women, irrespective of SNP status.

Conclusions:

• HDPs, notably BD2, are critical for urogenital tract defence against UPEC.
• Reduced BD2 levels in women with rUTIs, especially those with TLR5 SNPs, indicate a compromised innate defence.
• Targeting HDP induction via vaginal immunomodulatory agents presents a promising, antibiotic-sparing therapeutic avenue for rUTIs.