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

Publication ,  Journal Article
Ali, ASM; Mowbray, C; Lanz, M; Stanton, A; Bowen, S; Varley, CL; Hilton, P; Brown, K; Robson, W; Southgate, J; Aldridge, PD; Tyson-Capper, A ...
Published in: Sci Rep
September 8, 2017

The identification of the host defence peptides as target effectors in the innate defence of the uro-genital tract creates new translational possibilities for immunomodulatory therapies, specifically vaginal therapies to treat women suffering from rUTI, particularly those carrying the TLR5_C1174T SNP. Urinary tract infections (UTIs) are a microbial disease reported worldwide. Women are particularly susceptible with many suffering debilitating recurrent (r) infections. Treatment is by antibiotics, but such therapy is linked to antibiotic resistance and re-infection. This study explored the innate protective mechanisms of the urogenital tract with the aim of boosting such defences therapeutically. Modelling UTIs in vitro, human vaginal and bladder epithelial cells were challenged with uropathogenic Escherichia coli (CFT073) and microbial PAMPs including flagellin, LPS and peptidoglycan. Flagellin functioning via the TLR5/NFκB pathway was identified as the key UPEC virulence factor causing a significant increase (P < 0.05) in the production of the host-defence peptide (HDP), BD2. BD2-depleted urine samples from bladder infected mice supported increased UPEC growth, strengthening the significance of the HDPs in protecting the urogenital tissues from infection. Clinically, vaginal-douche BD2 concentrations were reduced (p < 0.05) in women suffering rUTIs, compared to age-matched healthy controls with concentrations further decreased (p < 0.05) in a TLR5392Stop SNP rUTI subgroup. Topical vaginal estrogen treatment increased (p < 0.001) BD2 concentrations in all women, including those carrying the SNP. These data identify therapeutic and antibiotic sparing roles for vaginal immunomodulatory agents that specifically target HDP induction, facilitate bacterial killing and disrupt the UPEC infection cycle.

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Published In

Sci Rep

DOI

EISSN

2045-2322

Publication Date

September 8, 2017

Volume

7

Issue

1

Start / End Page

11039

Location

England

Related Subject Headings

  • beta-Defensins
  • Young Adult
  • Vagina
  • Uropathogenic Escherichia coli
  • Urinary Tract Infections
  • Toll-Like Receptor 5
  • Recurrence
  • Models, Biological
  • Middle Aged
  • Mice
 

Citation

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Ali, A. S. M., Mowbray, C., Lanz, M., Stanton, A., Bowen, S., Varley, C. L., … Hall, J. (2017). Targeting Deficiencies in the TLR5 Mediated Vaginal Response to Treat Female Recurrent Urinary Tract Infection. Sci Rep, 7(1), 11039. https://doi.org/10.1038/s41598-017-10445-4
Ali, Ased S. M., Catherine Mowbray, Marcelo Lanz, Anna Stanton, Samantha Bowen, Claire L. Varley, Paul Hilton, et al. “Targeting Deficiencies in the TLR5 Mediated Vaginal Response to Treat Female Recurrent Urinary Tract Infection.Sci Rep 7, no. 1 (September 8, 2017): 11039. https://doi.org/10.1038/s41598-017-10445-4.
Ali ASM, Mowbray C, Lanz M, Stanton A, Bowen S, Varley CL, et al. Targeting Deficiencies in the TLR5 Mediated Vaginal Response to Treat Female Recurrent Urinary Tract Infection. Sci Rep. 2017 Sep 8;7(1):11039.
Ali, Ased S. M., et al. “Targeting Deficiencies in the TLR5 Mediated Vaginal Response to Treat Female Recurrent Urinary Tract Infection.Sci Rep, vol. 7, no. 1, Sept. 2017, p. 11039. Pubmed, doi:10.1038/s41598-017-10445-4.
Ali ASM, Mowbray C, Lanz M, Stanton A, Bowen S, Varley CL, Hilton P, Brown K, Robson W, Southgate J, Aldridge PD, Tyson-Capper A, Abraham S, Pickard RS, Hall J. Targeting Deficiencies in the TLR5 Mediated Vaginal Response to Treat Female Recurrent Urinary Tract Infection. Sci Rep. 2017 Sep 8;7(1):11039.

Published In

Sci Rep

DOI

EISSN

2045-2322

Publication Date

September 8, 2017

Volume

7

Issue

1

Start / End Page

11039

Location

England

Related Subject Headings

  • beta-Defensins
  • Young Adult
  • Vagina
  • Uropathogenic Escherichia coli
  • Urinary Tract Infections
  • Toll-Like Receptor 5
  • Recurrence
  • Models, Biological
  • Middle Aged
  • Mice