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

Lookup NU author(s): Ased Ali, Dr Catherine Mowbray, Marcelo Lanz, Anna Stanton, Paul Hilton, Dr Karen Brown, Wendy Robson, Dr Phillip Aldridge, Dr Alison Tyson-Capper, Professor Robert Pickard, Dr Judith Hall

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This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).


Abstract

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.


Publication metadata

Author(s): Ali ASM, Mowbray C, Lanz M, Stanton A, Bowen S, Varley CL, Hilton P, Brown K, Robson W, Southgate J, Aldridge P, Tyson-Capper A, Abraham S, Pickard RS, Hall J

Publication type: Article

Publication status: Published

Journal: Scientific Reports

Year: 2017

Volume: 7

Online publication date: 08/09/2017

Acceptance date: 06/07/2017

Date deposited: 08/09/2017

ISSN (electronic): 2045-2322

Publisher: Nature

URL: https://doi.org/10.1038/s41598-017-10445-4

DOI: 10.1038/s41598-017-10445-4


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