Please use this identifier to cite or link to this item: https://doi.org/10.1038/s41598-017-10445-4
Title: Targeting Deficiencies in the TLR5 Mediated Vaginal Response to Treat Female Recurrent Urinary Tract Infection
Authors: Ali, A.S.M
Mowbray, C
Lanz, M
Stanton, A
Bowen, S
Varley, C.L
Hilton, P
Brown, K
Robson, W
Southgate, J
Aldridge, P.D
Tyson-Capper, A
Abraham, S 
Pickard, R.S
Hall, J
Keywords: beta defensin
DEFB4A protein, human
TLR5 protein, human
toll like receptor 5
adult
aged
animal
biological model
disease model
epithelium cell
Escherichia coli infection
female
growth, development and aging
human
immunology
innate immunity
metabolism
microbiology
middle aged
mouse
recurrent disease
urinary tract infection
uropathogenic Escherichia coli
vagina
young adult
Adult
Aged
Animals
beta-Defensins
Disease Models, Animal
Epithelial Cells
Escherichia coli Infections
Female
Humans
Immunity, Innate
Mice
Middle Aged
Models, Biological
Recurrence
Toll-Like Receptor 5
Urinary Tract Infections
Uropathogenic Escherichia coli
Vagina
Young Adult
Issue Date: 2017
Publisher: Nature Publishing Group
Citation: Ali, A.S.M, Mowbray, C, Lanz, M, Stanton, A, Bowen, S, Varley, C.L, Hilton, P, Brown, K, Robson, W, Southgate, J, Aldridge, P.D, Tyson-Capper, A, Abraham, S, Pickard, R.S, Hall, J (2017). Targeting Deficiencies in the TLR5 Mediated Vaginal Response to Treat Female Recurrent Urinary Tract Infection. Scientific Reports 7 (1) : 11039. ScholarBank@NUS Repository. https://doi.org/10.1038/s41598-017-10445-4
Rights: Attribution 4.0 International
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/NF?B 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. © 2017 The Author(s).
Source Title: Scientific Reports
URI: https://scholarbank.nus.edu.sg/handle/10635/178583
ISSN: 2045-2322
DOI: 10.1038/s41598-017-10445-4
Rights: Attribution 4.0 International
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