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

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 SN...

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Autores principales: Ali, Ased S. M., Mowbray, Catherine, Lanz, Marcelo, Stanton, Anna, Bowen, Samantha, Varley, Claire L., Hilton, Paul, Brown, Karen, Robson, Wendy, Southgate, Jennifer, Aldridge, Phillip D., Tyson-Capper, Alison, Abraham, Soman, Pickard, Robert S., Hall, Judith
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2017
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5591273/
https://www.ncbi.nlm.nih.gov/pubmed/28887442
http://dx.doi.org/10.1038/s41598-017-10445-4
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author Ali, Ased S. M.
Mowbray, Catherine
Lanz, Marcelo
Stanton, Anna
Bowen, Samantha
Varley, Claire L.
Hilton, Paul
Brown, Karen
Robson, Wendy
Southgate, Jennifer
Aldridge, Phillip D.
Tyson-Capper, Alison
Abraham, Soman
Pickard, Robert S.
Hall, Judith
author_facet Ali, Ased S. M.
Mowbray, Catherine
Lanz, Marcelo
Stanton, Anna
Bowen, Samantha
Varley, Claire L.
Hilton, Paul
Brown, Karen
Robson, Wendy
Southgate, Jennifer
Aldridge, Phillip D.
Tyson-Capper, Alison
Abraham, Soman
Pickard, Robert S.
Hall, Judith
author_sort Ali, Ased S. M.
collection PubMed
description 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 TLR5(392Stop) 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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spelling pubmed-55912732017-09-13 Targeting Deficiencies in the TLR5 Mediated Vaginal Response to Treat Female Recurrent Urinary Tract Infection Ali, Ased S. M. Mowbray, Catherine Lanz, Marcelo Stanton, Anna Bowen, Samantha Varley, Claire L. Hilton, Paul Brown, Karen Robson, Wendy Southgate, Jennifer Aldridge, Phillip D. Tyson-Capper, Alison Abraham, Soman Pickard, Robert S. Hall, Judith Sci Rep Article 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 TLR5(392Stop) 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. Nature Publishing Group UK 2017-09-08 /pmc/articles/PMC5591273/ /pubmed/28887442 http://dx.doi.org/10.1038/s41598-017-10445-4 Text en © The Author(s) 2017 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
spellingShingle Article
Ali, Ased S. M.
Mowbray, Catherine
Lanz, Marcelo
Stanton, Anna
Bowen, Samantha
Varley, Claire L.
Hilton, Paul
Brown, Karen
Robson, Wendy
Southgate, Jennifer
Aldridge, Phillip D.
Tyson-Capper, Alison
Abraham, Soman
Pickard, Robert S.
Hall, Judith
Targeting Deficiencies in the TLR5 Mediated Vaginal Response to Treat Female Recurrent Urinary Tract Infection
title Targeting Deficiencies in the TLR5 Mediated Vaginal Response to Treat Female Recurrent Urinary Tract Infection
title_full Targeting Deficiencies in the TLR5 Mediated Vaginal Response to Treat Female Recurrent Urinary Tract Infection
title_fullStr Targeting Deficiencies in the TLR5 Mediated Vaginal Response to Treat Female Recurrent Urinary Tract Infection
title_full_unstemmed Targeting Deficiencies in the TLR5 Mediated Vaginal Response to Treat Female Recurrent Urinary Tract Infection
title_short Targeting Deficiencies in the TLR5 Mediated Vaginal Response to Treat Female Recurrent Urinary Tract Infection
title_sort targeting deficiencies in the tlr5 mediated vaginal response to treat female recurrent urinary tract infection
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5591273/
https://www.ncbi.nlm.nih.gov/pubmed/28887442
http://dx.doi.org/10.1038/s41598-017-10445-4
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