Toll-Like Receptor Polymorphisms and Susceptibility to Urinary Tract Infections in Adult Women

Hawn, Thomas R.; Scholes, Delia; Li, Shuying S.; Wang, Hongwei; Yang, Yin; Roberts, Pacita L.; Stapleton, Ann E.; Janer, Marta; Aderem, Alan; Stamm, Walter E.; Zhao, Lue Ping; Hooton, Thomas M.

doi:10.1371/journal.pone.0005990

Cited by 193 publications

(177 citation statements)

References 58 publications

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“…We further demonstrate a functional effect of this variant in the blood cytokine response to flagellin and to killed B. pseudomallei. Although TLR5 1174C.T is associated with susceptibility to Legionnaires' disease (Legionella pneumophila pneumonia) and recurrent urinary tract infections (6,28), our study is the first, to our knowledge, to identify an association of the variant with outcome from infection. TLR5 1174T has previously been shown to blunt flagellin-dependent IL-6 and IL-8 release in whole blood (6,14).…”

Section: Discussionmentioning

confidence: 80%

Impaired TLR5 Functionality Is Associated with Survival in Melioidosis

West

Chantratita

Chierakul

et al. 2013

The Journal of Immunology

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Melioidosis is infection caused by the flagellated saprophyte Burkholderia pseudomallei. TLR5 is a pathogen recognition receptor activated by bacterial flagellin. We studied a genetic variant that encodes a defective TLR5 protein, TLR51174C>T, to elucidate the role of TLR5 in melioidosis. We measured NF-κB activation induced by B. pseudomallei in human embryonic kidney–293 cells transfected with TLR5 and found that B. pseudomallei induced TLR51174C- but not TLR51174T-dependent activation of NF-κB. We tested the association of TLR51174C>T with outcome in 600 Thai subjects with melioidosis. In a dominant model, TLR51174C>T was associated with protection against in-hospital death (adjusted odds ratio: 0.20; 95% confidence interval: 0.08–0.50; p = 0.001) and organ failure (adjusted odds ratio: 0.37; 95% confidence interval: 0.19–0.71; p = 0.003). We analyzed blood cytokine production induced by flagellin or heat-killed B. pseudomallei by TLR51174C>T genotype in healthy subjects. Flagellin induced lower monocyte-normalized levels of IL-6, IL-8, TNF-α, IL-10, MCP-1, IL-1ra, G-CSF, and IL-1β in carriers of TLR51174T compared with carriers of TLR51174C. B. pseudomallei induced lower monocyte-normalized levels of IL-10 in carriers of TLR51174T. We conclude that the hypofunctional genetic variant TLR51174C>T is associated with reduced organ failure and improved survival in melioidosis. This conclusion suggests a deleterious immunoregulatory effect of TLR5 that may be mediated by IL-10 and identifies this receptor as a potential therapeutic target in melioidosis.

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Section: Discussionmentioning

confidence: 80%

Impaired TLR5 Functionality Is Associated with Survival in Melioidosis

West

Chantratita

Chierakul

et al. 2013

The Journal of Immunology

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“…Analysis of TLR4 polymorphism revealed that certain TLR4 genotypes correlate with UTI recurrence or persistent asymptomatic infection in adult women and children. [50][51][52] Also, TLR4 mutant mice develop chronic asymptomatic infections. 49 Although we did not observe changes in TLR4 gene expression in our in vitro UTI infection model, TLR4 may still be epigenetically altered by methylation or histone modification UTI causes CDKN2A hypermethylation C Tolg et al in response to UTI in vivo.…”

Section: Discussionmentioning

confidence: 99%

Uropathogenic E. coli infection provokes epigenetic downregulation of CDKN2A (p16INK4A) in uroepithelial cells

Tölg

Sabha

Cortese

et al. 2011

Laboratory Investigation

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Host cell and bacterial factors determine severity and duration of infections. To allow for bacteria pathogenicity and persistence, bacteria have developed mechanisms that modify expression of host genes involved in cell cycle progression, apoptosis, differentiation and the immune response. Recently, Helicobacter pylori infection of the stomach has been correlated with epigenetic changes in the host genome. To identify epigenetic changes during Escherichia coli induced urinary tract infection (UTI), we developed an in vitro model of persistent infection of human uroepithelial cells with uropathogenic E. coli (UPEC), resulting in intracellular bacteria colonies. Cells inoculated with FimH-negative E. coli (N-UPEC) that are not internalized and non-inoculated cells were used as controls. UPEC infection significantly induced de novo methyltransferase (DNMT) activity (12.5-fold P ¼ 0.002 UPEC vs non-inoculated and 250-fold P ¼ 0.001 UPEC vs N-UPEC inoculated cells) and Dnmt1 RNA expression (6-fold P ¼ 0.04 UPEC vs non-inoculated cells) compared with controls. DNMT1 protein levels were significantly increased in three uroepithelial cell lines (5637, J82, HT-1197) in response to UPEC infection as demonstrated by confocal analysis. Real-time PCR analysis of candidate genes previously associated with bacteria infection and/or innate immunity, revealed UPEC-induced downregulation of the tumor suppressor gene CDKN2A (3.3-fold P ¼ 0.007 UPEC vs non-inoculated and 3.3-fold P ¼ 0.001 UPEC vs N-UPEC) and the DNA repair gene MGMT (9-fold P ¼ 0.03 UPEC vs non-inoculated). Expression of CDH1, MLH1, DAPK1 and TLR4 was not affected. Pyrosequencing of CDKN2A and MGMT CpG islands revealed increased methylation in CDKN2A exon 1 (3.8-fold P ¼ 0.04 UPEC vs N-UPEC and UPEC vs non-inoculated). Methylation of MGMT was not affected. UPEC-induced methylation of CDKN2A exon 1 may increase bladder cancer and presage UTI risk, and be useful as a biological marker for UTI susceptibility or recurrence.

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“…Additionally, Toll‐like receptors (TLRs) located in the lower urogenital tissues respond to microbe‐associated molecular patterns, specifically flagellin, and trigger the release of host defence peptides as well as inflammatory molecules that function to clear potential UTIs 7, 8. The importance of the TLRs in defence of the urinary tract (UT) is emphasised by studies where individuals carrying the TLR5_C1174T (R392STOP) and TLR2_G2285A (R753Q) SNP genotypes link to an increased risk of infection 9, 10, 11…”

Section: Introductionmentioning

confidence: 99%

High molecular weight hyaluronic acid: a two‐pronged protectant against infection of the urogenital tract?

et al. 2018

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ObjectivesRecurrent urinary tract infections are associated with uropathogenic Escherichia coli (UPEC) ascending and infecting the urinary tract. Antibiotics provide only symptomatic relief, not prevent recurrence. Clinical evidence suggests that intravesical glycosaminoglycan therapy, such as hyaluronic acid (HA), helps reduce UTI recurrence. This has been investigated here using in vitro systems modelling the urogenital tract tissues.Methods RT4 bladder cells were preconditioned with high molecular weight HA (> 1500 kDa) at 2 mg mL−1 and challenged with UPEC to analyse barrier protection and bacterial adherence. Untreated and HA‐preconditioned VK2 E6/E7 vaginal cells were challenged with E. coli flagellin (50 ng mL−1) to mimic bacterial challenge, and media analysed for lipocalin‐2, human β‐defensin 2 and interleukin‐8 by ELISA. Experiments were repeated after siRNA knockdown of Toll‐like receptors 2, 4 and 5, and CD44 to investigate signalling.ResultsMicroscopic analyses showed reduced bacterial adherence and urothelial disruption with HA, suggesting that HA functions as a barrier protecting the epithelium from bacterial infection. Cells treated with HA and flagellin simultaneously produced more of the host antimicrobial peptide LCN2 and pro‐inflammatory IL‐8 (P < 0.05) compared to the no HA/flagellin challenges. Increased gene expression of DEFB4 (P < 0.05), but not the hBD2 peptide, was observed in the HA/flagellin‐challenged cells.ConclusionThese data suggest that exogenous HA has potential to protect the urogenital epithelia from UPEC infection via a two‐pronged approach that involves the physical enhancement of the epithelial barrier and augmentation of its innate immune response.

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Toll-Like Receptor Polymorphisms and Susceptibility to Urinary Tract Infections in Adult Women

Cited by 193 publications

References 58 publications

Impaired TLR5 Functionality Is Associated with Survival in Melioidosis

Impaired TLR5 Functionality Is Associated with Survival in Melioidosis

Uropathogenic E. coli infection provokes epigenetic downregulation of CDKN2A (p16INK4A) in uroepithelial cells

High molecular weight hyaluronic acid: a two‐pronged protectant against infection of the urogenital tract?

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