In silico and in vivo studies of truncated forms of flagellin (FliC) of enteroaggregative Escherichia coli fused to FimH from uropathogenic Escherichia coli as a vaccine candidate against urinary tract infections

Savar, Nastaran Sadat; Jahanian-Najafabadi, Ali; Mahdavi, Mehdi; Shokrgozar, Mohammad Ali; Jafari, Ameneh; Bouzari, Saeid

doi:10.1016/j.jbiotec.2014.01.037

Cited by 35 publications

(29 citation statements)

References 44 publications

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“…As a general rule, vaccination with whole pili has been ineffective at generating an antibody response that can protect against UTIs. However, adhesin-based vaccines have been shown to be effective at blocking host–pathogen interactions, thus preventing the establishment of disease 108–112 . Experiments using mouse and cynomolgus monkey models of UTIs determined that immunization with PapD–PapG or FimC–FimH chaperone–adhesin complexes protected against UTIs 108–112 .…”

Section: Treatment Of Urinary Tract Infectionsmentioning

confidence: 99%

“…However, adhesin-based vaccines have been shown to be effective at blocking host–pathogen interactions, thus preventing the establishment of disease 108–112 . Experiments using mouse and cynomolgus monkey models of UTIs determined that immunization with PapD–PapG or FimC–FimH chaperone–adhesin complexes protected against UTIs 108–112 . The effectiveness of the FimC–FimH vaccine was shown to be due, in large part, to antibodies that block the function of FimH in bladder colonization 110 .…”

Section: Treatment Of Urinary Tract Infectionsmentioning

confidence: 99%

“…Furthermore, the anti-FimH antibodies did not seem to alter the E. coli niche in the gut microbiota 109 . Modifications of this vaccine are currently under development, with the aim of inducing greater immune stimulation 108,112 . For example, one approach has been to fuse FimH to the flagellin FliC in order to induce a more substantial acute inflammatory response, which functions through TLR4 signalling via the MYD88 pathway 112 .…”

Section: Treatment Of Urinary Tract Infectionsmentioning

confidence: 99%

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Urinary tract infections: epidemiology, mechanisms of infection and treatment options

et al. 2015

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Urinary tract infections (UTIs) are a severe public health problem and are caused by a range of pathogens, but most commonly by Escherichia coli, Klebsiella pneumoniae, Proteus mirabilis, Enterococcus faecalis and Staphylococcus saprophyticus. High recurrence rates and increasing antimicrobial resistance among uropathogens threaten to greatly increase the economic burden of these infections. In this Review, we discuss how basic science studies are elucidating the molecular details of the crosstalk that occurs at the host–pathogen interface, as well as the consequences of these interactions for the pathophysiology of UTIs. We also describe current efforts to translate this knowledge into new clinical treatments for UTIs.

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Section: Treatment Of Urinary Tract Infectionsmentioning

confidence: 99%

Section: Treatment Of Urinary Tract Infectionsmentioning

confidence: 99%

Section: Treatment Of Urinary Tract Infectionsmentioning

confidence: 99%

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Urinary tract infections: epidemiology, mechanisms of infection and treatment options

et al. 2015

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“…These structures are key to infection and have been targeted in the development of new therapeutics 21. However, initial strategies employing a vaccine approach and whole pili immunogens have proven ineffective, and other methodologies including the use of a FimC‐FimH complex, UPEC toxins and siderophores have reduced, but not totally inhibited, UPEC infection of the bladder 22, 23, 24. In contrast, agents called mannosides, which function as FimH antagonists and reduce bacterial attachment, show strong potential, with in vivo approaches involving animal models demonstrating the efficacy of a new class, the C ‐mannosides 25.…”

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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“…Continued development of this vaccine has primarily been focused on inducing a greater immune stimulation in an attempt to increase the concentration of protective antibodies near the mucosal surface. To this end, investigators have attempted to fuse FimH to the flagellin FliC to stimulate a stronger acute inflammatory response (204). Similarly, coadministration of the FimC-FimH vaccine with a synthetic analogue of monophosphoryl lipid A has resulted in a phase 1 clinical trial that began in January 2014.…”

Section: Vaccines For Urinary Tract Infectionsmentioning

confidence: 99%

Innovative Solutions to Sticky Situations: Antiadhesive Strategies for Treating Bacterial Infections

2016

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Bacterial adherence to host tissue is an essential process in pathogenesis, necessary for invasion and colonization and often required for the efficient delivery of toxins and other bacterial effectors. As existing treatment options for common bacterial infections dwindle, we find ourselves rapidly approaching a tipping point in our confrontation with antibiotic-resistant strains and in desperate need of new treatment options. Bacterial strains defective in adherence are typically avirulent and unable to cause infection in animal models. The importance of this initial binding event in the pathogenic cascade highlights its potential as a novel therapeutic target. This article seeks to highlight a variety of strategies being employed to treat and prevent infection by targeting the mechanisms of bacterial adhesion. Advancements in this area include the development of novel antivirulence therapies using small molecules, vaccines, and peptides to target a variety of bacterial infections. These therapies target bacterial adhesion through a number of mechanisms, including inhibition of pathogen receptor biogenesis, competition-based strategies with receptor and adhesin analogs, and the inhibition of binding through neutralizing antibodies. While this article is not an exhaustive description of every advancement in the field, we hope it will highlight several promising examples of the therapeutic potential of antiadhesive strategies.

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In silico and in vivo studies of truncated forms of flagellin (FliC) of enteroaggregative Escherichia coli fused to FimH from uropathogenic Escherichia coli as a vaccine candidate against urinary tract infections

Cited by 35 publications

References 44 publications

Urinary tract infections: epidemiology, mechanisms of infection and treatment options

Urinary tract infections: epidemiology, mechanisms of infection and treatment options

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

Innovative Solutions to Sticky Situations: Antiadhesive Strategies for Treating Bacterial Infections

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