scholarly journals Rapid Bladder Interleukin-10 Synthesis in Response to Uropathogenic Escherichia coli Is Part of a Defense Strategy Triggered by the Major Bacterial Flagellar Filament FliC and Contingent on TLR5

mSphere ◽  
2019 ◽  
Vol 4 (6) ◽  
Author(s):  
Dhruba Acharya ◽  
Matthew J. Sullivan ◽  
Benjamin L. Duell ◽  
Kelvin G. K. Goh ◽  
Lahiru Katupitiya ◽  
...  
Keyword(s):  
Escherichia Coli ◽  
Immune Response ◽  
Urinary Tract Infection ◽  
Immune System ◽  
Urinary Tract ◽  
Interleukin 10 ◽  
Innate Immune ◽  
Content Type ◽  
E Coli ◽  
Flagellar Filament

ABSTRACT Urinary tract infection (UTI) caused by uropathogenic Escherichia coli (UPEC) engages interleukin-10 (IL-10) as an early innate immune response to regulate inflammation and promote the control of bladder infection. However, the mechanism of engagement of innate immunity by UPEC that leads to elicitation of IL-10 in the bladder is unknown. Here, we identify the major UPEC flagellar filament, FliC, as a key bacterial component sensed by the bladder innate immune system responsible for the induction of IL-10 synthesis. IL-10 responses of human as well as mouse bladder epithelial cell-monocyte cocultures were triggered by flagella of three major UPEC representative strains, CFT073, UTI89, and EC958. FliC purified to homogeneity induced IL-10 in vitro and in vivo as well as other functionally related cytokines, including IL-6. The genome-wide innate immunological context of FliC-induced IL-10 in the bladder was defined using RNA sequencing that revealed a network of transcriptional and antibacterial defenses comprising 1,400 genes that were induced by FliC. Of the FliC-responsive bladder transcriptome, altered expression of il10 and 808 additional genes were dependent on Toll-like receptor 5 (TLR5), according to analysis of TLR5-deficient mice. Examination of the potential of FliC and associated innate immune signature in the bladder to boost host defense, based on prophylactic or therapeutic administration to mice, revealed significant benefits for the control of UPEC. We conclude that detection of FliC through TLR5 triggers rapid IL-10 synthesis in the bladder, and FliC represents a potential immune modulator that might offer benefit for the treatment or prevention of UPEC UTI. IMPORTANCE Interleukin-10 is part of the immune response to urinary tract infection (UTI) due to E. coli, and it is important in the early control of infection in the bladder. Defining the mechanism of engagement of the immune system by the bacteria that enables the protective IL-10 response is critical to exploring how we might exploit this mechanism for new infection control strategies. In this study, we reveal part of the bacterial flagellar apparatus (FliC) is an important component that is sensed by and responsible for induction of IL-10 in the response to UPEC. We show this response occurs in a TLR5-dependent manner. Using infection prevention and control trials in mice infected with E. coli, this study also provides evidence that purified FliC might be of value in novel approaches for the treatment of UTI or in preventing infection by exploiting the FliC-triggered bladder transcriptome.

scholarly journals Molecular Basis of Uropathogenic Escherichia coli Evasion of the Innate Immune Response in the Bladder

2008 ◽  
Vol 76 (9) ◽  
pp. 3891-3900 ◽  
Author(s):  
Benjamin K. Billips ◽  
Anthony J. Schaeffer ◽  
David J. Klumpp
Keyword(s):  
Escherichia Coli ◽  
Immune Response ◽  
Urinary Tract Infection ◽  
Urinary Tract ◽  
Tract Infection ◽  
Innate Immune Response ◽  
Molecular Basis ◽  
Neutrophil Recruitment ◽  
Innate Immune ◽  
Cytokine Secretion

ABSTRACT In the urinary tract, the innate immune system detects conserved bacterial components and responds to infection by activating the proinflammatory transcription factor NF-κB, resulting in cytokine secretion and neutrophil recruitment. Uropathogenic Escherichia coli (UPEC), however, has been shown to evade the host innate immune response by suppressing NF-κB activation in urothelial cells, which results in decreased cytokine secretion and increased urothelial apoptosis. To understand the molecular basis of UPEC modulation of inflammation, we performed a genetic screen with UPEC strain NU14 to identify genes which are required for modulation of urothelial cytokine secretion. Disruption of ampG (peptidoglycan permease), waaL (lipopolysaccharide O antigen ligase), or alr (alanine racemase) resulted in increased urothelial interleukin-8 (IL-8) and IL-6 release from urothelial cell cultures. Targeted deletion of these genes also resulted in elevated urothelial cytokine production during UPEC infection. Conditioned media from bacterial cultures of NU14 ΔampG and NU14 ΔwaaL contained a heat-stable factor(s) which stimulated greater urothelial IL-8 secretion than that in NU14-conditioned medium. In a mouse model of urinary tract infection, NU14 ΔampG, NU14 ΔwaaL, and NU14 Δalr were attenuated compared to wild-type NU14 and showed reduced fitness in competition experiments. Instillation of NU14 ΔampG or NU14 ΔwaaL increased bladder neutrophil recruitment, indicating that enhanced urothelial cytokine secretion during urinary tract infection results in an altered host response. Thus, UPEC evasion of innate immune detection of bacterial components, such as lipopolysaccharide and peptidoglycan fragments, is likely an important factor in the ability of UPEC to colonize the urinary tract.

scholarly journals Modulation of Host Innate Immune Response in the Bladder by Uropathogenic Escherichia coli

2007 ◽  
Vol 75 (11) ◽  
pp. 5353-5360 ◽  
Author(s):  
Benjamin K. Billips ◽  
Sarah G. Forrestal ◽  
Matthew T. Rycyk ◽  
James R. Johnson ◽  
David J. Klumpp ◽  
...  
Keyword(s):  
Escherichia Coli ◽  
Immune Response ◽  
Urinary Tract ◽  
Innate Immune Response ◽  
Bacterial Colonization ◽  
Innate Immune ◽  
Upec Strain ◽  
Chemokine Production ◽  
E Coli ◽  
K 12

ABSTRACT Uropathogenic Escherichia coli (UPEC), the most frequent cause of urinary tract infection (UTI), is associated with an inflammatory response which includes the induction of cytokine/chemokine secretion by urothelial cells and neutrophil recruitment to the bladder. Recent studies indicate, however, that UPEC can evade the early activation of urothelial innate immune response in vitro. In this study, we report that infection with the prototypic UPEC strain NU14 suppresses tumor necrosis factor alpha (TNF-α)-mediated interleukin-8 (CXCL-8) and interleukin-6 (CXCL-6) secretion from urothelial cell cultures compared to infection with a type 1 piliated E. coli K-12 strain. Furthermore, examination of a panel of clinical E. coli isolates revealed that 15 of 17 strains also possessed the ability to suppress cytokine secretion. In a murine model of UTI, NU14 infection resulted in diminished levels of mRNAs encoding keratinocyte-derived chemokine, macrophage inflammatory peptide 2, and CXCL-6 in the bladder relative to infection with an E. coli K-12 strain. Furthermore, reduced stimulation of inflammatory chemokine production during NU14 infection correlated with decreased levels of bladder and urine myeloperoxidase and increased bacterial colonization. These data indicate that a broad phylogenetic range of clinical E. coli isolates, including UPEC, may evade the activation of innate immune response in the urinary tract, thereby providing a pathogenic advantage.

scholarly journals Escherichia coli Isolates That Carryvat,fyuA,chuA, andyfcVEfficiently Colonize the Urinary Tract

2012 ◽  
Vol 80 (12) ◽  
pp. 4115-4122 ◽  
Author(s):  
Rachel R. Spurbeck ◽  
Paul C. Dinh ◽  
Seth T. Walk ◽  
Ann E. Stapleton ◽  
Thomas M. Hooton ◽  
...  
Keyword(s):  
Escherichia Coli ◽  
Urinary Tract Infection ◽  
Urinary Tract ◽  
Tract Infection ◽  
Virulence Factors ◽  
Neonatal Meningitis ◽  
Content Type ◽  
E Coli ◽  
Core Set ◽  
Encoding Genes

ABSTRACTExtraintestinalEscherichia coli(ExPEC), a heterogeneous group of pathogens, encompasses avian, neonatal meningitis, and uropathogenicE. colistrains. While several virulence factors are associated with ExPEC, there is no core set of virulence factors that can be used to definitively differentiate these pathotypes. Here we describe a multiplex of four virulence factor-encoding genes,yfcV,vat,fyuA, andchuA, highly associated with uropathogenicE. colistrains that can distinguish three groups ofE. coli: diarrheagenic and animal-associatedE. colistrains, human commensal and avian pathogenicE. colistrains, and uropathogenic and neonatal meningitisE. colistrains. Furthermore, human intestinal isolates that encode all four predictor genes express them during exponential growth in human urine and colonize the bladder in the mouse model of ascending urinary tract infection in higher numbers than human commensal strains that do not encode the four predictor genes (P= 0.02), suggesting that the presence of the predictors correlates with uropathogenic potential.

scholarly journals Ciprofloxacin Pharmacokinetics/Pharmacodynamics against Susceptible and Low-Level Resistant Escherichia coli Isolates in an Experimental Ascending Urinary Tract Infection Model in Mice

2020 ◽  
Vol 65 (1) ◽  
pp. e01804-20
Author(s):  
Lotte Jakobsen ◽  
Carina Vingsbro Lundberg ◽  
Niels Frimodt-Møller
Keyword(s):  
Escherichia Coli ◽  
Urinary Tract Infection ◽  
Urinary Tract ◽  
Tract Infection ◽  
Infection Model ◽  
Bladder Tissue ◽  
Content Type ◽  
E Coli ◽  
Low Level ◽  
Level Resistance

ABSTRACTThe mouse ascending urinary tract infection model was used to study the pharmacokinetic/pharmacodynamic (PKPD) relationships of the effect of ciprofloxacin in subcutaneous treatment for 3 days with varying doses and dosing intervals against a susceptible Escherichia coli strain (MIC, 0.032 mg/liter). Further, a humanized dose of ciprofloxacin was administered for 3 days against three E. coli strains with low-level resistance, i.e., MICs of 0.06, 0.25, and 1 mg/liter, respectively. Against the susceptible isolate, ciprofloxacin was highly effective in clearing the urine with daily doses from 10 mg/kg, but the dosing regimen had to be divided into at least two doses for optimal effect. Ciprofloxacin could not clear the urine or kidneys for the low-level-resistant strains. PKPD correlations with all strains combined showed that for the AUC24/MIC there was a slightly higher correlation with effect in urine and kidneys (R2, 0.71 and 0.69, respectively) than the %T>MIC (R2, 0.41 and 0.61, respectively). Equal correlations for the two PKPD indices were found for reduction of colony counts (CFU) in the bladder tissue, but not even the highest dose of 28 mg/kg × 6 could clear the bladder tissue. In conclusion, ciprofloxacin is highly effective in clearing the urine and kidney tissue for fully susceptible E. coli, while even low-level resistance in E. coli obscures this effect. While the effect of ciprofloxacin is mostly AUC/MIC driven against E. coli infection in the urinary tract, the effect in urine depends on the presence of ciprofloxacin in the urine during most of a 24-h period.

scholarly journals Antimicrobial Activity Evaluation of Tebipenem (SPR859), an Orally Available Carbapenem, against a Global Set of Enterobacteriaceae Isolates, Including a Challenge Set of Organisms

2019 ◽  
Vol 63 (6) ◽  
Author(s):  
S. J. Ryan Arends ◽  
Paul R. Rhomberg ◽  
Nicole Cotroneo ◽  
Aileen Rubio ◽  
Robert K. Flamm ◽  
...  
Keyword(s):  
Escherichia Coli ◽  
Antimicrobial Activity ◽  
Urinary Tract Infection ◽  
Urinary Tract ◽  
Tract Infection ◽  
Broth Microdilution ◽  
Wild Type ◽  
Content Type ◽  
E Coli

ABSTRACT The antimicrobial activity of tebipenem and other carbapenem agents were tested in vitro against a set of recent clinical isolates responsible for urinary tract infection (UTI), as well as against a challenge set. Isolates were tested by reference broth microdilution and included Escherichia coli (101 isolates), Klebsiella pneumoniae (208 isolates), and Proteus mirabilis (103 isolates) species. Within each species tested, tebipenem showed equivalent MIC50/90 values to those of meropenem (E. coli MIC50/90, ≤0.015/0.03 mg/liter; K. pneumoniae MIC50/90, 0.03/0.06 mg/liter; and P. mirabilis MIC50/90, 0.06/0.12 mg/liter) and consistently displayed MIC90 values 8-fold lower than imipenem. Tebipenem and meropenem (MIC50, 0.03 mg/liter) showed equivalent MIC50 results against wild-type, AmpC-, and/or extended-spectrum β-lactamase (ESBL)-producing isolates. Tebipenem also displayed MIC50/90 values 4- to 8-fold lower than imipenem against the challenge set. All carbapenem agents were less active (MIC50, ≥8 mg/liter) against isolates carrying carbapenemase genes. These data confirm the in vitro activity of the orally available agent tebipenem against prevalent UTI Enterobacteriaceae species, including those producing ESBLs and/or plasmid AmpC enzymes.

scholarly journals Characteristics of NDM-1-Producing Escherichia coli Isolates That Belong to the Successful and Virulent Clone ST131

2011 ◽  
Vol 55 (6) ◽  
pp. 2986-2988 ◽  
Author(s):  
Gisele Peirano ◽  
Paul C. Schreckenberger ◽  
Johann D. D. Pitout
Keyword(s):  
United States ◽  
Escherichia Coli ◽  
Urinary Tract Infection ◽  
Urinary Tract ◽  
Tract Infection ◽  
The United States ◽  
Phylogenetic Group ◽  
Sequence Type ◽  
Content Type ◽  
E Coli

ABSTRACTAn NDM-1 carbapenemase-producingEscherichia coliisolate of sequence type 131 (ST131) that belonged to phylogenetic group B2 was obtained from a patient with a urinary tract infection who returned to the United States after a recent hospitalization while visiting India. NDM-1-producingE. coliST131 had significantly more virulence factors than NDM-1-producingE. coliST101, previously isolated from a patient in Canada. The presence of NDM β-lactamases in a very successful and virulentE. colisequence type is of concern.

scholarly journals Blocking Yersiniabactin Import Attenuates Extraintestinal Pathogenic Escherichia coli in Cystitis and Pyelonephritis and Represents a Novel Target To Prevent Urinary Tract Infection

2015 ◽  
Vol 83 (4) ◽  
pp. 1443-1450 ◽  
Author(s):  
Ariel R. Brumbaugh ◽  
Sara N. Smith ◽  
Sargurunathan Subashchandrabose ◽  
Stephanie D. Himpsl ◽  
Tracy H. Hazen ◽  
...  
Keyword(s):  
Escherichia Coli ◽  
Urinary Tract Infection ◽  
Urinary Tract ◽  
Iron Acquisition ◽  
Multidrug Resistant ◽  
Pathogenic Species ◽  
Content Type ◽  
E Coli ◽  
The Family ◽  
Novel Target

The emergence and spread of extended-spectrum beta-lactamases and carbapenemases among common bacterial pathogens are threatening our ability to treat routine hospital- and community-acquired infections. With the pipeline for new antibiotics virtually empty, there is an urgent need to develop novel therapeutics. Bacteria require iron to establish infection, and specialized pathogen-associated iron acquisition systems like yersiniabactin, common among pathogenic species in the familyEnterobacteriaceae, including multidrug-resistantKlebsiella pneumoniaeand pathogenicEscherichia coli, represent potentially novel therapeutic targets. Although the yersiniabactin system was recently identified as a vaccine target for uropathogenicE. coli(UPEC)-mediated urinary tract infection (UTI), its contribution to UPEC pathogenesis is unknown. Using anE. colimutant (strain 536ΔfyuA) unable to acquire yersiniabactin during infection, we established the yersiniabactin receptor as a UPEC virulence factor during cystitis and pyelonephritis, a fitness factor during bacteremia, and a surface-accessible target of the experimental FyuA vaccine. In addition, we determined through transcriptome sequencing (RNA-seq) analyses of RNA fromE. colicausing cystitis in women that iron acquisition systems, including the yersiniabactin system, are highly expressed by bacteria during natural uncomplicated UTI. Given that yersiniabactin contributes to the virulence of several pathogenic species in the familyEnterobacteriaceae, including UPEC, and is frequently associated with multidrug-resistant strains, it represents a promising novel target to combat antibiotic-resistant infections.

scholarly journals Draft Genome Sequence of Escherichia coli UMB1353, Isolated from the Female Urinary Tract

2020 ◽  
Vol 9 (23) ◽  
Author(s):  
Tanea Crawford ◽  
Taylor Miller-Ensminger ◽  
Adelina Voukadinova ◽  
Alan J. Wolfe ◽  
Catherine Putonti
Keyword(s):  
Escherichia Coli ◽  
Urinary Tract Infection ◽  
Urinary Tract ◽  
Genome Sequence ◽  
Draft Genome ◽  
Draft Genome Sequence ◽  
Antibiotic Resistant ◽  
Content Type ◽  
E Coli ◽  
Female Urinary Tract

ABSTRACT Here, we present the draft genome sequence of Escherichia coli UMB1353, isolated from a patient with a urinary tract infection. The sequence of this antibiotic-resistant E. coli strain contains one intact P2-like phage.

scholarly journals Genome Sequence of Escherichia coli Clone O25:H4 Sequence Type 131, Isolated from a Sudanese Patient with Urinary Tract Infection

2020 ◽  
Vol 9 (11) ◽  
Author(s):  
Sofia B. Mohamed ◽  
Mohamed M. Hassan ◽  
Sumaya Kambal ◽  
Abdalla Munir ◽  
Nusiba I. Abdalla ◽  
...  
Keyword(s):  
Escherichia Coli ◽  
Urinary Tract Infection ◽  
Urinary Tract ◽  
Tract Infection ◽  
Genome Sequence ◽  
Sequence Type ◽  
Whole Genome Sequence ◽  
Whole Genome ◽  
Content Type ◽  
E Coli

We report here the whole-genome sequence of Escherichia coli NUBRI-E, a representative of E. coli clone O25:H4 sequence type 131 with bla CTX-M-15, which was obtained from a Sudanese patient with a urinary tract infection.

scholarly journals Plasmidic qnr Genes Confer Clinical Resistance to Ciprofloxacin under Urinary Tract Physiological Conditions

2017 ◽  
Vol 61 (4) ◽  
Author(s):  
Guillermo Martín-Gutiérrez ◽  
José Manuel Rodríguez-Martínez ◽  
Álvaro Pascual ◽  
Jerónimo Rodríguez-Beltrán ◽  
Jesús Blázquez
Keyword(s):  
Escherichia Coli ◽  
Urinary Tract Infection ◽  
Urinary Tract ◽  
Susceptibility Testing ◽  
Urine Ph ◽  
Content Type ◽  
E Coli ◽  
Physiological Conditions ◽  
Ph Values ◽  
Clinical Resistance

ABSTRACT Escherichia coli variants expressing plasmid-mediated qnr genes are usually susceptible to fluoroquinolones by standard susceptibility testing. Here we show that, under specific urinary tract physiological conditions, susceptible laboratory and clinical strains harboring qnr determinants become fully resistant to ciprofloxacin (CIP). Therefore, physiological conditions, mainly urine pH values, should be considered when performing susceptibility testing of CIP activity against E. coli in treating urinary tract infection (UTI) and for selecting appropriate antibiotics for UTI treatment.

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