Clinical Escherichia coli isolates utilize alpha-hemolysin to inhibit in vitro epithelial cytokine production

Hilbert, David W.; Paulish-Miller, Teresa E.; Tan, CK; Carey, Alison J.; Ulett, Glen C.; Mordechai, Eli; Adelson, Martin E.; Gygax, Scott E.; Trama, Jason P.

doi:10.1016/j.micinf.2012.01.010

Cited by 38 publications

(33 citation statements)

References 52 publications

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“…We did not observe suppression of cytokine expression and/or neutrophil recruitment by our UPEC strains, regardless of HlyA1 production, by 6 h (data not shown) or 24 h after inoculation, as has previously been reported by others (46,(54)(55)(56)(57)(58). These groups measured the cytokine IL-6 and/or IL-8 after infection of different strains of bladder epithelial cell lines with clinical isolates (NU14, F11, UTI89) or with laboratory strains (HB101, MG1655) and showed that the laboratory strains induced significantly more cytokine release than the clinical isolates (54)(55)(56)(57).…”

Section: Resultssupporting

confidence: 89%

“…Hilbert et al showed that IL-6 and IL-8 release by urothelial 5637 cells was suppressed in an HlyA-dependent manner in vitro but that HlyA did not impact the release of IL-1␤ or IL-10 in vivo after 24 h (56). We also did not observe a significant role for HlyA1 in the establishment of the inflammatory response in our mouse UTI model at 24 h (46,54,56).…”

Section: Resultscontrasting

confidence: 63%

“…Second, we conducted our study 24 h after infection rather than 1 to 8 h after challenge. The immune suppression observed by others was limited to the first 4 to 8 h postchallenge in vitro and in vivo (46,54,56). In addition, the role of HlyA in immune suppression remains unclear.…”

Section: Resultsmentioning

confidence: 98%

“…These groups measured the cytokine IL-6 and/or IL-8 after infection of different strains of bladder epithelial cell lines with clinical isolates (NU14, F11, UTI89) or with laboratory strains (HB101, MG1655) and showed that the laboratory strains induced significantly more cytokine release than the clinical isolates (54)(55)(56)(57). In addition, Loughman and Hunstad observed a reduction in neutrophil recruitment to the mouse bladder after challenge with UPEC strain UTI89 or CFT073 compared to that after challenge with the laboratory strain MG1655 (58).…”

Section: Resultsmentioning

confidence: 99%

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Cytotoxic Necrotizing Factor 1 and Hemolysin from Uropathogenic Escherichia coli Elicit Different Host Responses in the Murine Bladder

et al. 2013

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Cytotoxic necrotizing factor 1 (CNF1) and hemolysin (HlyA1) are toxins produced by uropathogenic Escherichia coli (UPEC). We previously showed that these toxins contribute to the inflammation and tissue damage seen in a mouse model of ascending urinary tract infection. CNF1 constitutively activates small Rho GTPases by deamidation of a conserved glutamine residue, and HlyA1 forms pores in eukaryotic cell membranes. In this study, we used cDNA microarrays of bladder tissue isolated from mice infected intraurethrally with wild-type CP9, CP9cnf1, or CP9⌬hlyA to further evaluate the role that each toxin plays in the host response to UPEC. Regardless of the strain used, we found that UPEC itself elicited a significant change in host gene expression 24 h after inoculation. The largest numbers of upregulated genes were in the cytokine and chemokine signaling and Toll-like receptor signaling pathways. CNF1 exerted a strong positive influence on expression of genes involved in innate immunity and signal transduction and a negative impact on metabolism-and transport-associated genes. HlyA1 evoked an increase in expression of genes that encode innate immunity factors and a decrease in expression of genes involved in cytoskeletal and metabolic processes. Multiplex cytokine and myeloperoxidase assays corroborated our finding that a strong proinflammatory response was elicited by all strains tested. Bladders challenged intraurethrally with purified CNF1 displayed pathology similar to but significantly less intense than the pathology that we observed in CP9-challenged mice. Our data demonstrate substantial roles for CNF1 and HlyA1 in initiation of a strong proinflammatory response to UPEC in the bladder. U rinary tract infections (UTIs) are the most common bacterial infection in women and affect over 50% of women at some time throughout their lifetime (1). The clinical manifestations of UTIs vary from mild to severe, and common symptoms include dysuria, hematuria, pyuria, urinary frequency and urgency, suprapubic pain, and fever. The annual cost in the United States for diagnosis and treatment of UTIs is over $3 billion (2). Uncomplicated UTIs occur when commensal bacteria from the gastrointestinal (GI) tract transit to the periurethral area or vaginal introitus. The bacteria are then introduced into the urethra and ascend into the bladder to cause cystitis and, in more severe cases, into the kidneys to cause pyelonephritis (3-5). The etiological agents of 85% of uncomplicated UTIs are uropathogenic Escherichia coli (UPEC), a subgroup of extraintestinal pathogenic E. coli (1). UPEC expresses virulence factors that specifically facilitate colonization of and replication within the urinary tract.Cytotoxic necrotizing factor 1 (CNF1) is an ϳ115-kDa toxin that is expressed by ϳ40% of UPEC isolates and up to 30% of diarrheal E. coli isolates (6). CNF1 constitutively activates small Rho-family GTPases via deamidation of glutamine 63 of RhoA and glutamine 61 in Rac1 and Cdc42 (7,8). Constitutive activation of these small GTPases by C...

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Section: Resultssupporting

confidence: 89%

Section: Resultscontrasting

confidence: 63%

Section: Resultsmentioning

confidence: 98%

Section: Resultsmentioning

confidence: 99%

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Cytotoxic Necrotizing Factor 1 and Hemolysin from Uropathogenic Escherichia coli Elicit Different Host Responses in the Murine Bladder

et al. 2013

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“…For example, the pore-forming toxin alpha-hemolysin (HlyA), which is produced by about 50% of all UPEC isolates, can promote the lysis of red blood cells, potentially freeing much-needed iron for use by the pathogens (98). Alternatively, at sublytic concentrations, HlyA can inhibit host cell inflammatory and survival pathways and indirectly stimulate the degradation of host cytoskeletal components (98,174,175,242). In wild-type zebrafish, the survival of a reference UPEC isolate known as UTI89 is entirely dependent upon the expression of HlyA (231).…”

Section: Zebrafishmentioning

confidence: 99%

Strengths and Limitations of Model Systems for the Study of Urinary Tract Infections and Related Pathologies

Barber

Norton

Wiles

et al. 2016

Microbiol Mol Biol Rev

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SUMMARYUrinary tract infections (UTIs) are some of the most common bacterial infections worldwide and are a source of substantial morbidity among otherwise healthy women. UTIs can be caused by a variety of microbes, but the predominant etiologic agent of these infections is uropathogenicEscherichia coli(UPEC). An especially troubling feature of UPEC-associated UTIs is their high rate of recurrence. This problem is compounded by the drastic increase in the global incidence of antibiotic-resistant UPEC strains over the past 15 years. The need for more-effective treatments for UTIs is driving research aimed at bettering our understanding of the virulence mechanisms and host-pathogen interactions that occur during the course of these infections. Surrogate models of human infection, including cell culture systems and the use of murine, porcine, avian, teleost (zebrafish), and nematode hosts, are being employed to define host and bacterial factors that modulate the pathogenesis of UTIs. These model systems are revealing how UPEC strains can avoid or overcome host defenses and acquire scarce nutrients while also providing insight into the virulence mechanisms used by UPEC within compromised individuals, such as catheterized patients. Here, we summarize our current understanding of UTI pathogenesis while also giving an overview of the model systems used to study the initiation, persistence, and recurrence of UTIs and life-threatening sequelae like urosepsis. Although we focus on UPEC, the experimental systems described here can also provide valuable insight into the disease processes associated with other bacterial pathogens both within the urinary tract and elsewhere within the host.

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Biofilm

Mazzoli¹

2015

Encyclopedia of Inflammatory Diseases

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Clinical Escherichia coli isolates utilize alpha-hemolysin to inhibit in vitro epithelial cytokine production

Cited by 38 publications

References 52 publications

Cytotoxic Necrotizing Factor 1 and Hemolysin from Uropathogenic Escherichia coli Elicit Different Host Responses in the Murine Bladder

Cytotoxic Necrotizing Factor 1 and Hemolysin from Uropathogenic Escherichia coli Elicit Different Host Responses in the Murine Bladder

Strengths and Limitations of Model Systems for the Study of Urinary Tract Infections and Related Pathologies

Biofilm

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