FdeC, a Novel Broadly Conserved Escherichia coli Adhesin Eliciting Protection against Urinary Tract Infections

Nesta, Barbara; Spraggon, Glen; Alteri, Christopher J.; Moriel, Danilo Gomes; Rosini, Roberto; Veggi, Daniele; Smith, Sara N.; Bertoldi, Isabella; Pastorello, Ilaria; Ferlenghi, Ilaria; Fontana, Maria Rita; Frankel, Gad; Mobley, Harry L. T.; Rappuoli, Rino; Pizza, Mariagrazia; Serino, Laura; Soriani, Marco

doi:10.1128/mbio.00010-12

Cited by 110 publications

(101 citation statements)

References 35 publications

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“…On the other hand, nonfimbrial adhesins have garnered less attention than chaperone-usher adhesins. These adhesins, nevertheless, can also contribute to uropathogenesis (25)(26)(27)(28)(29)(30), underscoring the importance of continued study of this adhesin class.…”

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confidence: 99%

A Conserved PapB Family Member, TosR, Regulates Expression of the Uropathogenic Escherichia coli RTX Nonfimbrial Adhesin TosA while Conserved LuxR Family Members TosE and TosF Suppress Motility

2014

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A heterogeneous subset of extraintestinal pathogenic Escherichia coli (ExPEC) strains, referred to as uropathogenic E. coli (UPEC), causes most uncomplicated urinary tract infections. However, no core set of virulence factors exists among UPEC strains. Instead, the focus of the analysis of urovirulence has shifted to studying broad classes of virulence factors and the interactions between them. For example, the RTX nonfimbrial adhesin TosA mediates adherence to host cells derived from the upper urinary tract. The associated tos operon is well expressed in vivo but poorly expressed in vitro and encodes TosCBD, a predicted type 1 secretion system. TosR and TosEF are PapB and LuxR family transcription factors, respectively; however, no role has been assigned to these potential regulators. Thus, the focus of this study was to determine how TosR and TosEF regulate tosA and affect the reciprocal expression of adhesins and flagella. Among a collection of sequenced UPEC strains, 32% (101/317) were found to encode TosA, and nearly all strains (91% [92/101]) simultaneously carried the putative regulatory genes. Deletion of tosR alleviates tosA repression. The tos promoter was localized upstream of tosR using transcriptional fusions of putative promoter regions with lacZ. TosR binds to this region, affecting a gel shift. A 100-bp fragment 220 to 319 bp upstream of tosR inhibits binding, suggesting localization of the TosR binding site. TosEF, on the other hand, downmodulate motility when overexpressed by preventing the expression of fliC, encoding flagellin. Deletion of tosEF increased motility. Thus, we present an additional example of the reciprocal control of adherence and motility. U rinary tract infections (UTIs) are the second most common bacterial infection in humans (1). UTIs can be classified as complicated or uncomplicated infections. Uncomplicated UTIs, occurring in otherwise healthy individuals, are self-limited infections of the bladder, referred to as cystitis (2-4). However, upon bacterial ascension into the kidney, a more serious infection referred to as pyelonephritis can develop (2, 4). Pyelonephritis, in turn, can lead to the development of bacteremia and sometimes fatal urosepsis (5, 6).UTIs normally occur when uropathogens that colonize the intestine alongside commensal organisms gain access to the periurethral area and then ascend to the urinary bladder (7,8). A heterogeneous subset of extraintestinal pathogenic Escherichia coli (ExPEC) strains, referred to as uropathogenic E. coli (UPEC), causes the overwhelming majority of uncomplicated UTIs (4). UPEC strains carry a battery of virulence factors, including adhesins, toxins, and iron acquisition systems, which promote uropathogenesis (9, 10). However, no core set of virulence factors has been identified. Instead, any given UPEC strain appears to use various virulence factors from these three classes of virulence determinants to colonize the urinary tract (11,12). This thesis requires that we consider established, newly discovered, and putative virule...

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A Conserved PapB Family Member, TosR, Regulates Expression of the Uropathogenic Escherichia coli RTX Nonfimbrial Adhesin TosA while Conserved LuxR Family Members TosE and TosF Suppress Motility

2014

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“…Although eaeH was originally identified in ETEC, it is shared by other E. coli pathotypes, including strains associated with extraintestinal infections (33,54,55), including uropathogenic E. coli (48). Because E. coli is a normal component of the intestinal flora, targeting highly conserved antigens that are shared with some commensal isolates in vaccines could in theory have untoward consequences.…”

Section: Discussionmentioning

confidence: 99%

Contribution of the Highly Conserved EaeH Surface Protein to Enterotoxigenic Escherichia coli Pathogenesis

Sheikh

Luo

Roy³

et al. 2014

Infect Immun

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f Enterotoxigenic Escherichia coli (ETEC) strains are among the most common causes of diarrheal illness worldwide. These pathogens disproportionately afflict children in developing countries, where they cause substantial morbidity and are responsible for hundreds of thousands of deaths each year. Although these organisms are important targets for enteric vaccines, most development efforts to date have centered on a subset of plasmid-encoded fimbrial adhesins known as colonization factors and heatlabile toxin (LT). Emerging data suggest that ETEC undergoes considerable changes in its surface architecture, sequentially deploying a number of putative adhesins during its interactions with the host. We demonstrate here that one putative highly conserved, chromosomally encoded adhesin, EaeH, engages the surfaces of intestinal epithelial cells and contributes to bacterial adhesion, LT delivery, and colonization of the small intestine. Infectious diarrhea continues to cause tremendous suffering in developing countries, resulting in an estimated one to two million deaths each year. Enterotoxigenic Escherichia coli (ETEC) contributes significantly to premature deaths from diarrheal illness in young children (1, 2) and causes substantial morbidity in surviving children and adults (3). ETEC strains are perennially the leading etiology of diarrhea in travelers to areas where ETEC strains are endemic (4).By definition, these organisms secrete heat-labile (LT) and/or heat-stable (ST) enterotoxins that induce host cell production of cyclic nucleotides (cyclic AMP [cAMP] and cGMP, respectively) to activate protein kinases that ultimately result in phosphorylation of the cystic fibrosis transmembrane regulatory channel (CFTR) (5-7) and Na ϩ ion exchangers (8) on the surfaces of intestinal epithelial cells. Ensuing chloride secretion through CFTR, as well as the commensurate loss of salt and water into the intestinal lumen, results in the cholera-like watery diarrhea characteristic of ETEC infections (9).In the current paradigm for ETEC pathogenesis, this organism must effectively colonize the small intestine to deliver LT and/or ST efficiently. The majority of pathogenesis (10-12) and molecular epidemiology (13) studies, as well as subsequent vaccine development efforts (14, 15), have focused primarily on plasmid-encoded fimbrial colonization factors (CFs), which are felt to be critical for colonization of the small intestine.This longstanding but fairly simple view of ETEC pathogenesis in which bacteria adhere via CFs to the small intestine, where these pathogens release their toxin(s), likely underestimates the complexity of these pathogens. More recent investigations have highlighted a number of novel putative virulence factors (16, 17), unique interactions of ETEC with the epithelium (18)(19)(20), and an intricate orchestration of multiple pathogen-host events (21) that culminate in successful toxin delivery to epithelial cell targets (22). Collectively, the emerging data suggest that these sophisticated interactions of ETEC ...

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“…UPEC isolates encode dozens of adhesins that vary in their receptor specificity and whether or not they are assembled into pili (also known as fimbriae) (34,(48)(49)(50) (Fig. 1).…”

Section: The Life Cycle Of Upecmentioning

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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FdeC, a Novel Broadly Conserved Escherichia coli Adhesin Eliciting Protection against Urinary Tract Infections

Cited by 110 publications

References 35 publications

A Conserved PapB Family Member, TosR, Regulates Expression of the Uropathogenic Escherichia coli RTX Nonfimbrial Adhesin TosA while Conserved LuxR Family Members TosE and TosF Suppress Motility

A Conserved PapB Family Member, TosR, Regulates Expression of the Uropathogenic Escherichia coli RTX Nonfimbrial Adhesin TosA while Conserved LuxR Family Members TosE and TosF Suppress Motility

Contribution of the Highly Conserved EaeH Surface Protein to Enterotoxigenic Escherichia coli Pathogenesis

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

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