The Ins and Outs of siderophore mediated iron uptake by extra-intestinal pathogenic Escherichia coli

Garénaux, Amélie; Caza, Mélissa; Dozois, Charles M.

doi:10.1016/j.vetmic.2011.05.023

Cited by 108 publications

(103 citation statements)

References 115 publications

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“…3D). Notably, highly evolved iron acquisition strategies, including Aer and Ybt, are critical virulence factors for ExPEC and other pathogenic species within the Enterobacteriaceae (61,62). Therefore, by defining the protective efficacy of two stealth siderophores prevalent among pathogenic E. coli (39), we have determined that Ybt and Aer are valuable antigens that have not heretofore been included in any UTI vaccines and, more generally, exemplify the untapped resource of bacteria-specific small molecules as potential vaccine antigens.…”

Section: Discussionmentioning

confidence: 99%

Siderophore vaccine conjugates protect against uropathogenicEscherichia coliurinary tract infection

Mike

Smith

Sumner

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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Uropathogenic Escherichia coli (UPEC) is the primary cause of uncomplicated urinary tract infections (UTIs). Whereas most infections are isolated cases, 1 in 40 women experience recurrent UTIs. The rise in antibiotic resistance has complicated the management of chronic UTIs and necessitates new preventative strategies. Currently, no UTI vaccines are approved for use in the United States, and the development of a highly effective vaccine remains elusive. Here, we have pursued a strategy for eliciting protective immunity by vaccinating with small molecules required for pathogenesis, rather than proteins or peptides. Small iron-chelating molecules called siderophores were selected as antigens to vaccinate against UTI for this vaccine strategy. These pathogen-associated stealth siderophores evade host immune defenses and enhance bacterial virulence. Previous animal studies revealed that vaccination with siderophore receptor proteins protects against UTI. The poor solubility of these integral outer-membrane proteins in aqueous solutions limits their practical utility. Because their cognate siderophores are water soluble, we hypothesized that these bacterial-derived small molecules are prime vaccine candidates. To test this hypothesis, we immunized mice with siderophores conjugated to an immunogenic carrier protein. The siderophore-protein conjugates elicited an adaptive immune response that targeted bacterial stealth siderophores and protected against UTI. Our study has identified additional antigens suitable for a multicomponent UTI vaccine and highlights the potential use of bacterial-derived small molecules as antigens in vaccine therapies.vaccine conjugate | urinary tract infection | siderophore | UPEC | iron acquisition

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Section: Discussionmentioning

confidence: 99%

Siderophore vaccine conjugates protect against uropathogenicEscherichia coliurinary tract infection

Mike

Smith

Sumner

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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“…The host has a number of Fe binding proteins (e.g., transferrin) that serve to withhold Fe from the invading pathogen. K. pneumoniae, like other Enterobacteriaceae, produces and secretes SP that acquire Fe from host binding proteins and then reenter the bacterial cell by SP-specific receptors (24). Aerobactin, enterobactin, salmochelin, and yersiniabactin are SP that have been described in K. pneumoniae (25).…”

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confidence: 99%

Aerobactin Mediates Virulence and Accounts for Increased Siderophore Production under Iron-Limiting Conditions by Hypervirulent (Hypermucoviscous) Klebsiella pneumoniae

et al. 2014

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f Hypervirulent (hypermucoviscous) Klebsiella pneumoniae (hvKP) strains are an emerging variant of "classical" K. pneumoniae (cKP) that cause organ and life-threatening infection in healthy individuals. An understanding of hvKP-specific virulence mechanisms that enabled evolution from cKP is limited. Observations by our group and previously published molecular epidemiologic data led us to hypothesize that hvKP strains produced more siderophores than cKP strains and that this trait enhanced hvKP virulence. Quantitative analysis of 12 hvKP strains in iron-poor minimal medium or human ascites fluid showed a significant and distinguishing 6-to 10-fold increase in siderophore production compared to that for 14 cKP strains. Surprisingly, highpressure liquid chromatography (HPLC)-mass spectrometry and characterization of the hvKP strains hvKP1, A1142, and A1365 and their isogenic aerobactin-deficient (⌬iucA) derivatives established that aerobactin accounted for the overwhelming majority of increased siderophore production and that this was not due to gene copy number. Further, aerobactin was the primary factor in conditioned medium that enhanced the growth/survival of hvKP1 in human ascites fluid. Importantly the ex vivo growth/ survival of hvKP1 ⌬iucA was significantly less than that of hvKP1 in human ascites fluid, and the survival of outbred CD1 mice challenged subcutaneously or intraperitoneally with hvKP1 was significantly less than that of mice challenged with hvKP1 ⌬iucA. The lowest subcutaneous and intraperitoneal challenge inocula of 3 ؋ 10 2 and 3.2 ؋ 10 1 CFU, respectively, resulted in 100% mortality, demonstrating the virulence of hvKP1 and its ability to cause infection at a low dose. These data strongly support that aerobactin accounts for increased siderophore production in hvKP compared to cKP (a potential defining trait) and is an important virulence factor.

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“…To overcome iron starvation within the host, E. coli strains are able to produce up to 4 different siderophores: enterobactin, salmochelins, aerobactin, and yersiniabactin. Whereas most E. coli strains, including commensal strains, produce enterobactin, salmochelins, aerobactin, and yersiniabactin are associated with pathogenic E. coli strains (37,38). Salmochelins are glycosylated molecules of enterobactin that are synthesized by the iroBCDE gene products, while aerobactin is synthesized by the iucABCD gene products (39)(40)(41)(42).…”

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confidence: 99%

The Small RNA RyhB Contributes to Siderophore Production and Virulence of Uropathogenic Escherichia coli

et al. 2014

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eIn Escherichia coli, the small regulatory noncoding RNA (sRNA) RyhB and the global ferric uptake regulator (Fur) mediate iron acquisition and storage control. Iron is both essential and potentially toxic for most living organisms, making the precise maintenance of iron homeostasis necessary for survival. While the roles of these regulators in iron homeostasis have been well studied in a nonpathogenic E. coli strain, their impact on the production of virulence-associated factors is still unknown for a pathogenic E. coli strain. We thus investigated the roles of RyhB and Fur in iron homeostasis and virulence of the uropathogenic E. coli (UPEC) strain CFT073. In a murine model of urinary tract infection (UTI), deletion of fur alone did not attenuate virulence, whereas a ⌬ryhB mutant and a ⌬fur ⌬ryhB double mutant showed significantly reduced bladder colonization. The ⌬fur mutant was more sensitive to oxidative stress and produced more of the siderophores enterobactin, salmochelins, and aerobactin than the wild-type strain. In contrast, while RyhB was not implicated in oxidative stress resistance, the ⌬ryhB mutant produced lower levels of siderophores. This decrease was correlated with the downregulation of shiA (encoding a transporter of shikimate, a precursor of enterobactin and salmochelin biosynthesis) and iucD (involved in aerobactin biosynthesis) in this mutant grown in minimal medium or in human urine. iucD was also downregulated in bladders infected with the ⌬ryhB mutant compared to those infected with the wild-type strain. Our results thus demonstrate that the sRNA RyhB is involved in production of iron acquisition systems and colonization of the urinary tract by pathogenic E. coli.

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The Ins and Outs of siderophore mediated iron uptake by extra-intestinal pathogenic Escherichia coli

Cited by 108 publications

References 115 publications

Siderophore vaccine conjugates protect against uropathogenicEscherichia coliurinary tract infection

Siderophore vaccine conjugates protect against uropathogenicEscherichia coliurinary tract infection

Aerobactin Mediates Virulence and Accounts for Increased Siderophore Production under Iron-Limiting Conditions by Hypervirulent (Hypermucoviscous) Klebsiella pneumoniae

The Small RNA RyhB Contributes to Siderophore Production and Virulence of Uropathogenic Escherichia coli

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