Mutations That Impact the Enteropathogenic Escherichia coli Cpx Envelope Stress Response Attenuate Virulence in Galleria mellonella

Leuko, S.; Raivio, Tracy

doi:10.1128/iai.00081-12

Cited by 53 publications

(64 citation statements)

References 76 publications

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“…In EPEC, CpxRA is required to adapt to envelope stress; however, CpxRA activation leads to decreased TTS gene expression; these apparently contrasting roles suggest that cpxRA expression is under tight control in vivo (13). In support of this, it was previously shown that both inhibition and constitutive activation of CpxRA in EPEC negatively affect virulence in the wax worm larva model (30). Consistent with these data, attempts to complement the C. rodentium CpxRA TCS by using low-copy-number plasmids were successful in vitro but resulted in only inconsistent complementation in vivo, further suggesting that fine-tuning of cpxRA expression is important for infection (data not shown).…”

Section: Discussionmentioning

confidence: 62%

“…Therefore, the constitutive activation of CpxRA negatively impacts virulence gene expression in vitro. In addition to these findings, the deletion of cpxR and subsequent inactivation of CpxRA leads to decreases in cell adherence and in vitro infectivity of EPEC (30). These studies provide compelling evidence that CpxRA is involved in the regulation of essential colonization and virulence factors of EPEC and that the activation of this TCS must be carefully fine-tuned to protect cells against cell envelope stress while allowing for virulence gene expression.…”

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confidence: 92%

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The CpxRA Two-Component System Is Essential for Citrobacter rodentium Virulence

et al. 2015

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dCitrobacter rodentium is a murine intestinal pathogen used as a model for the foodborne human pathogens enterohemorrhagic Escherichia coli and enteropathogenic E. coli. During infection, these pathogens use two-component signal transduction systems to detect and adapt to changing environmental conditions. In E. coli, the CpxRA two-component signal transduction system responds to envelope stress by modulating the expression of a myriad of genes. Quantitative real-time PCR showed that cpxRA was expressed in the colon of C57BL/6J mice infected with C. rodentium. To determine whether CpxRA plays a role during C. rodentium infection, a cpxRA deletion strain was generated and found to have a colonization defect during infection. This defect was independent of an altered growth rate or a defective type III secretion system, and single-copy chromosomal complementation of cpxRA restored virulence. The C. rodentium strains were then tested in C3H/HeJ mice, a lethal intestinal infection model. Mice infected with the ⌬cpxRA strain survived infection, whereas mice infected with the wild-type or complemented strains succumbed to infection. Furthermore, we found that the cpxRA expression level was higher during early infection than at a later time point. Taken together, these data demonstrate that the CpxRA two-component signal transduction system is essential for the in vivo virulence of C. rodentium. In addition, these data suggest that fine-tuned cpxRA expression is important for infection. This is the first study that identifies a C. rodentium two-component transduction system required for pathogenesis. This study further indicates that CpxRA is an interesting target for therapeutics against enteric pathogens.

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Section: Discussionmentioning

confidence: 62%

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confidence: 92%

The CpxRA Two-Component System Is Essential for Citrobacter rodentium Virulence

et al. 2015

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“…The similarity of these results to the Cpx data, along with the inclusion of the ToxRregulated ompT in the list of CpxR-responsive genes, suggests that attenuation of CT and TCP production in the RND-deficient strain may be due to the activation of the Cpx system. Although the Cpx system has been linked to virulence in other pathogens (68)(69)(70)(71)(72)(73), our data indicate that the Cpx system does not affect V. cholerae virulence factor production. This was evidenced by the fact that cpxR deletion, constitutive activation of the Cpx system (i.e., cpxA*), or chemical activation of the Cpx system (i.e., with CuCl 2 ) did not affect CT or TCP production.…”

Section: Discussionmentioning

confidence: 72%

Reciprocal Regulation of Resistance-Nodulation-Division Efflux Systems and the Cpx Two-Component System in Vibrio cholerae

et al. 2014

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The Cpx two-component regulatory system has been shown in Escherichia coli to alleviate stress caused by misfolded cell envelope proteins. The Vibrio cholerae Cpx system was previously found to respond to cues distinct from those in the E. coli system, suggesting that this system fulfills a different physiological role in the cholera pathogen. Here, we used microarrays to identify genes that were regulated by the V. cholerae Cpx system. Our observations suggest that the activation of the V. cholerae Cpx system does not induce expression of genes involved in the mitigation of stress generated by misfolded cell envelope proteins but promotes expression of genes involved in antimicrobial resistance. In particular, activation of the Cpx system induced expression of the genes encoding the VexAB and VexGH resistance-nodulation-division (RND) efflux systems and their cognate outer membrane pore protein TolC. The promoters for these loci contained putative CpxR consensus binding sites, and ectopic cpxR expression activated transcription from the promoters for the RND efflux systems. CpxR was not required for intrinsic antimicrobial resistance, but CpxR activation enhanced resistance to antimicrobial substrates of VexAB and VexGH. Mutations that inactivated VexAB or VexGH efflux activity resulted in the activation of the Cpx response, suggesting that vexAB and vexGH and the cpxP-cpxRA system are reciprocally regulated. We speculate that the reciprocal regulation of the V. cholerae RND efflux systems and the Cpx two-component system is mediated by the intracellular accumulation of an endogenously produced metabolic by-product that is normally extruded from the cell by the RND efflux systems. Vibrio cholerae is a facultative human pathogen that causes cholera, a severe acute diarrheal disease that is estimated to afflict 3 to 5 million people annually (1). People acquire cholera by ingestion of V. cholerae-contaminated food or water (2). Once in the host environment, V. cholerae produces a variety of virulence factors that enable the pathogen to colonize the small intestine and to cause diarrhea. Two critical virulence factors coregulated by the virulence activator ToxR are the toxin-coregulated pilus (TCP), a type IV pilus that is essential for colonization, and cholera toxin (CT), an enterotoxin that causes the secretory diarrhea that is the hallmark of cholera (3-8). Like the expression of TCP, intestinal colonization is dependent upon V. cholerae overcoming host barriers in the human gastrointestinal tract. These barriers include antimicrobial compounds, such as bile salts, fatty acids, and components of the innate immune system. V. cholerae resistance to these factors is largely dependent upon the production of the resistance-nodulation-division (RND) family of efflux systems (9, 10).RND efflux systems are tripartite transporters that are ubiquitous among Gram-negative bacteria. Each RND efflux system is made up of three components: an outer membrane porin homologous to Escherichia coli tolC, an integral cytoplasmic m...

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“…(46,47), Legionella pneumophila (31,48), Shigella spp. (33)(34)(35), enteropathogenic E. coli (32,49,50), Actinobacillus suis (51), Haemophilus ducreyi (52,53), Xenorhabdus nematophila (37,54), and Yersinia pseudotuberculosis (55)(56)(57). However, direct evidence that the Cpx system can affect pathogen fitness and virulence in vivo within an animal host is limited to only a few studies (47,50,53,54).…”

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confidence: 99%

“…(33)(34)(35), enteropathogenic E. coli (32,49,50), Actinobacillus suis (51), Haemophilus ducreyi (52,53), Xenorhabdus nematophila (37,54), and Yersinia pseudotuberculosis (55)(56)(57). However, direct evidence that the Cpx system can affect pathogen fitness and virulence in vivo within an animal host is limited to only a few studies (47,50,53,54). In UPEC, the Cpx system has been examined primarily with respect to its ability to modulate the expression of P pili, filamentous adhesive organelles that can promote bacterial interactions with host kidney cells (27,28,58).…”

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confidence: 99%

The Cpx Stress Response System Potentiates the Fitness and Virulence of Uropathogenic Escherichia coli

et al. 2013

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Strains of uropathogenic Escherichia coli (UPEC) are the primary cause of urinary tract infections, representing one of the most widespread and successful groups of pathogens on the planet. To colonize and persist within the urinary tract, UPEC must be able to sense and respond appropriately to environmental stresses, many of which can compromise the bacterial envelope. The Cpx two-component envelope stress response system is comprised of the inner membrane histidine kinase CpxA, the cytosolic response regulator CpxR, and the periplasmic auxiliary factor CpxP. Here, by using deletion mutants along with mouse and zebrafish infection models, we show that the Cpx system is critical to the fitness and virulence of two reference UPEC strains, the cystitis isolate UTI89 and the urosepsis isolate CFT073. Specifically, deletion of the cpxRA operon impaired the ability of UTI89 to colonize the murine bladder and greatly reduced the virulence of CFT073 during both systemic and localized infections within zebrafish embryos. These defects coincided with diminished host cell invasion by UTI89 and increased sensitivity of both strains to complement-mediated killing and the aminoglycoside antibiotic amikacin. Results obtained with the cpxP deletion mutants were more complicated, indicating variable strain-dependent and niche-specific requirements for this well-conserved auxiliary factor.

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Mutations That Impact the Enteropathogenic Escherichia coli Cpx Envelope Stress Response Attenuate Virulence in Galleria mellonella

Abstract: ABSTRACTIn this paper, we show that the larvae of the greater wax moth,Galleria mellonella, can be used as a model to study enteropathogenicEscherichia coli(EPEC) virulence. Show more

Cited by 53 publications

References 76 publications

The CpxRA Two-Component System Is Essential for Citrobacter rodentium Virulence

The CpxRA Two-Component System Is Essential for Citrobacter rodentium Virulence

Reciprocal Regulation of Resistance-Nodulation-Division Efflux Systems and the Cpx Two-Component System in Vibrio cholerae

The Cpx Stress Response System Potentiates the Fitness and Virulence of Uropathogenic Escherichia coli

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