<i>Yersinia pestis</i>Two-Component Gene Regulatory Systems Promote Survival in Human Neutrophils

O’Loughlin, Jason L.; Spinner, Justin L.; Minnich, Scott A.; Kobayashi, Scott D.

doi:10.1128/iai.00718-09

Cited by 68 publications

(68 citation statements)

References 53 publications

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“…For example, activation of CpxRA in Shigella sonnei results in increased expression of virulence genes (18). Further supporting a role for the CpxRA TCS during infection, the insect pathogen Xenorhabdus nematophila and the human pathogens Yersinia pestis and uropathogenic E. coli require the CpxRA TCS for full virulence (19)(20)(21). These results are in direct contrast to what was observed for Haemophilus ducreyi, where activation of the CpxRA TCS results in the downregulation of known virulence genes (14).…”

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confidence: 54%

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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confidence: 54%

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

et al. 2015

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“…Certain known PhoP-regulated virulence factors have been shown to be upregulated in the flea, however, and their induction prior to transmission may enhance infectivity in the mammal by conferring resistance to the initial innate immune response encountered at the flea bite site (36). In addition to resistance to CAMPs, the PhoPPhoQ two-component regulatory system is required for Y. pestis resistance to killing by neutrophils (81), which the bacteria encounter very soon after transmission. In this regard, upregulation of the PhoP-PhoQ system prior to transmission in the flea may be especially important because the major antiphagocytic virulence factors encoded by the type III secretion system are not expressed at a low temperature in the flea and are not fully functional until a few hours after a shift to 37°C (57,75,82).…”

Section: Discussionmentioning

confidence: 99%

Induction of the Yersinia pestis PhoP-PhoQ Regulatory System in the Flea and Its Role in Producing a Transmissible Infection

et al. 2013

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cTransmission of Yersinia pestis is greatly enhanced after it forms a bacterial biofilm in the foregut of the flea vector that interferes with normal blood feeding. Here we report that the ability to produce a normal foregut-blocking infection depends on induction of the Y. pestis PhoP-PhoQ two-component regulatory system in the flea. Y. pestis phoP-negative mutants achieved normal infection rates and bacterial loads in the flea midgut but produced a less cohesive biofilm both in vitro and in the flea and had a greatly reduced ability to localize to and block the flea foregut. Thus, not only is the PhoP-PhoQ system induced in the flea gut environment, but also this induction is required to produce a normal transmissible infection. The altered biofilm phenotype in the flea was not due to lack of PhoPQ-dependent or PmrAB-dependent addition of aminoarabinose to the Y. pestis lipid A, because an aminoarabinose-deficient mutant that is highly sensitive to cationic antimicrobial peptides had a normal phenotype in the flea digestive tract. In addition to enhancing transmissibility, induction of the PhoP-PhoQ system in the arthropod vector prior to transmission may preadapt Y. pestis to resist the initial encounter with the mammalian innate immune response.

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“…KdpE has also been recently identified as an important virulence factor in a number of pathogens. It has been shown to be important in the intracellular survival of pathogens such as Yersinia pestis, Mycobacterium bovis, and Photorhabdus asymbiotica (57)(58)(59). We had previously shown that these two transcriptional factors, Cra and KdpE, directly bind to the promoter region of ler, the master regulator of the LEE genes, and consequently activate this island, leading to the formation of AE lesions (34).…”

Section: Discussionmentioning

confidence: 99%

The Interacting Cra and KdpE Regulators Are Involved in the Expression of Multiple Virulence Factors in Enterohemorrhagic Escherichia coli

2013

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The human pathogen enterohemorrhagic Escherichia coli (EHEC) O157:H7 codes for two interacting DNA binding proteins, Cra and KdpE, that coregulate expression of the locus of enterocyte effacement (LEE) genes in a metabolite-dependent manner. Cra is a transcription factor that uses fluctuations in the concentration of carbon metabolism intermediates to positively regulate virulence of EHEC. KdpE is a response regulator that activates the transcription of homeostasis genes in response to salt-induced osmolarity and virulence genes in response to changes in metabolite concentrations. Here, we probed the transcriptional profiles of the ⌬cra, ⌬kdpE, and ⌬cra ⌬kdpE mutant strains and show that Cra and KdpE share several targets besides the LEE, but both Cra and KdpE also have independent targets. Several genes within O-islands (genomic islands present in EHEC but absent from E. coli K-12), such as Z0639, Z0640, Z3388, Z4267, and espFu (encoding an effector necessary for formation of attaching and effacing lesions on epithelial cells), were directly regulated by both Cra and KdpE, while Z2077 was only regulated by Cra. These studies identified and confirmed new direct targets for Cra and KdpE that included putative virulence factors as well as characterized virulence factors, such as EspFu and EspG. These results map out the role of the two interacting regulators, Cra and KdpE, in EHEC pathogenesis and global gene regulation.

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Yersinia pestisTwo-Component Gene Regulatory Systems Promote Survival in Human Neutrophils

Cited by 68 publications

References 53 publications

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

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

Induction of the Yersinia pestis PhoP-PhoQ Regulatory System in the Flea and Its Role in Producing a Transmissible Infection

The Interacting Cra and KdpE Regulators Are Involved in the Expression of Multiple Virulence Factors in Enterohemorrhagic Escherichia coli

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