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Shiga toxin-producing Escherichia coli (STEC), especially of serotype O157:H7, cause a zoonotic food or waterborne enteric illness that is often associated with large epidemic outbreaks as well as the hemolytic uremic syndrome (HUS), the leading cause of acute renal failure in children. After ingestion, STEC colonize enterocytes of the large bowel with a characteristic attaching and effacing pathology, which is mediated by components of a type III secretion apparatus encoded by the LEE pathogenicity island. Shiga toxins are translocated from the bowel to the circularoty system and transported by leukocytes to capillary endothelial cells in renal glomeruli and other organs. After binding to the receptor globotriaosylceramide on target cells, the toxin is internalized by receptor-mediated endocytosis and interacts with the subcellular machinery to inhibit protein synthesis. This leads to pathophysiological changes that result in HUS. Specific therapeutic or preventive strategies are presently not available. The recent sequencing of genomes of two epidemic E. coli O157 strains has revealed novel pathogenicity islands which will likely provide new insights into the virulence of these bacteria.
Mol Biotechnol 2004 Feb
PMID:Infection by Shiga toxin-producing Escherichia coli: an overview. 1476 37

Shiga toxin (Stx) genes in Stx producing Escherichia coli (STEC) are encoded in prophages of the lambda family, such as H-19B. The subpopulation of STEC lysogens with induced prophages has been postulated to contribute significantly to Stx production and release. To study induced STEC, we developed a selectable in vivo expression technology, SIVET, a reporter system adapted from the RIVET system. The SIVET lysogen has a defective H-19B prophage encoding the TnpR resolvase gene downstream of the phage PR promoter and a cat gene with an inserted tet gene flanked by targets for the TnpR resolvase. Expression of resolvase results in excision of tet, restoring a functional cat gene; induced lysogens survive and are chloramphenicol resistant. Using SIVET we show that: (i) approximately 0.005% of the H-19B lysogens are spontaneously induced per generation during growth in LB. (ii) Variations in cellular physiology (e.g. RecA protein) rather than in levels of expressed repressor explain why members of a lysogen population are spontaneously induced. (iii) A greater fraction of lysogens with stx encoding prophages are induced compared to lysogens with non-Stx encoding prophages, suggesting increased sensitivity to inducing signal(s) has been selected in Stx encoding prophages. (iv) Only a small fraction of the lysogens in a culture spontaneously induce and when the lysogen carries two lambdoid prophages with different repressor/operators, 933W and H-19B, usually both prophages in the same cell are induced.
Mol Microbiol 2004 Mar
PMID:Characterizing spontaneous induction of Stx encoding phages using a selectable reporter system. 1500 95

This paper describes 5'-nuclease PCR assays for detecting eight O-serogroups, H7 flagellar antigen and stx genes from the Shiga toxin-producing Escherichia coli (STEC) associated with the world's most frequent clinical cases. A single set of primers was used to detect the genes stx1 and stx2 in the same reaction by 5'-nuclease PCR. Serotyping by 5'-nuclease PCR of STEC was based on the selection of primers and probes targeting the O-antigen gene clusters of E. coli O26, O55, O91, O111, O113, O157, the eae gene of E. coli O103, the O-island 29 of E. coli O145, and the flagellar H7 antigen gene. Results obtained on a collection of 190 strains indicate that the 5'-nuclease PCR assays used here could serve as a basis for rapid specific stx, O and H7 typing of these major pathogenic serogroups of E. coli. This work provides sensitive and specific tests for the rapid, reliable detection of the main pathogenic E. coli O-serogroups of major public health concern.
Mol Cell Probes 2004 Jun
PMID:Detection by 5'-nuclease PCR of Shiga-toxin producing Escherichia coli O26, O55, O91, O103, O111, O113, O145 and O157:H7, associated with the world's most frequent clinical cases. 1513 53

Bacterial virulence factors such as toxins are often encoded by bacteriophages. Among other examples, factors encoded by phages have been described in some of the emerging or re-emerging pathogens, including the pyrogenic exotoxin A production in group A streptococci, the cholera toxin in Vibrio cholerae, or enterotoxin production in enterohemorrhagic (EHEC) strains of E. coli. Most described virulence factors in Shiga toxin (Stx)-producing E. coli strains are located in mobile genetic elements such as plasmids and bacteriophages. Stx, which are one of the most important virulence elements in Shiga toxin-producing E. coli (STEC), are encoded in the genome of temperate bacteriophages infecting E. coli and other Enterobacteriaceae. Studies on Stx phages indicate that they are transmitted between different bacteria in vivo and in vitro. Phages could also be transmitted extraintestinally, hence the observed presence of infectious Shiga toxin phages in sewage and in fecally contaminated rivers. Stx phages also show a higher persistence under natural inactivation and disinfectant treatments in aquatic environments.This background shows that phages or lysogenic strains carrying Stx2 phages might be the natural reservoir of Stx2 genes and that lysogenization could be the main cause of the emergence of STEC strains, as suggested by several authors. It has also been suggested that lysogenization/conversion processes could take place in food and water and probably inside the human and animal gut. Ingestion of Stx2 phages could produce conversion of non-Stx2-E. coli strains, present inside the gut and producing new pathogenic strains. To control these phenomena, it is first necessary to gain more information about the distribution of Stx phages in the environment. For this purpose, a method of detecting Stx2 phages present in environmental water samples has been developed. The particularity of this method is that it allows detection of all (infectious and noninfectious) Stx2 phages in a water sample; in a second stage, the method allows detection of those phages able to infect and replicate on E. coli O157:H7. Although this method has been applied to Stx2 phages able to infect E. coli O157:H7, it is also applicable to detection in the natural environment of other genes carried by other bacteriophages and other bacteria.
Methods Mol Biol 2004
PMID:Abundance in sewage of bacteriophages infecting Escherichia coli O157:H7. 1515 20

An in vitro transport assay, established with a modified Shiga toxin B subunit (STxB) as a marker, has proved to be useful for the study of transport from the early/recycling endosome (EE/RE) to the trans-Golgi network (TGN). Here, we modified this assay to test antibodies to all known soluble N-ethylmaleimide-sensitive factor attachment protein receptors (SNAREs) that have been shown to localize in the Golgi and found that syntaxin 5, GS28, Ykt6, and GS15 antibodies specifically inhibited STxB transport. Because syntaxin 5, GS28, Ykt6, and GS15 exist as a unique SNARE complex, our observation indicates that these four SNAREs function as a complex in EE/RE-TGN transport. The importance of GS15 in EE/RE-TGN transport was further demonstrated by a block in recombinant STxB transport in HeLa cells when GS15 expression was knocked down by its small interfering iRNA. Morphological analyses showed that some GS15 and Ykt6 were redistributed from the Golgi to the endosomes when the recycling endosome was perturbed by SNX3-overexpression, suggesting that GS15 and Ykt6 might cycle between the endosomes and the Golgi apparatus. Further studies indicated that syntaxin 5 and syntaxin 16 exerted their role in EE/RE-TGN transport in an additive manner. The kinetics of inhibition exhibited by syntaxin 16 and syntaxin 5 antibodies is similar.
Mol Biol Cell 2004 Sep
PMID:Participation of the syntaxin 5/Ykt6/GS28/GS15 SNARE complex in transport from the early/recycling endosome to the trans-Golgi network. 1521 10

The precise cellular function of Arl1 and its effectors, the GRIP domain Golgins, is not resolved, despite our recent understanding that Arl1 regulates the membrane recruitment of these Golgins. In this report, we describe our functional study of Golgin-97. Using a Shiga toxin B fragment (STxB)-based in vitro transport assay, we demonstrated that Golgin-97 plays a role in transport from the endosome to the trans-Golgi network (TGN). The recombinant GRIP domain of Golgin-97 as well as antibodies against Golgin-97 inhibited the transport of STxB in vitro. Membrane-associated Golgin-97, but not its cytosolic pool, was required in the in vitro transport assay. The kinetic characterization of inhibition by anti-Golgin-97 antibody in comparison with anti-Syntaxin 16 antibody established that Golgin-97 acts before Syntaxin 16 in endosome-to-TGN transport. Knock down of Golgin-97 or Arl1 by their respective small interference RNAs (siRNAs) also significantly inhibited the transport of STxB to the Golgi in vivo. In siRNA-treated cells with reduced levels of Arl1, internalized STxB was instead distributed peripherally. Microinjection of Golgin-97 antibody led to the fragmentation of Golgi apparatus and the arrested transport to the Golgi of internalized Cholera toxin B fragment. We suggest that Golgin-97 may function as a tethering molecule in endosome-to-TGN retrograde traffic.
Mol Biol Cell 2004 Oct
PMID:Autoantigen Golgin-97, an effector of Arl1 GTPase, participates in traffic from the endosome to the trans-golgi network. 1526 79

Toxins can invade cells by using a direct endosome-to-Golgi endocytic pathway that bypasses late endosomes/prelysosomes. This is also a route used by endogenous proteins, including GPP130, which is an integral membrane protein retrieved via the bypass pathway from endosomes to its steady-state location in the cis-Golgi. An RNA interference-based test revealed that GPP130 was required for efficient exit of Shiga toxin B-fragment from endosomes en route to the Golgi apparatus. Furthermore, two proteins whose Golgi targeting depends on endosome-to-Golgi retrieval in the bypass pathway accumulated in early/recycling endosomes in the absence of GPP130. GPP130 activity seemed specific to bypass pathway trafficking because the targeting of other tested proteins, including those retrieved to the Golgi via the more conventional late endosome route, was unaltered. Thus, a distally cycling Golgi protein mediates exit from endosomes and thereby underlies Shiga toxin invasion and retrieval-based targeting of other cycling Golgi proteins.
Mol Biol Cell 2004 Nov
PMID:A cycling cis-Golgi protein mediates endosome-to-Golgi traffic. 1533 63

Comparative genomics demonstrated that the chromosomes from bacteria and their viruses (bacteriophages) are coevolving. This process is most evident for bacterial pathogens where the majority contain prophages or phage remnants integrated into the bacterial DNA. Many prophages from bacterial pathogens encode virulence factors. Two situations can be distinguished: Vibrio cholerae, Shiga toxin-producing Escherichia coli, Corynebacterium diphtheriae, and Clostridium botulinum depend on a specific prophage-encoded toxin for causing a specific disease, whereas Staphylococcus aureus, Streptococcus pyogenes, and Salmonella enterica serovar Typhimurium harbor a multitude of prophages and each phage-encoded virulence or fitness factor makes an incremental contribution to the fitness of the lysogen. These prophages behave like "swarms" of related prophages. Prophage diversification seems to be fueled by the frequent transfer of phage material by recombination with superinfecting phages, resident prophages, or occasional acquisition of other mobile DNA elements or bacterial chromosomal genes. Prophages also contribute to the diversification of the bacterial genome architecture. In many cases, they actually represent a large fraction of the strain-specific DNA sequences. In addition, they can serve as anchoring points for genome inversions. The current review presents the available genomics and biological data on prophages from bacterial pathogens in an evolutionary framework.
Microbiol Mol Biol Rev 2004 Sep
PMID:Phages and the evolution of bacterial pathogens: from genomic rearrangements to lysogenic conversion. 1535 70

We investigated the virulence properties and clonal relationship of 21 Escherichia coli strains of serogroup O78 isolated from diarrhoeic cattle and calves. Isolates were screened for 18 genes representing virulence features of different Escherichia coli pathotypes. None of the strains harboured enterotoxin-genes estIa/Ib, eltIa/Ib, or Shiga toxin (stx) genes, genes involved in adhesion (eae, f5, f41) hemolysin gene hlyA or invasion gene ipaC. With a high prevalence we detected enterotoxin astA (61.9%), genes involved in iron acquisition, like fyuA, irp (each 57.1%) and iucD (81.0%), and the operon sequence of Colicin V plasmids (38.1%). Some strains possessed toxin genes cdt-IIIB and cnf1/2 (both 14.3%), the invasion gene tia (23.8%), and the serine protease encoding gene espP (23.8%). Moreover, we could show that E. coli O78 strains under investigation were able to adhere to and invade MDBK-cells with varying efficiencies. The results indicate that the closely related O78 strains, constituting two major PFGE-clusters, harbor various virulence features for bovine intestinal disease but cannot be grouped into one of the common E. coli intestinal pathogenic or other pathotypes according to their virulence gene pattern. Nevertheless, the ability to adhere, invade or harbor toxin genes lets us suggest that O78 strains isolated from diarrheal cases in bovines urges further investigations on the zoonotic potential of these strains.
Mol Nutr Food Res 2004 Dec
PMID:Molecular characteristics of Escherichia coli serogroup O78 strains isolated from diarrheal cases in bovines urge further investigations on their zoonotic potential. 1553 7

Subtyping of Shiga toxin (Stx)-encoding genes by conventional polymerase chain reaction (PCR) is time-consuming. We developed a single step real-time fluorescence PCR with melting curve analysis to distinguish rapidly stx1 from its variants, stx1c and stx1d. Melting temperatures (Tm) of 206 Stx-producing Escherichia coli (STEC) identified to harbor stx1 or stx1c were analyzed using a specific hybridization probe over the variable region. 170 of 171 stx1-harboring STEC displayed Tm of 69 degrees C to 70 degrees C, whereas 34 of 35 strains containing stx1c had Tm of 65 degrees C-66 degrees C. This constant and reproducible difference of 4 degrees C demonstrated that melting curve analysis is a reliable technique to differentiate stx1 from stx1c. Two isolates displayed atypical Tm. Sequence analysis showed that one of them was 100% identical to stx1d within a 511 bp DNA stretch. Our data demonstrate that real-time PCR is a rapid and reliable tool to differentiate stx1 from stx1c and stx1d and to detect new stx1 variants. Because stx1-harboring STEC cause diarrhoea and hemolytic-uremic syndrome, whereas those containing stx1c are often shed asymptomatically, a rapid differentiation between stx1 and its variants using the procedure developed here has both clinical implications and a direct significance for the risk assessment analysis of STEC isolated from foods.
Mol Nutr Food Res 2004 Dec
PMID:A rapid method for the discrimination of genes encoding classical Shiga toxin (Stx) 1 and its variants, Stx1c and Stx1d, in Escherichia coli. 1553 10


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