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The Locus of Enterocyte Effacement and Associated Virulence Factors of Enterohemorrhagic

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  • Authors: Mark P. Stevens1, Gad M. Frankel2
  • Editors: Vanessa Sperandio3, Carolyn J. Hovde4
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    Affiliations: 1: The Roslin Institute and Royal (Dick) School of Veterinary Studies, University of Edinburgh, Midlothian, EH25 9RG, United Kingdom; 2: MRC Centre for Molecular Bacteriology and Infection, Department of Life Sciences, Imperial College London, London, SW7 2AZ, United Kingdom; 3: University of Texas Southwestern Medical Center, Dallas, TX; 4: University of Idaho, Moscow, ID
    • Source: microbiolspec August 2014 vol. 2 no. 4 doi:10.1128/microbiolspec.EHEC-0007-2013
  • Received 03 May 2013 Accepted 24 July 2013 Published 15 August 2014
  • Mark P. Stevens, [email protected]
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  • Abstract:

    A subset of Shiga toxin-producing strains, termed enterohemorrhagic (EHEC), is defined in part by the ability to produce attaching and effacing (A/E) lesions on intestinal epithelia. Such lesions are characterized by intimate bacterial attachment to the apical surface of enterocytes, cytoskeletal rearrangements beneath adherent bacteria, and destruction of proximal microvilli. A/E lesion formation requires the locus of enterocyte effacement (LEE), which encodes a Type III secretion system that injects bacterial proteins into host cells. The translocated proteins, termed effectors, subvert a plethora of cellular pathways to the benefit of the pathogen, for example, by recruiting cytoskeletal proteins, disrupting epithelial barrier integrity, and interfering with the induction of inflammation, phagocytosis, and apoptosis. The LEE and selected effectors play pivotal roles in intestinal persistence and virulence of EHEC, and it is becoming clear that effectors may act in redundant, synergistic, and antagonistic ways during infection. Vaccines that target the function of the Type III secretion system limit colonization of reservoir hosts by EHEC and may thus aid control of zoonotic infections. Here we review the features and functions of the LEE-encoded Type III secretion system and associated effectors of O157:H7 and other Shiga toxin-producing strains.

  • Citation: Stevens M, Frankel G. 2014. The Locus of Enterocyte Effacement and Associated Virulence Factors of Enterohemorrhagic . Microbiol Spectrum 2(4):EHEC-0007-2013. doi:10.1128/microbiolspec.EHEC-0007-2013.

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/content/journal/microbiolspec/10.1128/microbiolspec.EHEC-0007-2013
2014-08-15
2019-09-20

Abstract:

A subset of Shiga toxin-producing strains, termed enterohemorrhagic (EHEC), is defined in part by the ability to produce attaching and effacing (A/E) lesions on intestinal epithelia. Such lesions are characterized by intimate bacterial attachment to the apical surface of enterocytes, cytoskeletal rearrangements beneath adherent bacteria, and destruction of proximal microvilli. A/E lesion formation requires the locus of enterocyte effacement (LEE), which encodes a Type III secretion system that injects bacterial proteins into host cells. The translocated proteins, termed effectors, subvert a plethora of cellular pathways to the benefit of the pathogen, for example, by recruiting cytoskeletal proteins, disrupting epithelial barrier integrity, and interfering with the induction of inflammation, phagocytosis, and apoptosis. The LEE and selected effectors play pivotal roles in intestinal persistence and virulence of EHEC, and it is becoming clear that effectors may act in redundant, synergistic, and antagonistic ways during infection. Vaccines that target the function of the Type III secretion system limit colonization of reservoir hosts by EHEC and may thus aid control of zoonotic infections. Here we review the features and functions of the LEE-encoded Type III secretion system and associated effectors of O157:H7 and other Shiga toxin-producing strains.

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The Locus of Enterocyte Effacement and Associated Virulence Factors of Enterohemorrhagic
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Citation: Stevens M, Frankel G. 2014. The locus of enterocyte effacement and associated virulence factors of enterohemorrhagic . microbiolspec 2(4): doi:10.1128/microbiolspec.EHEC-0007-2013
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FIGURE 1a
Transmission electron micrograph (TEM) showing A/E lesions induced by EHEC O111:H– strain E45035N in the spiral colon of a neonatal calf (note raised electron-dense pedestals and microvillus effacement relative to proximal uninfected enterocyte). From reference 233 ; scale bar = 1 µm. TEM of A/E lesions induced by EHEC O157:H7 strain 85-170 12 h after inoculation of a bovine ligated ileal loop (note intimate adherence but relative absence of elongated pedestals). From reference 84 ; scale bar = 5 µm. Fluorescence micrograph showing nucleation of F-actin under EHEC O103:H3 strain PMK5 adhering to a HeLa cell (green, F-actin detected with Oregon green-phalloidin; red, bacteria stained with rabbit anti-O103 typing serum detected with anti-rabbit immunoglobulin-Alexa). From reference 240 ; scale bar = 5 µm.
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FIGURE 1a

Transmission electron micrograph (TEM) showing A/E lesions induced by EHEC O111:H– strain E45035N in the spiral colon of a neonatal calf (note raised electron-dense pedestals and microvillus effacement relative to proximal uninfected enterocyte). From reference 233 ; scale bar = 1 µm. TEM of A/E lesions induced by EHEC O157:H7 strain 85-170 12 h after inoculation of a bovine ligated ileal loop (note intimate adherence but relative absence of elongated pedestals). From reference 84 ; scale bar = 5 µm. Fluorescence micrograph showing nucleation of F-actin under EHEC O103:H3 strain PMK5 adhering to a HeLa cell (green, F-actin detected with Oregon green-phalloidin; red, bacteria stained with rabbit anti-O103 typing serum detected with anti-rabbit immunoglobulin-Alexa). From reference 240 ; scale bar = 5 µm.

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FIGURE 1b
Transmission electron micrograph (TEM) showing A/E lesions induced by EHEC O111:H– strain E45035N in the spiral colon of a neonatal calf (note raised electron-dense pedestals and microvillus effacement relative to proximal uninfected enterocyte). From reference 233 ; scale bar = 1 µm. TEM of A/E lesions induced by EHEC O157:H7 strain 85-170 12 h after inoculation of a bovine ligated ileal loop (note intimate adherence but relative absence of elongated pedestals). From reference 84 ; scale bar = 5 µm. Fluorescence micrograph showing nucleation of F-actin under EHEC O103:H3 strain PMK5 adhering to a HeLa cell (green, F-actin detected with Oregon green-phalloidin; red, bacteria stained with rabbit anti-O103 typing serum detected with anti-rabbit immunoglobulin-Alexa). From reference 240 ; scale bar = 5 µm.
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FIGURE 1b

Transmission electron micrograph (TEM) showing A/E lesions induced by EHEC O111:H– strain E45035N in the spiral colon of a neonatal calf (note raised electron-dense pedestals and microvillus effacement relative to proximal uninfected enterocyte). From reference 233 ; scale bar = 1 µm. TEM of A/E lesions induced by EHEC O157:H7 strain 85-170 12 h after inoculation of a bovine ligated ileal loop (note intimate adherence but relative absence of elongated pedestals). From reference 84 ; scale bar = 5 µm. Fluorescence micrograph showing nucleation of F-actin under EHEC O103:H3 strain PMK5 adhering to a HeLa cell (green, F-actin detected with Oregon green-phalloidin; red, bacteria stained with rabbit anti-O103 typing serum detected with anti-rabbit immunoglobulin-Alexa). From reference 240 ; scale bar = 5 µm.

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FIGURE 1c
Transmission electron micrograph (TEM) showing A/E lesions induced by EHEC O111:H– strain E45035N in the spiral colon of a neonatal calf (note raised electron-dense pedestals and microvillus effacement relative to proximal uninfected enterocyte). From reference 233 ; scale bar = 1 µm. TEM of A/E lesions induced by EHEC O157:H7 strain 85-170 12 h after inoculation of a bovine ligated ileal loop (note intimate adherence but relative absence of elongated pedestals). From reference 84 ; scale bar = 5 µm. Fluorescence micrograph showing nucleation of F-actin under EHEC O103:H3 strain PMK5 adhering to a HeLa cell (green, F-actin detected with Oregon green-phalloidin; red, bacteria stained with rabbit anti-O103 typing serum detected with anti-rabbit immunoglobulin-Alexa). From reference 240 ; scale bar = 5 µm.
microbiolspec/2/4/EHEC-0007-2013-fig1c_thmb.gif
microbiolspec/2/4/EHEC-0007-2013-fig1c.gif
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FIGURE 1c

Transmission electron micrograph (TEM) showing A/E lesions induced by EHEC O111:H– strain E45035N in the spiral colon of a neonatal calf (note raised electron-dense pedestals and microvillus effacement relative to proximal uninfected enterocyte). From reference 233 ; scale bar = 1 µm. TEM of A/E lesions induced by EHEC O157:H7 strain 85-170 12 h after inoculation of a bovine ligated ileal loop (note intimate adherence but relative absence of elongated pedestals). From reference 84 ; scale bar = 5 µm. Fluorescence micrograph showing nucleation of F-actin under EHEC O103:H3 strain PMK5 adhering to a HeLa cell (green, F-actin detected with Oregon green-phalloidin; red, bacteria stained with rabbit anti-O103 typing serum detected with anti-rabbit immunoglobulin-Alexa). From reference 240 ; scale bar = 5 µm.

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FIGURE 2
Genetic organization of LEE of O157:H7. Open reading frames are represented by thick arrows, and putative polycistronic operons are designated by thin arrows. Clear arrows represent open reading frames of unknown function and are designated or , depending on the direction of transcription relative to .
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FIGURE 2

Genetic organization of LEE of O157:H7. Open reading frames are represented by thick arrows, and putative polycistronic operons are designated by thin arrows. Clear arrows represent open reading frames of unknown function and are designated or , depending on the direction of transcription relative to .

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FIGURE 3
Schematic representation of the Type III secretion apparatus showing the predicted spatial organization of LEE-encoded proteins. Adapted from reference 30 .
microbiolspec/2/4/EHEC-0007-2013-fig3_thmb.gif
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FIGURE 3

Schematic representation of the Type III secretion apparatus showing the predicted spatial organization of LEE-encoded proteins. Adapted from reference 30 .

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FIGURE 4
Scanning electron micrograph showing EspA filaments (arrow) of EHEC O26:H11 strain H19 attaching to the surface of an erythrocyte. From reference 241 . Transmission electron micrograph of an EspA filament of wild-type EPEC O127:H6 strain E2348/69 showing Tir issuing from the tip. EspA filaments were immunolabeled with anti-EspA conjugated to 5-nm diameter gold particles, and Tir was detected with anti-Tir conjugated to 10-nm diameter gold particles. The specificity of Tir staining was confirmed using the same gold-labeled antibodies but an isogenic mutant. Panels B and C from reference 54 .
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FIGURE 4

Scanning electron micrograph showing EspA filaments (arrow) of EHEC O26:H11 strain H19 attaching to the surface of an erythrocyte. From reference 241 . Transmission electron micrograph of an EspA filament of wild-type EPEC O127:H6 strain E2348/69 showing Tir issuing from the tip. EspA filaments were immunolabeled with anti-EspA conjugated to 5-nm diameter gold particles, and Tir was detected with anti-Tir conjugated to 10-nm diameter gold particles. The specificity of Tir staining was confirmed using the same gold-labeled antibodies but an isogenic mutant. Panels B and C from reference 54 .

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FIGURE 5
Diagram summarizing the activities of a subset of EHEC Type III secreted proteins on the cytoskeleton. Note (a), the Tir:Nck pathway dependent on phosphorylation of the residue equivalent to tyrosine 474 of EPEC O127:H6 Tir operates in some non-O157 EHEC but not prototype O157:H7 strains. Effectors are represented by circles. Adapted from reference 164 .
microbiolspec/2/4/EHEC-0007-2013-fig5_thmb.gif
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FIGURE 5

Diagram summarizing the activities of a subset of EHEC Type III secreted proteins on the cytoskeleton. Note (a), the Tir:Nck pathway dependent on phosphorylation of the residue equivalent to tyrosine 474 of EPEC O127:H6 Tir operates in some non-O157 EHEC but not prototype O157:H7 strains. Effectors are represented by circles. Adapted from reference 164 .

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FIGURE 6
Diagram summarizing the activities of a subset of EHEC Type III secreted proteins on signaling pathways leading to inflammation and apoptosis. Effectors are represented by circles. Adapted from reference 164 .
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FIGURE 6

Diagram summarizing the activities of a subset of EHEC Type III secreted proteins on signaling pathways leading to inflammation and apoptosis. Effectors are represented by circles. Adapted from reference 164 .

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Tables

The Locus of Enterocyte Effacement and Associated Virulence Factors of Enterohemorrhagic
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Citation: Stevens M, Frankel G. 2014. The locus of enterocyte effacement and associated virulence factors of enterohemorrhagic . microbiolspec 2(4): doi:10.1128/microbiolspec.EHEC-0007-2013
/content/microbiolspec/10.1128/microbiolspec.EHEC-0007-2013.T1
TABLE 1
Type III secreted effector proteins of EHEC O157:H7 and their activities, where known or inferred from homologs in other A/E pathogens
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TABLE 1

Type III secreted effector proteins of EHEC O157:H7 and their activities, where known or inferred from homologs in other A/E pathogens

Source: microbiolspec August 2014 vol. 2 no. 4 doi:10.1128/microbiolspec.EHEC-0007-2013

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