Limits...
The effector repertoire of enteropathogenic E. coli: ganging up on the host cell.

Dean P, Kenny B - Curr. Opin. Microbiol. (2009)

Bottom Line: More recently, effectors encoded outside the LEE (non-LEE effectors) have been discovered and their functions are beginning to be uncovered.The recent completion of the EPEC genome sequence suggests its effector repertoire consists of at least 21 effector proteins.Here, we describe the genomic location of effectors and discuss recent advances made on effector cellular function as well as their role in the infection process.

View Article: PubMed Central - PubMed

Affiliation: Institute for Cell and Molecular Biosciences, Medical School, Newcastle University, Catherine Cookson Building, Framlington Place, Newcastle upon Tyne NE2 4HH, UK. p.dean@ncl.ac.uk

ABSTRACT
Diarrhoeal disease caused by enteropathogenic E. coli (EPEC) is dependent on a delivery system that injects numerous bacterial 'effector' proteins directly into host cells. The best-described EPEC effectors are encoded together on the locus of enterocyte effacement (LEE) pathogenicity island and display high levels of multifunctionality and cooperativity within the host cell. More recently, effectors encoded outside the LEE (non-LEE effectors) have been discovered and their functions are beginning to be uncovered. The recent completion of the EPEC genome sequence suggests its effector repertoire consists of at least 21 effector proteins. Here, we describe the genomic location of effectors and discuss recent advances made on effector cellular function as well as their role in the infection process.

Show MeSH

Related in: MedlinePlus

The complexity of EPEC effector function. The multifunctional and overlapping properties of the EPEC effectors are depicted here by grouping effector functions together. Three effectors have anti-phagocytic activities (shown here using the phagocytic-like gut-associated antigen presenting M-cells) whilst at least five effectors act on microvilli and four inhibit SGLT-1 and other transporter activity, four disrupt tight junctions and three are involved in pedestal and filopodia formation. At least three Nle effectors are also involved in inflammatory pathways. Microtubule and Golgi/ER disruption appears to be specific to EspG/Orf3 and NleA, respectively. Also shown are effectors which have known actin-modulating properties. TJ, tight junctions; MT, microtubules; AqP, aquaporins; NHE3, sodium hydrogen exchanger; Cl/OH, Cl−/OH− transporter; SGLT-1, sodium glucose cotransporter-1; ER, endoplasmic reticulum; MV, microvilli.
© Copyright Policy
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC2697328&req=5

fig1: The complexity of EPEC effector function. The multifunctional and overlapping properties of the EPEC effectors are depicted here by grouping effector functions together. Three effectors have anti-phagocytic activities (shown here using the phagocytic-like gut-associated antigen presenting M-cells) whilst at least five effectors act on microvilli and four inhibit SGLT-1 and other transporter activity, four disrupt tight junctions and three are involved in pedestal and filopodia formation. At least three Nle effectors are also involved in inflammatory pathways. Microtubule and Golgi/ER disruption appears to be specific to EspG/Orf3 and NleA, respectively. Also shown are effectors which have known actin-modulating properties. TJ, tight junctions; MT, microtubules; AqP, aquaporins; NHE3, sodium hydrogen exchanger; Cl/OH, Cl−/OH− transporter; SGLT-1, sodium glucose cotransporter-1; ER, endoplasmic reticulum; MV, microvilli.

Mentions: The functions of the LEE effectors are highly varied and Table 1 gives an up-to-date and comprehensive list of reported effector functions. An emerging theme for the LEE effectors, consistent with findings in other T3SS-pathogens, is their multiple and overlapping functions (termed functional redundancy) and their interdependence and cooperativity in subverting host cell activities (Table 1 and Figure 1). For example, Map and EspF synergise [16] whilst EspG and EspG2 function redundantly [17] in the disruption of epithelial TJ, with the Map/EspF TJ-disrupting activity proven in vivo [14,18]. Tir is essential for actin-pedestal formation following binding to Intimin but is also involved in TJ disruption, independent and dependent of Intimin (Dean and Kenny, unpublished). Tir also downregulates Map-induced filopodia formation (see [3]) and coordinates with EspF, Intimin and Map to cause microvilli effacement [19•]. Indeed, Knutton and colleagues have also reported overlapping roles for LEE effectors in microvilli effacement ex vivo, using human intestinal material [20]. In addition, Map and EspF both target mitochondria to alter organelle shape and cause dysfunction — an activity that occurs in vivo and proven to be important in disease [14,15]. Such effector cooperativity appears to be just the ‘tip of the iceberg’ as a systematic genetic study in which the LEE effectors were deleted in many different combinations eludes to an unprecedented level of functional cooperativity between effectors (Kenny et al., unpublished). To this end, all the major reported hallmarks of EPEC disease can be attributed to the cooperative efforts of the LEE effectors (Figure 1).


The effector repertoire of enteropathogenic E. coli: ganging up on the host cell.

Dean P, Kenny B - Curr. Opin. Microbiol. (2009)

The complexity of EPEC effector function. The multifunctional and overlapping properties of the EPEC effectors are depicted here by grouping effector functions together. Three effectors have anti-phagocytic activities (shown here using the phagocytic-like gut-associated antigen presenting M-cells) whilst at least five effectors act on microvilli and four inhibit SGLT-1 and other transporter activity, four disrupt tight junctions and three are involved in pedestal and filopodia formation. At least three Nle effectors are also involved in inflammatory pathways. Microtubule and Golgi/ER disruption appears to be specific to EspG/Orf3 and NleA, respectively. Also shown are effectors which have known actin-modulating properties. TJ, tight junctions; MT, microtubules; AqP, aquaporins; NHE3, sodium hydrogen exchanger; Cl/OH, Cl−/OH− transporter; SGLT-1, sodium glucose cotransporter-1; ER, endoplasmic reticulum; MV, microvilli.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC2697328&req=5

fig1: The complexity of EPEC effector function. The multifunctional and overlapping properties of the EPEC effectors are depicted here by grouping effector functions together. Three effectors have anti-phagocytic activities (shown here using the phagocytic-like gut-associated antigen presenting M-cells) whilst at least five effectors act on microvilli and four inhibit SGLT-1 and other transporter activity, four disrupt tight junctions and three are involved in pedestal and filopodia formation. At least three Nle effectors are also involved in inflammatory pathways. Microtubule and Golgi/ER disruption appears to be specific to EspG/Orf3 and NleA, respectively. Also shown are effectors which have known actin-modulating properties. TJ, tight junctions; MT, microtubules; AqP, aquaporins; NHE3, sodium hydrogen exchanger; Cl/OH, Cl−/OH− transporter; SGLT-1, sodium glucose cotransporter-1; ER, endoplasmic reticulum; MV, microvilli.
Mentions: The functions of the LEE effectors are highly varied and Table 1 gives an up-to-date and comprehensive list of reported effector functions. An emerging theme for the LEE effectors, consistent with findings in other T3SS-pathogens, is their multiple and overlapping functions (termed functional redundancy) and their interdependence and cooperativity in subverting host cell activities (Table 1 and Figure 1). For example, Map and EspF synergise [16] whilst EspG and EspG2 function redundantly [17] in the disruption of epithelial TJ, with the Map/EspF TJ-disrupting activity proven in vivo [14,18]. Tir is essential for actin-pedestal formation following binding to Intimin but is also involved in TJ disruption, independent and dependent of Intimin (Dean and Kenny, unpublished). Tir also downregulates Map-induced filopodia formation (see [3]) and coordinates with EspF, Intimin and Map to cause microvilli effacement [19•]. Indeed, Knutton and colleagues have also reported overlapping roles for LEE effectors in microvilli effacement ex vivo, using human intestinal material [20]. In addition, Map and EspF both target mitochondria to alter organelle shape and cause dysfunction — an activity that occurs in vivo and proven to be important in disease [14,15]. Such effector cooperativity appears to be just the ‘tip of the iceberg’ as a systematic genetic study in which the LEE effectors were deleted in many different combinations eludes to an unprecedented level of functional cooperativity between effectors (Kenny et al., unpublished). To this end, all the major reported hallmarks of EPEC disease can be attributed to the cooperative efforts of the LEE effectors (Figure 1).

Bottom Line: More recently, effectors encoded outside the LEE (non-LEE effectors) have been discovered and their functions are beginning to be uncovered.The recent completion of the EPEC genome sequence suggests its effector repertoire consists of at least 21 effector proteins.Here, we describe the genomic location of effectors and discuss recent advances made on effector cellular function as well as their role in the infection process.

View Article: PubMed Central - PubMed

Affiliation: Institute for Cell and Molecular Biosciences, Medical School, Newcastle University, Catherine Cookson Building, Framlington Place, Newcastle upon Tyne NE2 4HH, UK. p.dean@ncl.ac.uk

ABSTRACT
Diarrhoeal disease caused by enteropathogenic E. coli (EPEC) is dependent on a delivery system that injects numerous bacterial 'effector' proteins directly into host cells. The best-described EPEC effectors are encoded together on the locus of enterocyte effacement (LEE) pathogenicity island and display high levels of multifunctionality and cooperativity within the host cell. More recently, effectors encoded outside the LEE (non-LEE effectors) have been discovered and their functions are beginning to be uncovered. The recent completion of the EPEC genome sequence suggests its effector repertoire consists of at least 21 effector proteins. Here, we describe the genomic location of effectors and discuss recent advances made on effector cellular function as well as their role in the infection process.

Show MeSH
Related in: MedlinePlus