Table 1 Effectors of EPEC/EHEC that modulate cell detachment, pro-inflammatory signaling, and phagocytosis
Effector | Cellular targetsa | Biochemical activity/characteristicsb | Phenotype | In vivo role |
|---|---|---|---|---|
Inhibition of cell detachment and modulation of cell death | ||||
NleH1 NleH2 | Bax inhibitor-1 (BI-1) | Binds to N-terminal amino acid 1-40 of BI-1. N-terminal aa 1-100 of NleHs not required for binding to BI-1 | Inhibition of apoptosis induced via multiple stimuli | Various roles reported in vivo. NleH reduces the level of apoptotic colonic cells in mouse model [42] |
EspZ | CD98 | C-terminal amino acid domain 43-99 required for CD98 binding | Prevent cell detachment. Enhance activation of pro-survival FAK and AKT pathway. Binding to CD98 promotes β1-integrin activation of FAK. | Mutant espZ attenuated for colonization and hyperplasia in mice [44] |
NleD | JNKs, p38 | Zinc metalloprotease (motif 142HExxH146) | Cleaves MAP kinases JNK and p38 in the activation loop. Reduce JNK pro-apoptotic activity | Enhance colonization in calves, no role identified in mice and lamb infection models [45, 46] |
Cif | NEDD8 | Deamidase of NEDD8 and ubiquitin | Block cell cycle at G2/M and G1/S transitions [39] | Unknown |
EspO/ OspO | ILK (?) | Shigella's OspE C-terminal 68W essential for activity is conserved in EPEC/EHEC EspO/OpsO | Prevent cell detachment? | Unknown |
Inhibition of pro-inflammatory signaling | ||||
NleE | Unknown | C-terminal 208IDSYMK214 motif essential for activity | Inhibits TNFα, IL-1β and PRRs mediated activation of NF-kappaB and expression of pro-inflammatory cytokines in epithelial and immune cells. Acts by inhibition of IκBα phosphorylation blocking p65 nuclear translocation | Slight role in colonization and persistence reported [45, 60] |
NleC | p65, p50, c-Rel, IκBα | Zinc metalloprotease (motif 183HExxH187) N-terminal domain aa 33-64 required for p65 and p50 binding | Cleaves p65 and p50 to inhibit NF-kappaB activation. Cleavage of c-Rel and IκBα also reported. | No role identified in mice and lamb infection model [45, 46] |
NleB | Unknown | Unknown | Inhibit TNFα-mediated NF-kappaB activation | Required for colonization and disease in mouse model [45, 60] |
NleH1 | Ribosomal protein S3 (RPS3) | Activity in N-terminal 139 amino acid (N40 and K45 required for RPS3 inhibition) | Prevent RPS3 nuclear translocation and expression of RPS3-NF-kappaB dependent pro-inflammatory genes | NleH1 EHEC mutant hypervirulent in piglet infection model [55] |
NleH1 and NleH2 | Unknown | Serine-threonine kinase motif | Prevent IκBα ubiquitination and degradation | Required for colonization and reduction of inflammation in EPEC mouse model [58] |
NleD | JNK, p38 | Zinc metalloprotease (motif 142HExxH146) | Cleaves MAP kinases JNK and p38 in the activation loop. Contributes to overall bacterial mediated inhibition of IL-8 in vitro. | Mutant not attenuated in mice, calve and lamb models [45, 46]. Role in colonization in STM screen in calves |
Inhibition of phagocytosis | ||||
EspF | Unknown | N-term 101 amino acid for anti-phagocytic activity | Prevents PI3K-dependent phagocytosis of bacteria; Reduces uptake of EPEC bacteria in in vitro M cell model | EspF mutant attenuated in mice model. Specific role of anti-phagocytic activity unknown [77, 78] |
EspB | Myosin proteins | Domain from amino acid 159-218 essential for myosin binding | Prevents bacterial phagocytosis via inhibition of myosin-actin interaction | Citrobacter expressing EspB mutated for myosin binding are attenuated in mouse model [74] |
EspJ | Unknown | Unknown | Blocks FcγR and CR3-opsonophagocytosis | Role in bacterial clearance reported in mouse model [75] |
EspH | RhoGEFs | Binds to DH-PH domain of RhoGEFs and inhibits RhoGTPase signalling | Attenuates bacteria phagocytosis and FcγR-mediated phagocytosis | EspH mutant not or slightly attenuated for colonization in mice and rabbit model [44] |