Inhibition of NF-κB Signaling in Human Dendritic Cells by the Enteropathogenic <i>Escherichia coli</i> Effector Protein NleE

Vossenkämper, Anna; Marchès, Olivier; Fairclough, Peter D.; Warnes, Gary; Stagg, Andrew J.; Lindsay, James O.; Evans, Paul C.; Luong, Le Anh; Croft, Nicholas M.; Naik, Sandhia; Frankel, Gad; MacDonald, Thomas T.

doi:10.4049/jimmunol.1000500

Cited by 76 publications

(55 citation statements)

References 32 publications

(42 reference statements)

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“…In this study, we transfected HeLa cells with the mammalian expression vector pRK5::myc-nleF (HeLa-NleF) and analyzed the localization of an N-terminally tagged NleF protein 16,24, and 48 h later by immunofluorescence staining. At 16 h and 24 h posttransfection, NleF InvF TTCCTGCATTCATTGAAAGTAAAAATTGAGG InvR GAACAGATCCCTGATATAACTATCCCTAT 3F GATATGGAAGATACAACAAAAGTGTT 3R ACAGAAGAGGCAGGCCAGCA 4F TTAGAGGCCTGTGAGCCTGT 4R ATCAAAACCCCCTTAACAAATAAATC pKD4F TGTGTAGGCTGGAGCTGCTTC pKD4R CATATGAATATCCTCCTTAGTTCC 5F GTAAAGGTGGTAATGCTGTCGT 5R GAAGGAATACAAAGCCGTCAC 6F CCGCCGGGAATTCATGTTACCAACAAGTGGTTCTTCAGA EcoRI 6R TGCAGGATCCTCATCCACATTGTAAAGATCCTTTGTT PstI 7F AAGAATTCATGTTACCAACAAGTGGTTCT EcoRI 7R GCGGTGGATCCCTCATCCACATTGTAAAGATCC BamHI IL-8F AGAAACCACCGGAAGGAACCATCT IL-8R AGAGCTGCAGAAATCAGGAAGGCT GAPDHF TCGACAGTCAGCCGCATCTTCTTT GAPDHR ACCAAATCCGTTGACTCCGACCTT CASP4F GCAGACTCTATGCAAGAGAAG CASP4R TGGTCCAGCCTCCATATT CASP8F GGATGGCCACTGTGAATAA CASP8R CAGTCAGGATGGTGAGAATATC CASP9F GTGCTCTTGAGAGTTTGAGG CASP9R ACAGCCGTGAGAGAGAAT -either was diffusely localized or exhibited a punctate perinuclear localization ( Fig.…”

Section: Nlef Is Localized To the Mitochondria Previous Studies Havementioning

confidence: 99%

The Type III Secretion Effector NleF of Enteropathogenic Escherichia coli Activates NF-κB Early during Infection

et al. 2014

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bThe enteric pathogens enteropathogenic Escherichia coli (EPEC) and enterohemorrhagic E. coli employ a type 3 secretion system (T3SS) to manipulate the host inflammatory response during infection. Previously, it has been reported that EPEC, in a T3SS-dependent manner, induces an early proinflammatory response through activation of NF-B via extracellular signal-regulated kinases 1 and 2 (ERK1/2) and protein kinase C (PKC). However, the activation of NF-B during infection has not yet been attributed to an effector. At later time points postinfection, NF-B signaling is inhibited through the translocation of multiple effectors, including NleE and NleC. Here we report that the highly conserved non-LEE (locus of enterocyte effacement)-encoded effector F (NleF) shows both diffuse and mitochondrial localization during ectopic expression. Moreover, NleF induces the nuclear translocation of NF-B p65 and the expression of interleukin 8 (IL-8) following ectopic expression and during EPEC infection. Furthermore, the proinflammatory activity and localization of NleF were dependent on the C-terminal amino acids LQCG. While the C-terminal domain of NleF has previously been shown to be essential for interaction with caspase-4, caspase-8, and caspase-9, the proinflammatory activity of NleF was independent of interaction with caspase-4, -8, or -9. In conclusion, EPEC, through the T3SS-dependent translocation of NleF, induces a proinflammatory response in an NF-B-dependent manner in the early stages of infection.

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Section: Nlef Is Localized To the Mitochondria Previous Studies Havementioning

confidence: 99%

The Type III Secretion Effector NleF of Enteropathogenic Escherichia coli Activates NF-κB Early during Infection

et al. 2014

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“…Much research has focused on the active manipulation of DCs, either to augment favorable immunity or to suppress unwanted immune activation (9)(10)(11)(12)(13)(14). Also pathogens and tumors often escape immunity via modulation of DC immunogenicity (15)(16)(17)(18)(19). In many cases, the functional alterations of DCs by drugs, pathogens, or tumor-derived factors are ascribed to manipulation of NF-kB activity.…”

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confidence: 99%

A Nonredundant Role for Canonical NF-κB in Human Myeloid Dendritic Cell Development and Function

Laar

Bosch

Kooij

et al. 2010

The Journal of Immunology

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The plastic role of dendritic cells (DCs) in the regulation of immune responses has made them interesting targets for immunotherapy, but also for pathogens or tumors to evade immunity. Functional alterations of DCs are often ascribed to manipulation of canonical NF-κB activity. However, though this pathway has been linked to murine myeloid DC biology, a detailed analysis of its importance in human myeloid DC differentiation, survival, maturation, and function is lacking. The myeloid DC subsets include interstitial DCs and Langerhans cells. In this study, we investigated the role of canonical NF-κB in human myeloid DCs generated from monocytes (monocyte-derived DCs [mo-DCs]) or CD34+ progenitors (CD34-derived myeloid DCs [CD34-mDCs]). Inhibition of NF-κB activation during and after mo-DC, CD34-interstitial DC, or CD34-Langerhans cell differentiation resulted in apoptosis induction associated with caspase 3 activation and loss of mitochondrial transmembrane potential. Besides regulating survival, canonical NF-κB activity was required for the acquisition of a DC phenotype. Despite phenotypic differences, however, Ag uptake, costimulatory molecule and CCR7 expression, as well as T cell stimulatory capacity of cells generated under NF-κB inhibition were comparable to control DCs, indicating that canonical NF-κB activity during differentiation is redundant for the development of functional APCs. However, both mo-DC and CD34-mDC functionality were reduced by NF-κB inhibition during activation. In conclusion, canonical NF-κB activity is essential for the development and function of mo-DCs as well as CD34-mDCs. Insight into the role of this pathway may help in understanding how pathogens and tumors escape immunity and aid in developing novel treatment strategies aiming to interfere with human immune responses.

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“…Furthermore, NleE-dependent inhibition of NF-κB activation contributes significantly to the low levels of IL8 expression and IL-8 production in EPEC-infected epithelial cells (84,85). A concurrent study also demonstrated the ability of NleE to inhibit nuclear translocation of activated NF-κB and proinflammatory cytokine production in human dendritic cells (DCs) (94). IL-8, TNF, and IL-6 expression and production were suppressed in the presence of EPEC-delivered NleE in human monocyte DCs and Peyer's patch DCs.…”

Section: Effectors That Inhibit Inflammatory Signaling the Cysteine Mmentioning

confidence: 94%

The Inflammatory Response during Enterohemorrhagic Escherichia coli Infection

Pearson

Hartland²

2014

Microbiol Spectr

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The inflammatory response is an integral part of host defense against enterohemorrhagic Escherichia coli (EHEC) infection and also contributes to disease pathology. In this article we explore the factors leading to inflammation during EHEC infection and the mechanisms EHEC and other attaching and effacing (A/E) pathogens have evolved to suppress inflammatory signaling. EHEC stimulates an inflammatory response in the intestine through host recognition of bacterial components such as flagellin and lipopolysaccharide. In addition, the activity of Shiga toxin and some type III secretion system effectors leads to increased tissue inflammation. Various infection models of EHEC and other A/E pathogens have revealed many of the immune factors that mediate this response. In particular, the outcome of infection is greatly influenced by the ability of an infected epithelial cell to mount an effective host inflammatory response. The inflammatory response of infected enterocytes is counterbalanced by the activity of type III secretion system effectors such as NleE and NleC that modify and inhibit components of the signaling pathways that lead to proinflammatory cytokine production. Overall, A/E pathogens have taught us that innate mucosal immune responses in the gastrointestinal tract during infection with A/E pathogens are highly complex and ultimate clearance of the pathogen depends on multiple factors, including inflammatory mediators, bacterial burden, and the function and integrity of resident intestinal epithelial cells.

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Inhibition of NF-κB Signaling in Human Dendritic Cells by the Enteropathogenic Escherichia coli Effector Protein NleE

Abstract: Material

Cited by 76 publications

References 32 publications

The Type III Secretion Effector NleF of Enteropathogenic Escherichia coli Activates NF-κB Early during Infection

The Type III Secretion Effector NleF of Enteropathogenic Escherichia coli Activates NF-κB Early during Infection

A Nonredundant Role for Canonical NF-κB in Human Myeloid Dendritic Cell Development and Function

The Inflammatory Response during Enterohemorrhagic Escherichia coli Infection

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