Role of Viral Factor E3L in Modified Vaccinia Virus Ankara Infection of Human HeLa Cells: Regulation of the Virus Life Cycle and Identification of Differentially Expressed Host Genes

Ludwig, Holger; Mages, Jörg; Staib, Caroline; Lehmann, Michael H.; Lang, Roland; Sutter, Gerd

doi:10.1128/jvi.79.4.2584-2596.2005

Cited by 49 publications

(61 citation statements)

References 76 publications

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“…The VACV E3L gene product is known as an IFN resistance protein, as a determinant of host range and viral pathogenesis, and as a modulator of cellular apoptotic and signal transduction pathways (35,36,42). The E3 protein binds to dsRNA, and this interaction mediates or enhances its binding to ISG15 and PKR, respectively (25,57).…”

Section: Discussionmentioning

confidence: 99%

Regulation of Vaccinia Virus E3 Protein by Small Ubiquitin-Like Modifier Proteins

González-Santamaría

Campagna

García

et al. 2011

J Virol

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The vaccinia virus (VACV) E3 protein is essential for virulence and has antiapoptotic activity and the ability to impair the host innate immune response. Here we demonstrate that E3 interacts with SUMO1 through a small ubiquitin-like modifier (SUMO)-interacting motif (SIM). SIM integrity is required for maintaining the stability of the viral protein and for the covalent conjugation of E3 to SUMO1 or SUMO2, a modification that has a negative effect on the E3 transcriptional transactivation of the p53-upregulated modulator of apoptosis (PUMA) and APAF-1 genes. We also demonstrate that E3 is ubiquitinated, a modification that does not destabilize the wild-type protein but triggers the degradation of an E3-⌬SIM mutant. This report constitutes the first demonstration of the important roles that both SUMO and ubiquitin play in the regulation of the VACV protein E3.

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Section: Discussionmentioning

confidence: 99%

Regulation of Vaccinia Virus E3 Protein by Small Ubiquitin-Like Modifier Proteins

González-Santamaría

Campagna

García

et al. 2011

J Virol

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“…Mining of transcriptome datasets from primary mouse macrophages stimulated with LPS or the RAW 264.7 macrophage cell line after activation with a set of TLR ligands, our laboratory identified DUSP1, DUSP2, and DUSP16 as the most strongly induced MKP; thus, there is substantial overlap between these studies in the human and mouse system (36,37). Finally, genome-wide analyses of the host pathogen interaction have revealed induction of several DUSP family members in macrophages infected with mycobacteria (38), Gram-negative and -positive bacteria (39), and virusinfected HeLa cells (40).…”

Section: Table I Classification Of Dusp Mkpmentioning

confidence: 99%

“…Likewise, the impact of DUSP on the host response to infection can now be investigated using a range of different pathogens. Because bacterial and viral pathogens induce DUSP1 expression (38,40), a lack of this presumable immune evasion mechanism may be expected to shift the balance in these infections to a more robust protective response. It is an important question whether changes in the production of inflammatory cytokines and mediators depending on the functionality of DUSP confer a state of more efficient pathogen control to the innate immune system, or may in contrast lead to increased immunopathology.…”

Section: Dusp As Targets For the Manipulation Of Immune Responses?mentioning

confidence: 99%

DUSP Meet Immunology: Dual Specificity MAPK Phosphatases in Control of the Inflammatory Response

Lang

Hammer

Mages

2006

The Journal of Immunology

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293

247

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The MAPK family members p38, JNK, and ERK are all activated downstream of innate immunity’s TLR to induce the production of cytokines and inflammatory mediators. However, the relative intensity and duration of the activation of different MAPK appears to determine the type of immune response. The mammalian genome encodes a large number of dual specificity phosphatases (DUSP), many of which act as MAPK phosphatases. In this study, we review the emergence of several DUSP as genes that are differentially expressed and regulated in immune cells. Recently, a series of investigations in mice deficient in DUSP1, DUSP2, or DUSP10 revealed specificity in the regulation of the different MAPK proteins, and defined essential roles in models of local and systemic inflammation. The DUSP family is proposed as a set of molecular control devices specifying and modulating MAPK signaling, which may be targeted to unleash or attenuate innate and adaptive immune effector functions.

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“…DNA microarray technology allows monitoring of the expression of several thousand individual genes (22) and has been used to identify the differential expression of cellular genes in response to infection by several animal viruses, including VV strains WR (Western Reserve) and MVA (modified vaccinia Ankara) (15,16,29,55).…”

mentioning

confidence: 99%

Host Response to the Attenuated Poxvirus Vector NYVAC: Upregulation of Apoptotic Genes and NF-κB-Responsive Genes in Infected HeLa Cells

Guerra¹,

López-Fernández²,

Pascual-Montano

et al. 2006

J Virol

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Attenuated strains of vaccinia virus (VV) were developed in response to the need for safer vaccines (37). NYVAC is a derivative of the VV Copenhagen strain in which 18 open reading frames were specifically deleted from the parental viral genome; genes involved in host range, virulence, and pathogenesis were thus lost (49). NYVAC-derived vectors are able to express antigens from a wide range of species (50). A number of examples have been reported, using NYVAC as a recombinant vaccine delivery system against pathogens and tumors (5,10,31,46). Clinical trials using NYVAC-based vectors show a good safety profile, with induction of high levels of immunity against heterologous antigens (24, 34).Since phase I/II clinical trials using this vector are currently under way, particularly for human immunodeficiency virus type 1 (HIV-1) (www.eurovacc.org), it is essential to obtain a comprehensive understanding of the effect of NYVAC infection on human host gene expression (34). DNA microarray technology allows monitoring of the expression of several thousand individual genes (22) and has been used to identify the differential expression of cellular genes in response to infection by several animal viruses, including VV strains WR (Western Reserve) and MVA (modified vaccinia Ankara) (15,16,29,55).Host genes that govern vital cell processes such as replication, transcription, and translation are downregulated during the course of WR infection. The expression of genes involved in apoptosis or the proteasome-ubiquitin degradation pathway is also repressed; few genes are upregulated after WR infection (15). A larger number of genes than that seen with WR is upregulated during strain MVA infection; most encode immune modulator proteins, some of which may be involved in host resistance and immune modulation during MVA infection (16). Wiskott-Aldrich syndrome protein (WASP) family members are upregulated after MVA or WR infection (15,16). This family includes the gene that codes for the N-WASP protein, implicated in the actin-mediated motility of VV as a mechanism for intercellular viral spreading (8,11). Additional studies show that WASP is required for VV pathogenesis (17). The results of microarray analysis have implicated cell signaling events and cell proteins as important regulators of VV infection.For this study, we used cDNA microarray technology to analyze host gene expression changes in HeLa cell cultures following NYVAC infection. This is the first large-scale analysis of the transcriptional response of HeLa cells to NYVAC infection. It provides a better understanding of the mechanisms of vaccine protection against VV infection and will aid in the development of NYVAC recombinant-based vaccines against pathogens and tumors. MATERIALS AND METHODSCells, viruses, and infection conditions. HeLa cells (ATCC) were cultured in Dulbecco's medium supplemented with 10% newborn bovine serum and antibiotics. The VV WR strain was cultured in monkey BSC-40 cells, purified by sucrose gradient banding, and titrated on BSC-40 cells by a p...

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Role of Viral Factor E3L in Modified Vaccinia Virus Ankara Infection of Human HeLa Cells: Regulation of the Virus Life Cycle and Identification of Differentially Expressed Host Genes

Cited by 49 publications

References 76 publications

Regulation of Vaccinia Virus E3 Protein by Small Ubiquitin-Like Modifier Proteins

Regulation of Vaccinia Virus E3 Protein by Small Ubiquitin-Like Modifier Proteins

DUSP Meet Immunology: Dual Specificity MAPK Phosphatases in Control of the Inflammatory Response

Host Response to the Attenuated Poxvirus Vector NYVAC: Upregulation of Apoptotic Genes and NF-κB-Responsive Genes in Infected HeLa Cells

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