Structural Conservation and Functional Diversity of the Poxvirus Immune Evasion (PIE) Domain Superfamily

Nelson, Christopher A.; Epperson, Megan L.; Singh, Sukrit; Elliott, Jabari I.; Fremont, Daved H.

doi:10.3390/v7092848

Cited by 31 publications

(29 citation statements)

References 83 publications

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“…Nevertheless, as the overall geometry and surface charges of the protein are maintained, the negative influence of these modifications would be expected to be minimal and the structural analysis could explain the broad-spectrum chemokine-binding specificity of the BPSV-CBP. In addition, structural similarity between the CBPs of BPSV and ORFV is consistent with a recent study on structural analysis of poxvirus immune evasion proteins [41] where a conserved β-sandwich fold was identified among four groups of apparently-unrelated poxviral proteins, and identified them as members of a poxvirus immune evasion domain superfamily.…”

Section: Resultssupporting

confidence: 88%

A Broad-Spectrum Chemokine-Binding Protein of Bovine Papular Stomatitis Virus Inhibits Neutrophil and Monocyte Infiltration in Inflammatory and Wound Models of Mouse Skin

et al. 2016

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Bovine papular stomatitis virus (BPSV) is a Parapoxvirus that induces acute pustular skin lesions in cattle and is transmissible to humans. Previous studies have shown that BPSV encodes a distinctive chemokine-binding protein (CBP). Chemokines are critically involved in the trafficking of immune cells to sites of inflammation and infected tissue, suggesting that the CBP plays a role in immune evasion by preventing immune cells reaching sites of infection. We hypothesised that the BPSV-CBP binds a wide range of inflammatory chemokines particularly those involved in BPSV skin infection, and inhibits the recruitment of immune cells from the blood into inflamed skin. Molecular analysis of the purified protein revealed that the BPSV-CBP is a homodimeric polypeptide with a MW of 82.4 kDa whilst a comprehensive screen of inflammatory chemokines by surface plasmon resonance showed high-affinity binding to a range of chemokines within the CXC, CC and XC subfamilies. Structural analysis of BPSV-CBP, based on the crystal structure of orf virus CBP, provided a probable explanation for these chemokine specificities at a molecular level. Functional analysis of the BPSV-CBP using transwell migration assays demonstrated that it potently inhibited chemotaxis of murine neutrophils and monocytes in response to CXCL1, CXCL2 as well as CCL2, CCL3 and CCL5 chemokines. In order to examine the effects of CBP in vivo, we used murine skin models to determine its impact on inflammatory cell recruitment such as that observed during BPSV infection. Intradermal injection of BPSV-CBP blocked the influx of neutrophils and monocytes in murine skin in which inflammation was induced with lipopolysaccharide. Furthermore, intradermal injection of BPSV-CBP into injured skin, which more closely mimics BPSV lesions, delayed the influx of neutrophils and reduced the recruitment of MHC-II+ immune cells to the wound bed. Our findings suggest that the CBP could be important in pathogenesis of BPSV infections.

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Section: Resultssupporting

confidence: 88%

A Broad-Spectrum Chemokine-Binding Protein of Bovine Papular Stomatitis Virus Inhibits Neutrophil and Monocyte Infiltration in Inflammatory and Wound Models of Mouse Skin

et al. 2016

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“…The M2 protein belongs to the poxvirus immune evasion (PIE) superfamily based on the presence of a conserved ␤-sandwich fold (50). M2 is nonessential for replication in cell culture (45,51) and is a glycosylated protein that is expressed early in infection, localizes to the endoplasmic reticulum (ER), and is one of several VACV proteins that can inhibit NF-B as one of its functions (52,53).…”

Section: Discussionmentioning

confidence: 99%

Identification of Poxvirus Genome Uncoating and DNA Replication Factors with Mutually Redundant Roles

Liu

Panda

Mendez-Rios

et al. 2018

J Virol

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Genome uncoating is essential for replication of most viruses. For poxviruses, the process is divided into two stages: removal of the envelope, allowing early gene expression, and breaching of the core wall, allowing DNA release, replication, and late gene expression. Subsequent studies showed that the host proteasome and the viral D5 protein, which has an essential role in DNA replication, are required for vaccinia virus (VACV) genome uncoating. In a search for additional VACV uncoating proteins, we noted a report that described a defect in DNA replication and late expression when the gene encoding a 68-kDa ankyrin repeat/F-box protein (68k-ank), associated with the cellular SCF (Skp1, cullin1, F-box-containing complex) ubiquitin ligase complex, was deleted from the attenuated modified vaccinia virus Ankara (MVA). Here we showed that the 68k-ank deletion mutant exhibited diminished genome uncoating, formation of DNA prereplication sites, and degradation of viral cores as well as an additional, independent defect in DNA synthesis. Deletion of the 68k-ank homolog of VACV strain WR, however, was without effect, suggesting the existence of compensating genes. By inserting VACV genes into an MVA 68k-ank deletion mutant, we discovered that M2, a member of the poxvirus immune evasion (PIE) domain superfamily and a regulator of NF-κB, and C5, a member of the BTB/Kelch superfamily associated with cullin-3-based ligase complexes, independently rescued the 68k-ank deletion phenotype. Thus, poxvirus uncoating and DNA replication are intertwined processes involving at least three viral proteins with mutually redundant functions in addition to D5. Poxviruses comprise a family of large DNA viruses that infect vertebrates and invertebrates and cause diseases of medical and zoological importance. Poxviruses, unlike most other DNA viruses, replicate in the cytoplasm, and their large genomes usually encode 200 or more proteins with diverse functions. About 90 genes may be essential for chordopoxvirus replication based either on their conservation or individual gene deletion studies. However, this number may underestimate the true number of essential functions because of redundancy. Here we show that any one of three seemingly unrelated and individually nonessential proteins is required for the incompletely understood processes of genome uncoating and DNA replication, an example of synthetic lethality. Thus, poxviruses appear to have a complex genetic interaction network that has not been fully appreciated and which will require multifactor deletion screens to assess.

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“…Some of these are receptor mimics and are secreted from infected cells to block their cognate cytokine; examples are known to block IFN-a/b, IFN-g, TNF, IL-18 and chemokines (Upton et al, 1992;Nelson et al, 2015). Although fewer in number, some poxviruses also encode versions of cytokines (IL-10) and growth factors (EGF and VEGF) (Ouyang et al, 2014;Buller et al, 1988;Wise et al, 2012).…”

Section: Discussionmentioning

confidence: 99%

Genomic characterization of a novel poxvirus from a flying fox: evidence for a new genus?

O’Dea

Pang

et al. 2016

Journal of General Virology

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The carcass of an Australian little red flying fox (Pteropus scapulatus) which died following entrapment on a fence was submitted to the laboratory for Australian bat lyssavirus exclusion testing, which was negative. During post-mortem, multiple nodules were noted on the wing membranes, and therefore degenerate PCR primers targeting the poxvirus DNA polymerase gene were used to screen for poxviruses. The poxvirus PCR screen was positive and sequencing of the PCR product demonstrated very low, but significant, similarity with the DNA polymerase gene from members of the Poxviridae family. Next-generation sequencing of DNA extracted from the lesions returned a contig of 132 353 nucleotides (nt), which was further extended to produce a near full-length viral genome of 133 492 nt. Analysis of the genome revealed it to be AT-rich with inverted terminal repeats of at least 1314 nt and to contain 143 predicted genes. The genome contains a surprisingly large number (29) of genes not found in other poxviruses, one of which appears to be a homologue of the mammalian TNF-related apoptosis-inducing ligand (TRAIL) gene. Phylogenetic analysis indicates that the poxvirus described here is not closely related to any other poxvirus isolated from bats or other species, and that it likely should be placed in a new genus.

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Structural Conservation and Functional Diversity of the Poxvirus Immune Evasion (PIE) Domain Superfamily

Cited by 31 publications

References 83 publications

A Broad-Spectrum Chemokine-Binding Protein of Bovine Papular Stomatitis Virus Inhibits Neutrophil and Monocyte Infiltration in Inflammatory and Wound Models of Mouse Skin

A Broad-Spectrum Chemokine-Binding Protein of Bovine Papular Stomatitis Virus Inhibits Neutrophil and Monocyte Infiltration in Inflammatory and Wound Models of Mouse Skin

Identification of Poxvirus Genome Uncoating and DNA Replication Factors with Mutually Redundant Roles

Genomic characterization of a novel poxvirus from a flying fox: evidence for a new genus?

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