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1.
Emerg Infect Dis ; 29(6): 1206-1209, 2023 06.
Artigo em Inglês | MEDLINE | ID: mdl-37022936

RESUMO

Tanapox is a rarely diagnosed zoonosis known to be endemic to equatorial Africa. All previously reported human cases were acquired within 10° north or south of the Equator, most recently 19 years ago. We describe a human case of tanapox in South Africa (24° south of the Equator). Expanded surveillance for this pathogen is warranted.


Assuntos
Infecções por Poxviridae , Yatapoxvirus , Animais , Humanos , África do Sul/epidemiologia , Zoonoses , Infecções por Poxviridae/diagnóstico
2.
J Cancer Res Ther ; 16(4): 708-712, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32930107

RESUMO

Insufficiency of standard cancer therapeutic agents and a high degree of toxicity associated with chemotherapy and radiotherapy have created a dearth of therapeutic options for metastatic cancers. Oncolytic viruses (OVs) are an emerging therapeutic option for the treatment of various human cancers. Several OVs, including poxviruses, are currently in preclinical and clinical studies and have shown to be effective in treating metastatic cancer types. Tanapoxvirus (TANV), a member of the Poxviridae family, is being developed as an OV for different human cancers due to its desirable safety and efficacy features. TANV causes a mild self-limiting febrile disease in humans, does not spread human to human, and its large genome makes it a relatively safer OV for use in humans. TANV is relatively well characterized at both molecular and clinical levels. Some of the TANV-encoded proteins that are a part of the virus' immune evasion strategy are also characterized. TANV replicates considerably slower than vaccinia virus. TANV has been shown to replicate in different human cancer cells in vitro and regresses human tumors in a nude mouse model. TANV is currently being developed as a therapeutic option for several human cancers including breast cancer, ovarian cancer, colorectal cancer, pancreatic cancer, retinoblastoma, and melanoma. This review provides a comprehensive summary from the discovery to the development of TANV as an OV candidate for a wide array of human cancers.


Assuntos
Neoplasias/terapia , Terapia Viral Oncolítica/métodos , Yatapoxvirus/fisiologia , Animais , Modelos Animais de Doenças , Humanos , Neoplasias/imunologia , Neoplasias/patologia , Neoplasias/virologia , Yatapoxvirus/genética , Yatapoxvirus/imunologia
3.
FEBS J ; 287(17): 3733-3750, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32412687

RESUMO

Premature programmed cell death or apoptosis of cells is a strategy utilized by multicellular organisms to counter microbial threats. Tanapoxvirus (TANV) is a large double-stranded DNA virus belonging to the poxviridae that causes mild monkeypox-like infections in humans and primates. TANV encodes for a putative apoptosis inhibitory protein 16L. We show that TANV16L is able to bind to a range of peptides spanning the BH3 motif of human proapoptotic Bcl-2 proteins and is able to counter growth arrest of yeast induced by human Bak and Bax. We then determined the crystal structures of TANV16L bound to three identified interactors, Bax, Bim and Puma BH3. TANV16L adopts a globular Bcl-2 fold comprising 7 α-helices and utilizes the canonical Bcl-2 binding groove to engage proapoptotic host cell Bcl-2 proteins. Unexpectedly, TANV16L is able to adopt both a monomeric and a domain-swapped dimeric topology where the α1 helix from one protomer is swapped into a neighbouring unit. Despite adopting two different oligomeric forms, the canonical ligand binding groove in TANV16L remains unchanged from monomer to domain-swapped dimer. Our results provide a structural and mechanistic basis for tanapoxvirus-mediated inhibition of host cell apoptosis and reveal the capacity of Bcl-2 proteins to adopt differential oligomeric states whilst maintaining the canonical ligand binding groove in an unchanged state. DATABASE: Structural data are available in the Protein Data Bank (PDB) under the accession numbers 6TPQ, 6TQQ and 6TRR.


Assuntos
Proteínas Reguladoras de Apoptose/química , Apoptose , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Proteínas não Estruturais Virais/química , Yatapoxvirus/fisiologia , Sequência de Aminoácidos , Proteínas Reguladoras de Apoptose/metabolismo , Proteína 11 Semelhante a Bcl-2/metabolismo , Humanos , Modelos Moleculares , Ligação Proteica , Conformação Proteica , Domínios Proteicos , Mapeamento de Interação de Proteínas , Proteínas Proto-Oncogênicas/metabolismo , Proteínas Recombinantes/metabolismo , Saccharomyces cerevisiae/genética , Alinhamento de Sequência , Homologia de Sequência de Aminoácidos , Relação Estrutura-Atividade , Proteínas não Estruturais Virais/metabolismo , Proteína Killer-Antagonista Homóloga a bcl-2/fisiologia , Proteína X Associada a bcl-2/metabolismo , Proteína X Associada a bcl-2/fisiologia
4.
Curr Cancer Drug Targets ; 18(6): 577-591, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-28669340

RESUMO

BACKGROUND: Oncolytic viruses (OVs), which preferentially infect cancer cells and induce host anti-tumor immune responses, have emerged as an effective melanoma therapy. Tanapoxvirus (TANV), which possesses a large genome and causes mild self-limiting disease in humans, is potentially an ideal OV candidate. Interleukin-2 (IL-2), a T-cell growth factor, plays a critical role in activating T cells, natural killer (NK) cells and macrophages in both the innate and adaptive immune system. OBJECTIVE: We aimed to develop a recombinant TANV expressing mouse IL-2 (TANVΔ66R/mIL- 2), replacing the viral thymidine kinase (TK) gene (66R) with the mouse (m) mIL-2 transgene resulting in TANVΔ66R/mIL-2. METHODS: Human melanoma tumors were induced in female athymic nude mice by injecting SKMEL- 3 cells subcutaneously. Mice were treated with an intratumoral injection of viruses when the tumor volumes reached 45 ± 4.5 mm3. RESULTS: In cell culture, expression of IL-2 attenuated virus replication of not only TANVΔ66R/ mIL-2, but also TANVGFP. It was demonstrated that IL-2 inhibited virus replication through intracellular components and without activating the interferon-signaling pathway. Introduction of mIL-2 into TANV remarkably increased its anti-tumor activity, resulting in a more significant regression than with wild-type (wt) TANV and TANVΔ66R. Histopathological studies showed that extensive cell degeneration with a significantly increased peri-tumor accumulation of mononuclear cells in the tumors treated with TANVΔ66R/mIL-2, compared to wtTANV or TANVΔ66R. CONCLUSION: We conclude that TANVΔ66R/mIL-2 is potentially therapeutic for human melanomas in the absence of T cells, and IL-2 expression resulted in an overall increase of therapeutic efficacy.


Assuntos
Interleucina-2/metabolismo , Melanoma/terapia , Terapia Viral Oncolítica/métodos , Linfócitos T/imunologia , Yatapoxvirus/genética , Animais , Apoptose , Proliferação de Células , Feminino , Humanos , Interleucina-2/administração & dosagem , Interleucina-2/genética , Melanoma/imunologia , Melanoma/patologia , Melanoma/virologia , Camundongos , Camundongos Nus , Células Tumorais Cultivadas , Replicação Viral , Ensaios Antitumorais Modelo de Xenoenxerto
5.
Med Oncol ; 34(7): 129, 2017 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-28593604

RESUMO

Matrix metalloproteinases (MMPs), which are involved in degradation of extracellular matrix, are critical regulators in tumor progression, metastasis and angiogenesis. Although induction of MMPs is frequently observed during the viral infection, the effect of MMPs on viral replication varies between viruses. MMP-9, for instance, is upregulated and promotes the replication of some viruses, such as herpes simplex virus, but inhibits the replication of others. Here, we report that infection with tanapox virus (TPV) promotes the expression of MMP-9 in the melanoma cells. In addition, we show that MMP-9 exerts an anti-viral effect on TPV replication and plays a protective role in TPV-infected melanoma cells in vitro. Moreover, the neutralization of MMP-9 in melanoma cells remarkably enhances the TPV infection and leads to a significant reduction in cell survival. In summary, this study contributes to understanding of the role played by MMP-9 in TPV infectivity and provides more insights for using TPV as cancer virotherapy in future studies. Since TPV has shown substantial oncolytic efficacy in promoting melanoma tumor regression in animal models, identifying mechanisms that suppress MMP-9 expression upon TPV infection can potentially improve its use as a melanoma virotherapy.


Assuntos
Metaloproteinase 9 da Matriz/metabolismo , Melanoma/metabolismo , Terapia Viral Oncolítica/métodos , Yatapoxvirus/fisiologia , Linhagem Celular Tumoral , Humanos , Melanoma/terapia , Melanoma/virologia , Replicação Viral
6.
Med Oncol ; 34(6): 112, 2017 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-28466296

RESUMO

Human triple negative breast cancer (TNBC) is an aggressive disease, associated with a high rate of recurrence and metastasis. Current therapeutics for TNBC are limited, highly toxic and show inconsistent efficacy due to a high degree of intra-tumoral and inter-tumoral heterogeneity. Oncolytic viruses (OVs) are an emerging treatment option for cancers. Several OVs are currently under investigation in preclinical and clinical settings. Here, we examine the oncolytic potential of two tanapoxvirus (TPV) recombinants expressing mouse monocyte chemoattractant protein (mMCP)-1 [also known as mCCL2] and mouse interleukin (mIL)-2, in human TNBC, in vitro and in vivo. Both wild-type (wt) TPV and TPV recombinants demonstrated efficient replicability in human TNBC cells and killed cancer cell efficiently in a dose-dependent manner in vitro. TPV/∆66R/mCCL2 and TPV/∆66R/mIL-2 expressing mCCL2 and mIL-2, respectively, suppressed the growth of MDA-MB-231 tumor xenografts in nude mice significantly, as compared to the mock-injected tumors. Histological analysis of tumors showed areas of viable tumor cells, necrotic foci and immune cell accumulation in virus-treated tumors. Moreover, TPV/∆66R/mIL-2-treated tumors showed a deep infiltration of mononuclear immune cells into the tumor capsule and focal cell death in tumors. In conclusion, TPV recombinants expressing mCCL2 and mIL-2 showed a significant therapeutic effect in MDA-MB-231 tumor xenografts, in nude mice through induction of potent antitumor immune responses. Considering the oncolytic potency of armed oncolytic TPV recombinants expressing mCCL2 and mIL-2 in an experimental nude mouse model, these viruses merit further investigation as alternative treatment options for human breast cancer.


Assuntos
Quimiocina CCL2/metabolismo , Imunoterapia/métodos , Interleucina-2/metabolismo , Vírus Oncolíticos/genética , Neoplasias de Mama Triplo Negativas/metabolismo , Yatapoxvirus/genética , Animais , Aotidae , Linhagem Celular , Quimiocina CCL2/genética , Quimiocina CCL2/imunologia , Humanos , Interleucina-2/genética , Interleucina-2/imunologia , Masculino , Camundongos , Camundongos Nus , Vírus Oncolíticos/metabolismo , Neoplasias de Mama Triplo Negativas/genética , Neoplasias de Mama Triplo Negativas/imunologia , Ensaios Antitumorais Modelo de Xenoenxerto , Yatapoxvirus/metabolismo
7.
Virus Genes ; 53(3): 477-482, 2017 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-28188458

RESUMO

Oncolytic viruses (OVs) have emerged as a promising approach for melanoma treatment by causing tumor lysis and inducing immuno-modulatory activities. Tanapoxvirus (TPV), which causes a mild self-limiting disease in humans and contains a large DNA genome, appears as a promising OV candidate. TPV recombinants were generated with the thymidine kinase/66R gene deletion (TPVΔ66R), the 15L gene deletion (TPVΔ15L), or with both the 15L and 66R gene ablation (TPVΔ15LΔ66R). Our previous studies have shown that treatment of TPVΔ15L resulted in significant tumor regression in xenotransplanted human melanoma in nude mice. Here, we demonstrate that an anti-viral activity identified as interferon-λ1 (IFN-λ1) was secreted in a remarkably higher quantity from human lung fibroblast WI-38 and melanoma SK-MEL-3 cells infected with TPVΔ15L. Furthermore, we show that IFN-λ1 exhibits a more pronounced anti-proliferative effect in melanoma cells than IFN-α and IFN-ß in vitro. Additional experiments strongly suggest that TPVΔ15L kills melanoma cells partially through inducing IFN-λ1. Taken together, our results demonstrate the immuno-modulatory activities associated with TPVΔ15L and suggest further exploration of TPVΔ15L as a melanoma virotherapy.


Assuntos
Proliferação de Células , Citocinas/metabolismo , Melanoma/terapia , Melanoma/virologia , Proteínas Virais/metabolismo , Yatapoxvirus/genética , Animais , Antivirais/farmacologia , Linhagem Celular Tumoral , Fibroblastos/imunologia , Fibroblastos/virologia , Deleção de Genes , Vetores Genéticos , Interferon-alfa , Interferon beta , Pulmão/virologia , Melanoma/imunologia , Melanoma/patologia , Camundongos , Camundongos Nus , Neurregulinas/genética , Terapia Viral Oncolítica/métodos , Vírus Oncolíticos/genética , Deleção de Sequência , Timidina Quinase/genética , Proteínas Virais/genética , Replicação Viral
8.
Virus Genes ; 53(1): 52-62, 2017 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-27738905

RESUMO

Neuregulin (NRG), an epidermal growth factor is known to promote the growth of various cell types, including human melanoma cells through ErbB family of tyrosine kinases receptors. Tanapoxvirus (TPV)-encoded protein TPV-15L, a functional mimic of NRG, also acts through ErbB receptors. Here, we show that the TPV-15L protein promotes melanoma proliferation. TPV recombinant generated by deleting the 15L gene (TPVΔ15L) showed replication ability similar to that of wild-type TPV (wtTPV) in owl monkey kidney cells, human lung fibroblast (WI-38) cells, and human melanoma (SK-MEL-3) cells. However, a TPV recombinant with both 15L and the thymidine kinase (TK) gene 66R ablated (TPVΔ15LΔ66R) replicated less efficiently compared to TPVΔ15L and the parental virus. TPVΔ15L exhibited more robust tumor regression in the melanoma-bearing nude mice compared to other TPV recombinants. Our results indicate that deletion of TPV-15L gene product which facilitates the growth of human melanoma cells can be an effective strategy to enhance the oncolytic potential of TPV for the treatment of melanoma.


Assuntos
Melanoma/patologia , Neurregulinas/genética , Terapia Viral Oncolítica , Vírus Oncolíticos/genética , Deleção de Sequência , Proteínas Virais/genética , Yatapoxvirus/genética , Animais , Apoptose/genética , Linhagem Celular , Proliferação de Células , Modelos Animais de Doenças , Vetores Genéticos/genética , Humanos , Masculino , Melanoma/metabolismo , Melanoma/terapia , Camundongos , Camundongos Nus , Terapia Viral Oncolítica/métodos , Carga Tumoral , Replicação Viral , Ensaios Antitumorais Modelo de Xenoenxerto
9.
J Exp Clin Cancer Res ; 34: 19, 2015 Feb 19.
Artigo em Inglês | MEDLINE | ID: mdl-25887490

RESUMO

Colorectal cancers are significant causes of morbidity and mortality and existing therapies often perform poorly for individuals afflicted with advanced disease. Oncolytic virotherapy is an emerging therapeutic modality with great promise for addressing this medical need. Herein we describe the in vivo testing of recombinant variants of the tanapoxvirus (TPV). Recombinant viruses were made ablated for either the 66R gene (encoding a thymidine kinase), the 2L gene (encoding a TNF-binding protein), or both. Some of the recombinants were armed to express mouse chemotactic protein 1 (mCCL2/mMCP-1), mouse granulocyte-monocyte colony stimulating factor (mGM-CSF), or bacterial flagellin (FliC). Tumors were induced in athymic nude mice by implantation of HCT 116 cells and subsequently treated by a single intratumoral injection of one of the recombinant TPVs. Histological examination showed a common neoplastic cell type and a range of immune cell infiltration, necrosis, and tumor cell organization. Significant regression was seen in tumors treated with virus TPV/Δ2L/Δ66R/fliC, and to a lesser extent the recombinants TPV/Δ2L and TPV/Δ66R. Our results suggest that oncolytic recombinants of the TPV armed with activators of the innate immune response may be effective virotherapeutic agents for colorectal cancers in humans and should be explored further to fully realize their potential.


Assuntos
Neoplasias Colorretais/patologia , Flagelina/genética , Expressão Gênica , Vetores Genéticos/genética , Terapia Viral Oncolítica , Vírus Oncolíticos/genética , Yatapoxvirus/genética , Animais , Linhagem Celular Tumoral , Neoplasias Colorretais/terapia , Modelos Animais de Doenças , Terapia Genética , Vetores Genéticos/administração & dosagem , Humanos , Masculino , Camundongos , Transdução Genética , Transgenes , Ensaios Antitumorais Modelo de Xenoenxerto
10.
Int J Health Geogr ; 13: 34, 2014 Sep 25.
Artigo em Inglês | MEDLINE | ID: mdl-25255815

RESUMO

BACKGROUND: Tanapox virus is a zoonotic infection that causes mild febrile illness and one to several nodular skin lesions. The disease is endemic in parts of Africa. The principal reservoir for the virus that causes Tanapox is unknown, but has been hypothesized to be a non-human primate. This study employs ecological niche modeling (ENM) to determine areas of tropical Africa suitable for the occurrence of human Tanapox and a list of hypothetical reservoirs. The resultant niche model will be a useful tool to guide medical surveillance activities in the region. METHODS: This study uses the Desktop GARP software to predict regions where human Tanapox might be expected to occur based on historical human case locations and environmental data. Additional modeling of primate species, using occurrence data from museum records was performed to determine suitable disease reservoirs. RESULTS: The final ENM predicts a potential distribution of Tanapox over much of equatorial Africa, exceeding the borders of Kenya and Democratic Republic of Congo (DRC) where it has been historically reported. Five genera of non-human primates were found to be potential reservoir taxa. CONCLUSIONS: Validity testing suggests the model created here is robust (p < 0.04). Several genera of primates were identified as having ENMs overlapping with that of Tanapox and are suggested as potential reservoirs, mainly members of the Genus Cercopithecus. The ENM modeling technique has several limitations and results should be interpreted with caution. This study may increase knowledge and engage further research in this neglected disease.


Assuntos
Reservatórios de Doenças/virologia , Ecossistema , Mapeamento Geográfico , Modelos Teóricos , Infecções por Poxviridae/epidemiologia , Infecções Tumorais por Vírus/epidemiologia , Yatapoxvirus/isolamento & purificação , Animais , República Democrática do Congo/epidemiologia , Haplorrinos , Humanos , Quênia/epidemiologia , Pan troglodytes , Papio
11.
J Virol ; 87(6): 3018-26, 2013 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-23269801

RESUMO

Studies on large double-stranded DNA (dsDNA) viruses such as poxviruses have been helpful in identifying a number of viral and cellular growth factors that contribute to our broad understanding of virus-host interaction. Orthopoxviruses and leporipoxviruses are among the most studied viruses in this aspect. However, tanapoxvirus (TPV), a member of the genus Yatapoxvirus, still remains largely unexplored, as the only known hosts for this virus are humans and monkeys. Here, we describe the initial characterization of an epidermal growth factor (EGF)-like growth factor mimicking human neuregulin from TPV, expressed by the TPV-15L gene. Assays using a baculovirus-expressed and tagged TPV-15L protein demonstrated the ability to phosphorylate neuregulin receptors. Neuregulins represent a large family of EGF-like growth factors that play important roles in embryonic endocardium development, Schwann and oligodendrocyte survival and differentiation, localized acetylcholine receptor expression at the neuromuscular junction, and epithelial morphogenesis. Interestingly, certain neuregulin molecules are able to target specific tissues through interactions with heparin sulfate proteoglycans via an immunoglobulin (Ig)-like domain. Analyses of TPV-15L revealed no Ig-like domain, but it retains the ability to bind heparin and phosphorylate neuregulin receptors, providing compelling evidence that TPV-15L is a functional mimetic of neuregulin. TPV-15L knockout virus experiments demonstrate that the virus replicates in human umbilical vein endothelial cells less efficiently than wild-type TPV-Kenya, indicating that this is a nonessential protein for virus viability but can serve a stimulatory role for replication in some cultured cells. However, the precise role of this protein in host-virus interaction still remains to be deduced.


Assuntos
Células Endoteliais/virologia , Neurregulinas/metabolismo , Proteínas Virais/metabolismo , Fatores de Virulência/metabolismo , Replicação Viral , Yatapoxvirus/patogenicidade , Sequência de Aminoácidos , Animais , Linhagem Celular , Técnicas de Inativação de Genes , Humanos , Dados de Sequência Molecular , Neurregulinas/genética , Alinhamento de Sequência , Proteínas Virais/genética , Fatores de Virulência/genética , Yatapoxvirus/fisiologia
12.
PLoS Pathog ; 8(8): e1002876, 2012.
Artigo em Inglês | MEDLINE | ID: mdl-22927815

RESUMO

Interleukin 18 (IL18) is a cytokine that plays an important role in inflammation as well as host defense against microbes. Mammals encode a soluble inhibitor of IL18 termed IL18 binding protein (IL18BP) that modulates IL18 activity through a negative feedback mechanism. Many poxviruses encode homologous IL18BPs, which contribute to virulence. Previous structural and functional studies on IL18 and IL18BPs revealed an essential binding hot spot involving a lysine on IL18 and two aromatic residues on IL18BPs. The aromatic residues are conserved among the very diverse mammalian and poxviruses IL18BPs with the notable exception of yatapoxvirus IL18BPs, which lack a critical phenylalanine residue. To understand the mechanism by which yatapoxvirus IL18BPs neutralize IL18, we solved the crystal structure of the Yaba-Like Disease Virus (YLDV) IL18BP and IL18 complex at 1.75 Šresolution. YLDV-IL18BP forms a disulfide bonded homo-dimer engaging IL18 in a 2∶2 stoichiometry, in contrast to the 1∶1 complex of ectromelia virus (ECTV) IL18BP and IL18. Disruption of the dimer interface resulted in a functional monomer, however with a 3-fold decrease in binding affinity. The overall architecture of the YLDV-IL18BP:IL18 complex is similar to that observed in the ECTV-IL18BP:IL18 complex, despite lacking the critical lysine-phenylalanine interaction. Through structural and mutagenesis studies, contact residues that are unique to the YLDV-IL18BP:IL18 binding interface were identified, including Q67, P116 of YLDV-IL18BP and Y1, S105 and D110 of IL18. Overall, our studies show that YLDV-IL18BP is unique among the diverse family of mammalian and poxvirus IL-18BPs in that it uses a bivalent binding mode and a unique set of interacting residues for binding IL18. However, despite this extensive divergence, YLDV-IL18BP binds to the same surface of IL18 used by other IL18BPs, suggesting that all IL18BPs use a conserved inhibitory mechanism by blocking a putative receptor-binding site on IL18.


Assuntos
Peptídeos e Proteínas de Sinalização Intercelular/química , Interleucina-18/química , Multimerização Proteica , Proteínas Virais/química , Yatapoxvirus/química , Substituição de Aminoácidos , Linhagem Celular , Cristalografia por Raios X , Humanos , Peptídeos e Proteínas de Sinalização Intercelular/genética , Peptídeos e Proteínas de Sinalização Intercelular/metabolismo , Interleucina-18/genética , Interleucina-18/metabolismo , Mutagênese , Mutação de Sentido Incorreto , Infecções por Poxviridae/genética , Infecções por Poxviridae/metabolismo , Estrutura Quaternária de Proteína , Estrutura Terciária de Proteína , Proteínas Virais/genética , Proteínas Virais/metabolismo , Yatapoxvirus/genética , Yatapoxvirus/metabolismo
13.
Recent Pat DNA Gene Seq ; 5(2): 97-103, 2011 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-21529335

RESUMO

Viruses have evolved strategies to counteract host defenses. Some tactics employ viral proteins to neutralize host immune effector proteins such as cytokines, chemokines and their receptors, which help coordinate the host responses against the virus. Tumor necrosis factor (TNF) is one of the crucial pro-inflammatory/anti-viral cytokines involved in inflammatory and autoimmune diseases. Poxvirus anti-immune proteins represent some of the most complex and efficient mechanisms of regulating TNF and its pathological effects. These proteins have considerable potential for treating TNF-related diseases. Here we discuss two major classes of poxvirus-TNF inhibitors focusing on the tanapoxvirus (TPV)-2L protein, previously called TPV-gp38. TPV-2L has been shown to interact and biologically neutralize human (h)TNF, and has been indirectly associated with the inhibition of other cytokines (hIFN-γ, hIL-2 and hIL-5). The TPV-2L protein alone has been expressed, purified and shown to bind with high affinity to hTNF, but lacked binding to the other cytokines. Further studies identified sequential binding of hß2-microglobulin and hα2-macroglobulin to TPV-2L. The ability of a single viral protein to form multi-protein complexes suggests that TPV might also possess other novel strategies of evading the immune system. Reviewed here are patented poxvirus TNF-binding proteins and their genes to evaluate their potential therapeutic value.


Assuntos
Poxviridae/metabolismo , Fator de Necrose Tumoral alfa/antagonistas & inibidores , Proteínas Virais/química , Humanos , Evasão da Resposta Imune , Complexos Multiproteicos/imunologia , Complexos Multiproteicos/metabolismo , Poxviridae/imunologia , Ligação Proteica , Fator de Necrose Tumoral alfa/metabolismo , Proteínas Virais/imunologia , Proteínas Virais/metabolismo , Yatapoxvirus/imunologia , Yatapoxvirus/metabolismo , alfa-Macroglobulinas/metabolismo , Microglobulina beta-2/metabolismo
14.
FEBS Lett ; 584(21): 4453-7, 2010 Nov 05.
Artigo em Inglês | MEDLINE | ID: mdl-20937275

RESUMO

The Yaba-like disease viruses (YLDV) are members of the Yatapoxvirus family and have double-stranded DNA genomes. The E3L protein, which is essential for pathogenesis in the vaccinia virus, consists of two domains: an N-terminal Z-DNA binding domain and a C-terminal RNA binding domain. The crystal structure of the E3L orthologue of YLDV (yabZα(E3L)) bound to Z-DNA revealed that the overall structure of yabZα(E3L) and its interaction with Z-DNA are very similar to those of hZα(ADAR1). Here we have performed NMR hydrogen exchange experiments on the complexes between yabZα(E3L) and d(CGCGCG)(2) with a variety of protein-to-DNA molar ratios. This study revealed that yabZα(E3L) could efficiently change the B-form helix of the d(CGCGCG)(2) to left-handed Z-DNA via the active-mono B-Z transition pathway like hZα(ADAR1).


Assuntos
DNA/química , Hidrogênio , Espectroscopia de Ressonância Magnética/métodos , Conformação de Ácido Nucleico , Proteínas Virais/química , Proteínas Virais/metabolismo , Yatapoxvirus , Sequência de Aminoácidos , Animais , Sequência de Bases , DNA/genética , DNA/metabolismo , Humanos , Camundongos , Modelos Moleculares , Dados de Sequência Molecular , Estrutura Terciária de Proteína , Prótons
15.
Virology ; 386(2): 462-8, 2009 Apr 10.
Artigo em Inglês | MEDLINE | ID: mdl-19232662

RESUMO

Tanapox virus (TPV) encodes and expresses a secreted TNF-binding protein, TPV-2L or gp38, that displays inhibitory properties against TNF from diverse mammalian species, including human, monkey, canine and rabbit. TPV-2L also has sequence similarity with the MHC-class I heavy chain and interacts differently with human TNF as compared to the known cellular TNF receptors or any of the known virus-encoded TNF receptor homologs derived from many poxviruses. In order to determine the TNF binding region in TPV-2L, various TPV-2L C-terminal truncations and internal deletions were created and the muteins were expressed using recombinant baculovirus vectors. C-terminal deletions from TPV-2L resulted in reduced binding affinity for human TNF and specific mutants of TNF that discriminate between TNF-R1 and TNF-R2. However, deletion of C-terminal 42 amino acid residues totally abolished the binding of human TNF and its mutants. Removal of any of the predicted internal domains resulted in a mutant TPV-2L protein incapable of binding to human TNF. Deletion of C-terminal residues also affected the ability of TPV-2L to block TNF-induced cellular cytotoxicity. In addition to TNF, TPV-2L can also form complexes with human beta2-microglobulin to form a novel macromolecular complex. In summary, the TPV-2L protein is a bona fide MHC-1 heavy chain family member that binds and inhibits human TNF in a fashion very distinct from other known poxvirus-encoded TNF inhibitors, and also can form a novel complex with the human MHC-1 light chain, beta2-microglobulin.


Assuntos
Fator de Necrose Tumoral alfa/metabolismo , Proteínas Virais/metabolismo , Yatapoxvirus/metabolismo , Microglobulina beta-2/metabolismo , Animais , Baculoviridae/genética , Sítios de Ligação , Linhagem Celular , Humanos , Camundongos , Ligação Proteica , Receptores do Fator de Necrose Tumoral/metabolismo , Deleção de Sequência , Proteínas Virais/genética , Yatapoxvirus/genética
16.
J Virol ; 83(2): 498-511, 2009 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-18971273

RESUMO

Tumor necrosis factor (TNF) and members of the interferon (IFN) family have been shown to independently inhibit the replication of a variety of viruses. In addition, previous reports have shown that treatment with various combinations of these antiviral cytokines induces a synergistic antiviral state that can be significantly more potent than addition of any of these cytokines alone. The mechanism of this cytokine synergy and its effects on global gene expression, however, are not well characterized. Here, we use DNA microarray analysis to demonstrate that treatment of uninfected primary human fibroblasts with TNF plus IFN-beta induces a distinct synergistic state characterized by significant perturbations of several hundred genes which are coinduced by the individual cytokines alone, as well as the induction of more than 850 novel host cell genes. This synergy is mediated directly by the two ligands, not by intermediate secreted factors, and is necessary and sufficient to completely block the productive replication and spread of myxoma virus in human fibroblasts. In contrast, the replication of two other poxviruses, vaccinia virus and tanapox virus, are only partially inhibited in these cells by the synergistic antiviral state, whereas the spread of both of these viruses to neighboring cells was efficiently blocked. Taken together, our data indicate that the combination of TNF and IFN-beta induces a novel synergistic antiviral state that is highly distinct from that induced by either cytokine alone.


Assuntos
Fibroblastos/imunologia , Fibroblastos/virologia , Fatores Imunológicos/imunologia , Interferon beta/imunologia , Myxoma virus/imunologia , Fator de Necrose Tumoral alfa/imunologia , Células Cultivadas , Sinergismo Farmacológico , Perfilação da Expressão Gênica , Humanos , Fatores Imunológicos/farmacologia , Interferon beta/farmacologia , Myxoma virus/fisiologia , Análise de Sequência com Séries de Oligonucleotídeos , Fator de Necrose Tumoral alfa/farmacologia , Vírus Vaccinia/imunologia , Ensaio de Placa Viral , Replicação Viral/imunologia , Yatapoxvirus/imunologia
17.
Virology ; 368(1): 32-40, 2007 Nov 10.
Artigo em Inglês | MEDLINE | ID: mdl-17632198

RESUMO

Tanapox virus (TPV) belongs to the genus Yatapoxvirus and causes a relatively benign zoonotic disease in man, with symptoms that resemble a mild version of human monkeypox. In order to investigate the underlying mechanisms of TPV pathogenesis, the tropism and replication characteristics of TPV were examined in a variety of primary human cells. A GFP expressing TPV (TPV-GFP) was constructed and used to infect primary human dermal fibroblasts (pHDFs) and peripheral blood mononuclear cells (PBMCs), both of which are believed to be major in vivo targets of poxvirus infection. pHDFs fully supported productive replication and cell-cell spread of TPV-GFP. However, induction of cell cycle arrest in pHDFs by contact mediated inhibition or rapamycin treatment eliminated the ability of TPV to fully stimulate cell cycle progression and dramatically reduced viral replication. TPV-GFP-infected human PBMCs were screened for permissiveness by FACS analysis. CD14+ cells (monocytes) were the primary cellular target for TPV infection. A small proportion of CD3+ cells (T cells) were positive for GFP expression, yet TPV was not able to replicate and spread in cultured peripheral blood lymphocytes, regardless of their state of activation. Primary human monocytes, however, demonstrated robust TPV replication, yet these cells no longer supported replication of TPV once they differentiated into macrophages. This unique ex vivo tropism of TPV gives key insights into the basis for the self-limiting pathogenicity of TPV in man.


Assuntos
Fibroblastos/virologia , Monócitos/virologia , Yatapoxvirus/fisiologia , Complexo CD3/análise , Células Cultivadas , Genes Reporter , Proteínas de Fluorescência Verde/biossíntese , Proteínas de Fluorescência Verde/genética , Humanos , Receptores de Lipopolissacarídeos/análise , Linfócitos T/virologia , Replicação Viral/fisiologia , Yatapoxvirus/genética , Yatapoxvirus/crescimento & desenvolvimento
18.
Virus Res ; 129(1): 11-25, 2007 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-17574698

RESUMO

Members of the genus Yatapoxvirus, which include Tanapox virus (TPV) and Yaba monkey tumor virus, infect primates including humans. Two strains of TPV isolated 50 years apart from patients infected from the equatorial region of Africa have been sequenced. The original isolate from a human case in the Tana River Valley, Kenya, in 1957 (TPV-Kenya) and an isolate from an infected traveler in the Republic of Congo in 2004 (TPV-RoC). Although isolated 50 years apart the genomes were highly conserved. The genomes differed at only 35 of 144,565 nucleotide positions (99.98% identical). We predict that TPV-RoC encodes 155 ORFs, however a single transversion (at nucleotide 10241) in TPV-Kenya resulted in the coding capacity for two predicted ORFs (11.1L and 11.2L) in comparison to a single ORF (11L) in TPV-RoC. The genomes of TPV are A+T rich (73%) and 96% of the sequence encodes predicted ORFs. Comparative genomic analysis identified several features shared with other chordopoxviruses. A conserved sequence within the terminal inverted repeat region that is also present in the other members of the Yatapoxviruses as well as members of the Capripoxviruses, Swinepox virus and an unclassified Deerpox virus suggests the existence of a conserved near-terminal sequence secondary structure. Two previously unidentified gene families were annotated that are represented by ORF TPV28L, which matched homologues in certain other chordopoxviruses, and TPV42.5L, which is highly conserved among currently reported chordopoxvirus sequences.


Assuntos
DNA Viral/genética , Genoma Viral , Infecções por Poxviridae/virologia , Infecções Tumorais por Vírus/virologia , Yatapoxvirus/genética , África , Sequência de Aminoácidos , Humanos , Dados de Sequência Molecular , Fases de Leitura Aberta , Alinhamento de Sequência , Homologia de Sequência
19.
Proc Natl Acad Sci U S A ; 104(23): 9822-7, 2007 Jun 05.
Artigo em Inglês | MEDLINE | ID: mdl-17517620

RESUMO

Type I (IFN-alpha/beta) and type III (IFN-lambdas) IFNs are important components of the host antiviral response. Although type III IFNs possess intrinsic antiviral activity similar to that of type I IFNs, they signal through a specific unique receptor complex, and their functional importance for antiviral resistance is largely uncharacterized. Here, we report the first virus defense mechanism that directly targets type III IFNs. Y136 from Yaba-like disease virus, a yatapoxvirus, is a secreted glycoprotein related to protein B18 from Vaccinia virus, a known type I IFN-binding protein and a member of the Ig superfamily. Surprisingly, whereas B18 inhibits only type I IFNs, Y136 inhibits both type I and type III IFNs. Y136 inhibits IFN-induced signaling and suppresses IFN-mediated biological activities including up-regulation of MHC class I antigen expression and induction of the antiviral state. These data demonstrate that poxviruses have developed unique strategies to counteract IFN-mediated antiviral protection and highlight the importance of type III IFNs in antiviral defense. These results suggest that type III IFNs may be an effective treatment for some poxviral infections.


Assuntos
Citocinas/antagonistas & inibidores , Interferon Tipo I/antagonistas & inibidores , Interleucinas/antagonistas & inibidores , Transdução de Sinais/imunologia , Proteínas Virais de Fusão/imunologia , Proteínas Virais/imunologia , Yatapoxvirus/química , Animais , Células CHO , Células COS , Linhagem Celular Tumoral , Chlorocebus aethiops , Cricetinae , Cricetulus , Ensaio de Desvio de Mobilidade Eletroforética , Citometria de Fluxo , Humanos , Immunoblotting , Imunoprecipitação , Interferons , Transdução de Sinais/efeitos dos fármacos , Proteínas Virais de Fusão/farmacologia , Proteínas Virais/farmacologia
20.
J Gen Virol ; 87(Pt 4): 809-816, 2006 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-16528029

RESUMO

Yaba-like disease virus (YLDV) gene 7L encodes a seven-transmembrane G protein-coupled receptor with 53 % amino acid identity to human CC chemokine receptor 8 (CCR8). Initial characterization of 7L showed that this 56 kDa cell-surface glycoprotein binds human CCL1 with high affinity (Kd=0.6 nM) and induces signal transduction by activation of heterotrimeric G proteins and downstream protein kinases. Further characterization of YLDV 7L is presented here and shows that murine CC chemokines can induce G-protein activation via the 7L receptor, despite having a low binding affinity for this receptor. In addition, when expressed by recombinant vaccinia virus (VACV), YLDV 7L was found on the outer envelope of VACV extracellular enveloped virus. The contribution of 7L to poxvirus pathogenesis was investigated by infection of mice with a recombinant VACV expressing 7L (vDeltaB8R-7L) and was compared with the outcome of infection by parental and revertant control viruses. In both intranasal and intradermal models, expression of 7L caused attenuation of VACV. The role of this protein in viral virulence is discussed.


Assuntos
Quimiocinas CC/metabolismo , Receptores de Quimiocinas/química , Receptores Virais , Vírus Vaccinia/metabolismo , Yatapoxvirus/patogenicidade , Administração Intranasal , Animais , Linhagem Celular , Humanos , Injeções Intradérmicas , Camundongos , Camundongos Endogâmicos BALB C , Receptores CCR8 , Receptores Virais/química , Receptores Virais/genética , Receptores Virais/imunologia , Receptores Virais/metabolismo , Recombinação Genética , Transdução de Sinais , Vaccinia/patologia , Vaccinia/virologia , Vírus Vaccinia/genética , Vírus Vaccinia/patogenicidade , Vírion/metabolismo , Virulência , Yatapoxvirus/genética , Yatapoxvirus/metabolismo
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