The Experts below are selected from a list of 309 Experts worldwide ranked by ideXlab platform

Grant Mcfadden - One of the best experts on this subject based on the ideXlab platform.

  • Immune evasion by Poxviruses
    Future Virology, 2020
    Co-Authors: Grant Mcfadden, Steven H. Nazarian
    Abstract:

    Through eons of co-evolution, Poxviruses and their hosts have come to an elegant point of equilibrium whereby the host immune system is systematically modulated in favor of the virus. Owing to the large coding capacity of Poxviruses, many gene products are dedicated as virulence factors. Key targets of these immunomodulators include mediators of inflammation, chemotaxis, apoptosis and the antiviral state. It is not surprising that these systems have become targets since they are crucial for mounting an effective immune response against Poxviruses. The following discussion will focus on a select group of poxvirus proteins that are able to modulate particular components of the host response efficiently to ensure propagation of the virus.

  • Immunomodulation by Poxviruses
    Poxviruses, 2020
    Co-Authors: Steven H. Nazarian, Grant Mcfadden
    Abstract:

    Large DNA viruses, such as Poxviruses, encode an array of gene products, both secreted and intracellular, that systematically debilitate the various host responses to virus infection. The primary targets of the secreted gene products are members of the inflammatory innate immune system, such as the interferons, tumor necrosis factors, diverse interleukins, complement and the chemokine pathways. Poxvirus-infected cells also maintain a low profile to escape the cell-mediated arm of the adaptive immune response. Virulence factors that mediate this ‘virostealth’ are generally expressed intracellularly and interfere with host signaling processes or antigen presentation. Poxviruses also interfere with the cellular apoptotic response by regulating several key checkpoints within the cell. While many poxvirus virulence factors exhibit some sequence relationship with host proteins, suggesting that these genes may have been acquired from an ancestral host, others show no obvious similarity to any known host genes. Due to the intimate nature of the coevolution with their hosts, poxviral immunomodulators have proved useful in examining diverse aspects of immunology, virology and cell biology.

  • Origin and Evolution of Poxviruses
    Origin and Evolution of Viruses, 2020
    Co-Authors: John W. Barrett, Grant Mcfadden
    Abstract:

    ABSTRACT The family Poxviridae is a large and diverse family of double-stranded DNA viruses with ubiquitous distribution. Poxviruses parasitize invertebrates, birds, reptiles and mammals suggesting that the family Poxviridae is an ancient virus family. The genomes are linear and encode a large complement of genes. Essential viral functions are clustered in the central region of the genome and a core group of critical genes are conserved among all Poxviruses. In contrast, species-specific genes, necessary for host infection and virus virulence, are maintained near the termini. The success of the poxvirus family members is based on the acquisition of cellular genes that have evolved under viral/host selection to permit the virus to modulate the host immune response.

  • Chapter 3 Poxvirus Host Range Genes
    Advances in Virus Research, 2020
    Co-Authors: Steven J. Werden, Masmudur M. Rahman, Grant Mcfadden
    Abstract:

    As a family of viruses, Poxviruses collectively exhibit a broad host range and most of the individual members are capable of replicating in a wide array of cell types from various host species, at least in vitro. At the cellular level, poxvirus tropism is dependent not upon specific cell surface receptors, but rather upon: (1) the ability of the cell to provide intracellular complementing factors needed for productive virus replication, and (2) the ability of the specific virus to successfully manipulate intracellular signaling networks that regulate cellular antiviral processes downstream of virus entry. The large genomic coding capacity of Poxviruses enables the virus to express a unique collection of viral proteins that function as host range factors, which specifically target and manipulate host signaling pathways to establish optimal cellular conditions for viral replication. Functionally, the known host range factors from Poxviruses have been associated with manipulation of a diverse array of cellular targets, which includes cellular kinases and phosphatases, apoptosis, and various antiviral pathways. To date, only a small number of poxvirus host range genes have been identified and studied, and only a handful of these have been functionally characterized. For this reason, poxvirus host range factors represent a potential gold mine for the discovery of novel pathogen–host protein interactions. This review summarizes our current understanding of the mechanisms by which the known poxvirus host range genes, and their encoded factors, expand tropism through the manipulation of host cell intracellular signaling pathways.

  • Leporipoviruses and SuiPoxviruses
    Encyclopedia of Virology, 2020
    Co-Authors: Grant Mcfadden
    Abstract:

    Members of the genera Leporipoxvirus and Suipoxvirus are Poxviruses that infect a relatively narrow range of vertebrate host species, namely leporids and swine, respectively. All cause benign, self-limiting dermal infections in their native host species, except for myxoma virus, which causes a lethal disease called myxomatosis in the European rabbit. The replication of these large DNA viruses occurs in the cytoplasm of infected cells, similar to that of other Poxviruses. All of these viruses express approximately 150 viral proteins, a substantial fraction of which mediate host tropism, pathogenesis, and immunomodulation. Myxoma virus virulence factors have been studied extensively, and have been shown to inhibit a variety of host immune molecules, such as tumor necrosis factor and interferon. Secreted anti-immune proteins from myxoma virus have shown efficacy as novel biotherapeutics to treat inflammatory diseases. The extreme pathogenicity of myxoma virus in European rabbits and its narrow host range were major factors in the decision to deliberately release myxoma virus in the attempt to control feral rabbit populations in Australia in the 1950s. Myxoma virus can also infect and kill human cancer cells and is under preclinical analysis as a novel oncolytic therapy to treat cancer.

Stefan Rothenburg - One of the best experts on this subject based on the ideXlab platform.

  • Poxviruses and the evolution of host range and virulence
    Infection Genetics and Evolution, 2014
    Co-Authors: Sherry L Haller, Grant Mcfadden, Chen Peng, Stefan Rothenburg
    Abstract:

    Poxviruses as a group can infect a large number of animals. However, at the level of individual viruses, even closely related Poxviruses display highly diverse host ranges and virulence. For example, variola virus, the causative agent of smallpox, is human-specific and highly virulent only to humans, whereas related cowpox viruses naturally infect a broad spectrum of animals and only cause relatively mild disease in humans. The successful replication of Poxviruses depends on their effective manipulation of the host antiviral responses, at the cellular-, tissue- and species-specific levels, which constitutes a molecular basis for differences in poxvirus host range and virulence. A number of poxvirus genes have been identified that possess host range function in experimental settings, and many of these host range genes target specific antiviral host pathways. Herein, we review the biology of Poxviruses with a focus on host range, zoonotic infections, virulence, genomics and host range genes as well as the current knowledge about the function of poxvirus host range factors and how their interaction with the host innate immune system contributes to poxvirus host range and virulence. We further discuss the evolution of host range and virulence in Poxviruses as well as host switches and potential poxvirus threats for human and animal health.

  • The poxvirus C7L host range factor superfamily.
    Current Opinion in Virology, 2012
    Co-Authors: Stefan Rothenburg, Grant Mcfadden
    Abstract:

    Host range factors, expressed by the poxvirus family, determine the host tropism of species, tissue, and cell specificity. C7L family members exist in the genomes of most sequenced mammalian Poxviruses, suggesting an evolutionarily conserved effort adapting to the hosts. In general, C7L orthologs influence the host tropism in mammalian cell culture, and for some Poxviruses it is essential for the complete viral life cycle in vitro and in vivo. The C7L family members lack obvious sequence homology with any other known viral or cellular proteins. Here we review recent findings from an evolutionary perspective and summarize recent progress that broadens our view on the role of C7L family members in mediating poxvirus host range and antagonizing the host defense system.

Yan Xiang - One of the best experts on this subject based on the ideXlab platform.

  • C7L Family of Poxvirus Host Range Genes Inhibits Antiviral Activities Induced by Type I Interferons and Interferon Regulatory Factor 1
    Journal of Virology, 2012
    Co-Authors: Xiangzhi Meng, John W. Schoggins, Lloyd F. Rose, Alexander Ploss, Charles M. Rice, Yan Xiang
    Abstract:

    Vaccinia virus (VACV) K1L and C7L function equivalently in many mammalian cells to support VACV replication and antagonize antiviral activities induced by type I interferons (IFNs). While K1L is limited to orthoPoxviruses, genes that are homologous to C7L are found in diverse mammalian Poxviruses. In this study, we showed that the C7L homologues from sheeppox virus and swinepox virus could rescue the replication defect of a VACV mutant deleted of both K1L and C7L (vK1L−C7L−). Interestingly, the sheeppox virus C7L homologue could rescue the replication of vK1L−C7L− in human HeLa cells but not in murine 3T3 and LA-4 cells, in contrast to all other C7L homologues. Replacing amino acids 134 and 135 of the sheeppox virus C7L homologue, however, made it functional in the two murine cell lines, suggesting that these two residues are critical for antagonizing a putative host restriction factor which has some subtle sequence variation in human and murine cells. Furthermore, the C7L family of host range genes from diverse mammalian Poxviruses were all capable of antagonizing type I IFN-induced antiviral activities against VACV. Screening of a library of more than 350 IFN-stimulated genes (ISGs) identified interferon-regulated factor 1 (IRF1) as an inhibitor of vK1L−C7L− but not wild-type VACV. Expression of either K1L or C7L, however, rendered vK1L−C7L− resistant to IRF1-induced antiviral activities. Altogether, our data show that K1L and C7L antagonize IRF1-induced antiviral activities and that the host modulation function of C7L is evolutionally conserved in all Poxviruses that can readily replicate in tissue-cultured mammalian cells.

  • identification from diverse mammalian Poxviruses of host range regulatory genes functioning equivalently to vaccinia virus c7l
    Virology, 2008
    Co-Authors: Xiangzhi Meng, Jie Chao, Yan Xiang
    Abstract:

    Abstract Vaccinia virus (VACV) C7L is a host-range gene that regulates cellular tropism of VACV. Distantly related C7L homologues are encoded by nearly all mammalian Poxviruses, but whether they are host-range genes functioning similar to VACV C7L has not been determined. Here, we used VACV as a model system to analyze five different C7L homologues from diverse mammalian Poxviruses for their abilities to regulate poxvirus cellular tropism. Three C7L homologues (myxoma virus M63R, M64R and cowpox virus 020), when expressed with an epitope tag and from a VACV mutant lacking the host-range genes K1L and C7L (vK1L−C7L−), failed to support productive viral replication in human and murine cells. In nonpermissive cells, these viruses did not synthesize viral late proteins, expressed a reduced level of the early protein E3L, and were defective at suppressing cellular PKR activation. In contrast, two other C7L homologues, myxoma virus (MYXV) M62R and yaba-like disease virus (YLDV) 67R, when expressed with an epitope tag and from vK1L − C7L − , supported normal viral replication in human and murine cells and restored the ability of the virus to suppress PKR activation. Furthermore, M62R rescued the defect of vK1L − C7L − at replicating and disseminating in mice following intranasal inoculation. These results show that MYXV M62R and YLDV 67R function equivalently to C7L at supporting VACV replication in mammalian hosts and suggest that a C7L-like host-range gene is essential for the replication of many mammalian Poxviruses in mammalian hosts.

Geoffrey L. Smith - One of the best experts on this subject based on the ideXlab platform.

  • The Genome Sequence of Yaba-like Disease Virus, a Yatapoxvirus☆
    Virology, 2001
    Co-Authors: Karim Essani, Geoffrey L. Smith
    Abstract:

    Abstract The genome sequence of Yaba-like disease virus (YLDV), an unclassified member of the yatapoxvirus genus, has been determined. Excluding the terminal hairpin loops, the YLDV genome is 144,575 bp in length and contains inverted terminal repeats (ITRs) of 1883 bp. Within 20 nucleotides of the termini, there is a sequence that is conserved in other Poxviruses and is required for the resolution of concatemeric replicative DNA intermediates. The nucleotide composition of the genome is 73% A+T, but the ITRs are only 63% A+T. The genome contains 151 tightly packed open reading frames (ORFs) that either are ≥180 nucleotides in length or are conserved in other Poxviruses. ORFs within 23 kb of each end are transcribed toward the termini, whereas ORFs within the central region of the genome are encoded on either DNA strand. In the central region ORFs have a conserved position, orientation, and sequence compared with vaccinia virus ORFs and encode many enzymes, transcription factors, or structural proteins. In contrast, ORFs near the termini are more divergent and in seven cases are without counterparts in other Poxviruses. The YLDV genome encodes several predicted immunomodulators; examples include two proteins with similarity to CC chemokine receptors and predicted secreted proteins with similarity to MHC class I antigen, OX-2, interleukin-10/mda-7, poxvirus growth factor, serpins, and a type I interferon-binding protein. Phylogenic analyses indicated that YLDV is very closely related to yaba monkey tumor virus, but outside the yatapoxvirus genus YLDV is more closely related to swinepox virus and leporiPoxviruses than to other chordopoxvirus genera.

  • Poxviruses interfering with interferon
    Seminars in Virology, 1998
    Co-Authors: Geoffrey L. Smith, Julian A Symons, Antonio Alcami
    Abstract:

    Abstract Interferon (IFN) is an important innate defense against virus infection and many viruses have consequently evolved ways to interfere with the action of IFN. The Poxviruses are an excellent example and devote at least four proteins to this task. Two function within the infected cell to block the action of IFN-induced antiviral proteins, and two are secreted to capture type I and type II IFNs before they can bind to cellular IFN receptors. The vaccinia virus IFN receptors have a surprisingly broad species specificity that may aid virus replication in several species and provide clues about the enigmatic origin of vaccinia virus.

  • Poxviruses capturing cytokines and chemokines
    Seminars in Virology, 1998
    Co-Authors: Antonio Alcami, Julian A Symons, Anu Khanna, Geoffrey L. Smith
    Abstract:

    Abstract Cytokines play a critical role in the regulation of immune responses and constitute important targets for virus immune evasion mechanisms. One strategy used by large DNA viruses is to encode proteins that mimic cytokines or cytokine receptors, which modulate the activity of cytokines during infection. Poxviruses encode a unique set of proteins that are secreted from the infected cell and function as soluble cytokine receptors or binding proteins and sequester tumor necrosis factor, interleukin-1β, or chemokines. Characterization of these poxvirus proteins is providing information on virus pathogenesis, the function of cytokines, and new strategies for immune modulation and therapeutic intervention.

  • Soluble interferon-γ receptors encoded by Poxviruses
    Comparative Immunology Microbiology and Infectious Diseases, 1996
    Co-Authors: Antonio Alcami, Geoffrey L. Smith
    Abstract:

    Abstract Poxviruses encode a broad range of proteins that counteract the formidable attack of the immune response initiated in the host after infection, among which are proteins that mimic the extracellular binding domain of host cytokine receptors and are secreted from virus-infected cells. A soluble interferon-γ receptor (IFN-γR) is produced early after infection and efficiently blocks the binding of IFN-γ to cellular receptors, thus inhibiting both the anti-viral and immune functions of IFN-γ. An IFN-γR is highly conserved among members of the poxvirus family, suggesting a major role in viral pathogenesis. The highly species-specific nature of the IFN system enables questions concerning the evolutionary relationship between Poxviruses and their hosts to be addressed. The IFN-γR encoded by myxoma virus, a natural pathogen of rabbits, is specific for rabbit IFN-γ. However, the IFN-γR encoded by orthoPoxviruses (vaccinia, cowpox, camelpox, ectromelia) shows a novel, broad species specificity suggesting that these viruses have evolved in several species. The implications for the unknown origin and natural host(s) of vaccinia virus are discussed.

  • receptors for gamma interferon encoded by Poxviruses implications for the unknown origin of vaccinia virus
    Trends in Microbiology, 1996
    Co-Authors: Antonio Alcami, Geoffrey L. Smith
    Abstract:

    Abstract Poxviruses encode soluble interferon-γ receptors (IFN-γRs) that inhibit IFN-γ activity and play a major role in virus pathogenesis. In contrast to the highly species specific cellular homologues, the vaccinia IFN-γ has novel broad species specificity. This has implications for the unknown origin and natural host(s) of vaccinia virus, the vaccine used for smallpox eradication.

John C Bell - One of the best experts on this subject based on the ideXlab platform.

  • targeted and armed oncolytic Poxviruses for cancer the lead example of jx 594
    Current Pharmaceutical Biotechnology, 2012
    Co-Authors: Caroline J Breitbach, John C Bell, Steve H Thorne, David Kirn
    Abstract:

    Oncolytic viruses (OVs) are designed to replicate in, and subsequently lyse cancer cells. Numerous oncolytic virus platforms are currently in development. Here we review preclinical and clinical experience with JX-594, the lead candidate from the targeted and armed oncolytic poxvirus class. JX-594 is derived from a vaccinia vaccine strain that has been engineered for 1) enhanced cancer targeting and 2) has been “armed” with the therapeutic transgene granulocytemacrophage colony stimulating factor (GM-CSF) to stimulate anti-tumoral immunity. Poxviruses have many ideal features for use as oncolytic agents. The development of oncolytic vaccinia viruses is supported by a large safety database accumulated in the smallpox eradication program. In addition, Poxviruses have evolved unique capabilities for systemic spread through the blood that can be harnessed for the treatment of metastatic disease. JX-594 demonstrates a high degree of cancer selectivity and systemic efficacy by multiple mechanisms-of-action (MOAs) in preclinical testing. Data from Phase 1 and 2 clinical trials has confirmed that these features result in potent and systemic efficacy in patients with treatment refractory metastatic cancers.

  • a selectable and excisable marker system for the rapid creation of recombinant Poxviruses
    PLOS ONE, 2011
    Co-Authors: David H Evans, Julia L Rintoul, Jiahu Wang, Don Brad Gammon, Nicholas Van Buuren, Kenneth Garson, Karen Jardine, Michele Barry, John C Bell
    Abstract:

    Background Genetic manipulation of poxvirus genomes through attenuation, or insertion of therapeutic genes has led to a number of vector candidates for the treatment of a variety of human diseases. The development of recombinant Poxviruses often involves the genomic insertion of a selectable marker for purification and selection purposes. The use of marker genes however inevitably results in a vector that contains unwanted genetic information of no therapeutic value. Methodology/Principal Findings Here we describe an improved strategy that allows for the creation of marker-free recombinant Poxviruses of any species. The Selectable and Excisable Marker (SEM) system incorporates a unique fusion marker gene for the efficient selection of poxvirus recombinants and the Cre/loxP system to facilitate the subsequent removal of the marker. We have defined and characterized this new methodological tool by insertion of a foreign gene into vaccinia virus, with the subsequent removal of the selectable marker. We then analyzed the importance of loxP orientation during Cre recombination, and show that the SEM system can be used to introduce site-specific deletions or inversions into the viral genome. Finally, we demonstrate that the SEM strategy is amenable to other Poxviruses, as demonstrated here with the creation of an ectromelia virus recombinant lacking the EVM002 gene. Conclusion/Significance The system described here thus provides a faster, simpler and more efficient means to create clinic-ready recombinant Poxviruses for therapeutic gene therapy applications.