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Antonio Alcami - One of the best experts on this subject based on the ideXlab platform.
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Comparative Pathogenesis, Genomics and Phylogeography of Mousepox
'MDPI AG', 2021Co-Authors: Carla Mavian, Alberto López-bueno, Rocío Martín, Andreas Nitsche, Antonio AlcamiAbstract:Ectromelia virus (ECTV), the causative agent of Mousepox, has threatened laboratory mouse colonies worldwide for almost a century. Mousepox has been valuable for the understanding of poxvirus pathogenesis and immune evasion. Here, we have monitored in parallel the pathogenesis of nine ECTVs in BALB/cJ mice and report the full-length genome sequence of eight novel ECTV isolates or strains, including the first ECTV isolated from a field mouse, ECTV-MouKre. This approach allowed us to identify several genes, absent in strains attenuated through serial passages in culture, that may play a role in virulence and a set of putative genes that may be involved in enhancing viral growth in vitro. We identified a putative strong inhibitor of the host inflammatory response in ECTV-MouKre, an isolate that did not cause local foot swelling and developed a moderate virulence. Most of the ECTVs, except ECTV-Hampstead, encode a truncated version of the P4c protein that impairs the recruitment of virions into the A-type inclusion bodies, and our data suggest that P4c may play a role in viral dissemination and transmission. This is the first comprehensive report that sheds light into the phylogenetic and geographic relationship of the worldwide outbreak dynamics for the ECTV species
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mechanism of action of the viral chemokine binding protein e163 from ectromelia virus
Journal of Biological Chemistry, 2018Co-Authors: Haleh Heidarieh, Antonio AlcamiAbstract:Chemokines interact with glycosaminoglycans (GAGs) at the cellular surface and to specific cell-surface receptors to activate signaling pathways. The GAG interaction allows the formation of a chemotactic gradient of chemokine required for cell haptotaxis and chemokine oligomerization. Poxviruses encode secreted chemokine-binding proteins with no sequence similarity to their cellular counterparts to modulate the host immune system. The E163 protein from ectromelia virus, the causative agent of Mousepox, binds chemokines through their GAG-binding domain. In addition, E163 interacts with GAGs to be anchored at the cell surface, but its ability to interfere with chemokine-GAG interactions has not been demonstrated. We report the identification of the GAG-binding regions in E163 and the generation of mutant forms deficient of GAG binding. Chemokine binding assays show that some of the E163 GAG-binding sites are also involved in the interaction with chemokines. By using recombinant GAG-binding mutant forms we demonstrate that E163 prevents the interaction of chemokines with cell-surface GAGs, providing mechanisms for the immunomodulatory activity of the viral chemokine-binding protein E163.
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A Method for the Generation of Ectromelia Virus (ECTV) Recombinants: In Vivo Analysis of ECTV vCD30 Deletion
2015Co-Authors: Ali Alejo, Abel Viejo-borbolla, Francisco Javier Salguero¤c, Antonio AlcamiAbstract:Background: Ectromelia virus (ECTV) is the causative agent of Mousepox, a lethal disease of mice with similarities to human smallpox. Mousepox progression involves replication at the initial site of infection, usually the skin, followed by a rapid spread to the secondary replicative organs, spleen and liver, and finally a dissemination to the skin, where the typical rash associated with this and other orthopoxviral induced diseases appears. Case fatality rate is genetically determined and reaches up to 100 % in susceptible mice strains. Like other poxviruses, ECTV encodes a number of proteins with immunomodulatory potential, whose role in Mousepox progression remains largely undescribed. Amongst these is a secreted homologue of the cellular tumour necrosis factor receptor superfamily member CD30 which has been proposed to modulate a Th1 immune response in vivo. Methodology/Principal Findings: To evaluate the contribution of viral CD30 (vCD30) to virus pathogenesis in the infected host, we have adapted a novel transient dominant method for the selection of recombinant ECTVs. Using this method, we have generated an ECTV vCD30 deletion mutant, its corresponding revertant control virus as well as a virus encoding the extracellular domain of murine CD30. These viruses contain no exogenous marker DNA sequences in their genomes, as opposed to other ECTVs reported up to date. Conclusions/Significance: We show that the vCD30 is expressed as a secreted disulfide linked trimer and that the absenc
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the genome sequence of ectromelia virus naval and cornell isolates from outbreaks in north america
Virology, 2014Co-Authors: Carla Mavian, Antonio Alcami, Alberto Lopezbueno, Neil A Bryant, Kathy Seeger, Michael A Quail, David Harris, B G BarrellAbstract:Ectromelia virus (ECTV) is the causative agent of Mousepox, a disease of laboratory mouse colonies and an excellent model for human smallpox. We report the genome sequence of two isolates from outbreaks in laboratory mouse colonies in the USA in 1995 and 1999: ECTV-Naval and ECTV-Cornell, respectively. The genome of ECTV-Naval and ECTV-Cornell was sequenced by the 454-Roche technology. The ECTV-Naval genome was also sequenced by the Sanger and Illumina technologies in order to evaluate these technologies for poxvirus genome sequencing. Genomic comparisons revealed that ECTV-Naval and ECTV-Cornell correspond to the same virus isolated from independent outbreaks. Both ECTV-Naval and ECTV-Cornell are extremely virulent in susceptible BALB/c mice, similar to ECTV-Moscow. This is consistent with the ECTV-Naval genome sharing 98.2% DNA sequence identity with that of ECTV-Moscow, and indicates that the genetic differences with ECTV-Moscow do not affect the virulence of ECTV-Naval in the Mousepox model of footpad infection.
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2002. Inhibition of type 1 cytokine-mediated inflammation by a soluble CD30 homologue encoded by ectromelia (Mousepox) virus
2013Co-Authors: Margarida Saraiva, Philip Smith, Padraic G. Fallon, Antonio AlcamiAbstract:CD30 is up-regulated in several human diseases and viral infections but its role in immune regulation is poorly understood. Here, we report the expression of a functional soluble CD30 homologue, viral CD30 (vCD30), encoded by ectromelia (Mousepox) virus, a poxvirus that causes a severe disease related to human smallpox. We show that vCD30 is a 12-kD secreted protein that not only binds CD30L with high affinity and prevents its interaction with CD30, but it also induces reverse signaling in cells expressing CD30L. vCD30 blocked the generation of interferon �–producing cells in vitro and was a potent inhibitor of T helper cell (Th)1- but not Th2-mediated inflammation in vivo. The finding of a CD30 homologue encoded by ectromelia virus suggests a role for CD30 in antiviral defense. Characterization of the immunological properties of vCD30 has uncovered a role of CD30–CD30L interactions in the generation of inflammatory responses. Key words: poxviruses • immunomodulation • cytokine • TNFR superfamily • Th-
Luis J Sigal - One of the best experts on this subject based on the ideXlab platform.
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chronic lymphocytic choriomeningitis infection causes susceptibility to Mousepox and impairs natural killer cell maturation and function
Journal of Virology, 2020Co-Authors: Carolina R Melosilva, Pedro Alvespeixoto, Maria Ferez, Cory J Knudson, Colby Stotesbury, Eric B Wong, Margarida Correianeves, Luis J SigalAbstract:Chronic viral infections. like those of humans with cytomegalovirus, human immunodeficiency virus (even when under antiretroviral therapy), and hepatitis C virus or those of mice with lymphocytic choriomeningitis virus (LCMV) clone 13 (CL13), result in immune dysfunction that predisposes the host to severe infections with unrelated pathogens. It is known that C57BL/6 (B6) mice are resistant to Mousepox, a lethal disease caused by the orthopoxvirus ectromelia virus (ECTV), and that this resistance requires natural killer (NK) cells and other immune cells. We show that most B6 mice chronically infected with CL13 succumb to Mousepox but that most of those that recovered from acute infection with the LCMV Armstrong (Arm) strain survive. We also show that B6 mice chronically infected with CL13 and those that recovered from Arm infection have a reduced frequency and a reduced number of NK cells. However, at steady state, NK cells in mice that have recovered from Arm infection mature normally and, in response to ECTV, get activated, become more mature, proliferate, and increase their cytotoxicity in vivo Conversely, in mice chronically infected with CL13, NK cells are immature and residually activated, and following ECTV infection, they do not mature, proliferate, or increase their cytotoxicity. Given the well-established importance of NK cells in resistance to Mousepox, these data suggest that the NK cell dysfunction caused by CL13 persistence may contribute to the susceptibility of CL13-infected mice to Mousepox. Whether chronic infections similarly affect NK cells in humans should be explored.IMPORTANCE Infection of adult mice with the clone 13 (CL13) strain of lymphocytic choriomeningitis virus (LCMV) is extensively used as a model of chronic infection. In this paper, we show that mice chronically infected with CL13 succumb to challenge with ectromelia virus (ECTV; the agent of Mousepox) and that natural killer (NK) cells in CL13-infected mice are reduced in numbers and have an immature and partially activated phenotype but do respond to ECTV. These data may provide additional clues why humans chronically infected with certain pathogens are less resistant to viral diseases.
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resistance to ectromelia virus infection requires cgas in bone marrow derived cells which can be bypassed with cgamp therapy
PLOS Pathogens, 2019Co-Authors: Eric B Wong, Colby Stotesbury, Maria Ferez, Brian Montoya, Luis J SigalAbstract:Cells sensing infection produce Type I interferons (IFN-I) to stimulate Interferon Stimulated Genes (ISGs) that confer resistance to viruses. During lympho-hematogenous spread of the mouse pathogen ectromelia virus (ECTV), the adaptor STING and the transcription factor IRF7 are required for IFN-I and ISG induction and resistance to ECTV. However, it is unknown which cells sense ECTV and which pathogen recognition receptor (PRR) upstream of STING is required for IFN-I and ISG induction. We found that cyclic-GMP-AMP (cGAMP) synthase (cGAS), a DNA-sensing PRR, is required in bone marrow-derived (BMD) but not in other cells for IFN-I and ISG induction and for resistance to lethal Mousepox. Also, local administration of cGAMP, the product of cGAS that activates STING, rescues cGAS but not IRF7 or IFN-I receptor deficient mice from Mousepox. Thus, sensing of infection by BMD cells via cGAS and IRF7 is critical for resistance to a lethal viral disease in a natural host.
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the pathogenesis and immunobiology of Mousepox
Advances in Immunology, 2016Co-Authors: Luis J SigalAbstract:Ectromelia virus is a mouse-specific orthopoxvirus that, following footpad infection or natural transmission, causes Mousepox in most strains of mice, while a few strains, such as C57BL/6, are resistant to the disease but not to the infection. Mousepox is an acute, systemic, highly lethal disease of remarkable semblance to smallpox, caused by the human-specific variola virus. Starting in 1929 with its discovery by Marchal, work with ECTV has provided essential information for our current understanding on how viruses spread lympho-hematogenously, the genetic control of antiviral resistance, the role of different components of the innate and adaptive immune system in the control of primary and secondary infections with acute viruses, and how the mechanisms of immune evasion deployed by the virus affect virulence in vivo. Here, I review the literature on the pathogenesis and immunobiology of ECTV infection in vivo.
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Antibody Inhibition of a Viral Type 1 Interferon Decoy Receptor Cures a Viral Disease by Restoring Interferon Signaling in the Liver
2012Co-Authors: Daniel Rubio, Felicia Roscoe, Tracy E. Krouse, Mary Ellen Truckenmiller, Christopher C. Norbury, Paul N. Hudson, Inger K. Damon, Luis J SigalAbstract:Type 1 interferons (T1-IFNs) play a major role in antiviral defense, but when or how they protect during infections that spread through the lympho-hematogenous route is not known. Orthopoxviruses, including those that produce smallpox and Mousepox, spread lympho-hematogenously. They also encode a decoy receptor for T1-IFN, the T1-IFN binding protein (T1-IFNbp), which is essential for virulence. We demonstrate that during Mousepox, T1-IFNs protect the liver locally rather than systemically, and that the T1-IFNbp attaches to uninfected cells surrounding infected foci in the liver and the spleen to impair their ability to receive T1-IFN signaling, thus facilitating virus spread. Remarkably, this process can be reversed and Mousepox cured late in infection by treating with antibodies that block the biological function of the T1-IFNbp. Thus, our findings provide insights on how T1-IFNs function and are evaded during a viral infection in vivo, and unveil a nove
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Antibody inhibition of a viral type 1 interferon decoy receptor cures a viral disease by restoring interferon signaling in the liver.
Public Library of Science (PLoS), 2012Co-Authors: Daniel Rubio, Antonio Alcami, Felicia Roscoe, Tracy E. Krouse, Mary Ellen Truckenmiller, Christopher C. Norbury, Paul N. Hudson, Inger K. Damon, Luis J SigalAbstract:Type 1 interferons (T1-IFNs) play a major role in antiviral defense, but when or how they protect during infections that spread through the lympho-hematogenous route is not known. Orthopoxviruses, including those that produce smallpox and Mousepox, spread lympho-hematogenously. They also encode a decoy receptor for T1-IFN, the T1-IFN binding protein (T1-IFNbp), which is essential for virulence. We demonstrate that during Mousepox, T1-IFNs protect the liver locally rather than systemically, and that the T1-IFNbp attaches to uninfected cells surrounding infected foci in the liver and the spleen to impair their ability to receive T1-IFN signaling, thus facilitating virus spread. Remarkably, this process can be reversed and Mousepox cured late in infection by treating with antibodies that block the biological function of the T1-IFNbp. Thus, our findings provide insights on how T1-IFNs function and are evaded during a viral infection in vivo, and unveil a novel mechanism for antibody-mediated antiviral therapy
Mark R L Buller - One of the best experts on this subject based on the ideXlab platform.
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deficiency in th2 cytokine responses exacerbate orthopoxvirus infection
PLOS ONE, 2015Co-Authors: Isaac G. Sakala, Mark R L Buller, Geeta Chaudhri, Preethi Eldi, Gunasegaran KarupiahAbstract:Ectromelia virus (ECTV) causes Mousepox in mice, a disease very similar to smallpox in humans. ECTV and variola virus (VARV), the agent of smallpox, are closely related orthopoxviruses. Mousepox is an excellent small animal model to study the genetic and immunologic basis for resistance and susceptibility of humans to smallpox. Resistance to Mousepox is dependent on a strong polarized type 1 immune response, associated with robust natural killer (NK) cell, cytotoxic T lymphocyte (CTL) and gamma interferon (IFN-γ) responses. In contrast, ECTV-susceptible mice generate a type 2 response, associated with weak NK cell, CTL and IFN-γ responses but robust IL-4 responses. Nonetheless, susceptible strains infected with mutant ECTV lacking virus-encoded IFN-γ binding protein (vIFN-γbp) (ECTV-IFN-γbpΔ) control virus replication through generation of type 1 response. Since the IL-4/IL-13/STAT-6 signaling pathways polarize type 2/T helper 2 (Th2) responses with a corresponding suppression of IFN-γ production, we investigated whether the combined absence of vIFN-γbp, and one or more host genes involved in Th2 response development, influence generation of protective immunity. Most mutant mouse strains infected with wild-type (WT) virus succumbed to disease more rapidly than WT animals. Conversely, the disease outcome was significantly improved in WT mice infected with ECTV-IFN-γbpΔ but absence of IL-4/IL-13/STAT-6 signaling pathways did not provide any added advantage. Deficiency in IL-13 or STAT-6 resulted in defective CTL responses, higher mortality rates and accelerated deaths. Deficiencies in IL-4/IL-13/STAT-6 signaling pathways significantly reduced the numbers of IFN-γ producing CD4 and CD8 T cells, indicating an absence of a switch to a Th1-like response. Factors contributing to susceptibility or resistance to Mousepox are far more complex than a balance between Th1 and Th2 responses.
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Mousepox a small animal model of smallpox
Methods of Molecular Biology, 2012Co-Authors: David J. Esteban, Scott Parker, Jill Schriewer, Hollyce Hartzler, Mark R L BullerAbstract:Ectromelia virus infections in the laboratory mouse have emerged as a valuable model to investigate human orthopoxvirus infections to understand the progression of disease, to discover and characterize antiviral treatments, and to study the host-pathogen relationship as it relates to pathogenesis and the immune response. Here we describe how to safely work with the virus and protocols for common procedures for the study of ectromelia virus in the laboratory mouse including the preparation of virus stocks, the use of various routes of inoculation, and collection of blood and tissue from infected animals. In addition, several procedures are described for assessing the host response to infection: for example, measurement of virus-specific CD8 T cells and the use of ELISA and neutralization assays to measure orthopoxvirus-specific antibody titers.
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surviving Mousepox infection requires the complement system
PLOS Pathogens, 2008Co-Authors: Elizabeth A Moulton, John P Atkinson, Mark R L BullerAbstract:Poxviruses subvert the host immune response by producing immunomodulatory proteins, including a complement regulatory protein. Ectromelia virus provides a mouse model for smallpox where the virus and the host's immune response have co-evolved. Using this model, our study investigated the role of the complement system during a poxvirus infection. By multiple inoculation routes, ectromelia virus caused increased mortality by 7 to 10 days post-infection in C57BL/6 mice that lack C3, the central component of the complement cascade. In C3−/− mice, ectromelia virus disseminated earlier to target organs and generated higher peak titers compared to the congenic controls. Also, increased hepatic inflammation and necrosis correlated with these higher tissue titers and likely contributed to the morbidity in the C3−/− mice. In vitro, the complement system in naive C57BL/6 mouse sera neutralized ectromelia virus, primarily through the recognition of the virion by natural antibody and activation of the classical and alternative pathways. Sera deficient in classical or alternative pathway components or antibody had reduced ability to neutralize viral particles, which likely contributed to increased viral dissemination and disease severity in vivo. The increased mortality of C4−/− or Factor B−/− mice also indicates that these two pathways of complement activation are required for survival. In summary, the complement system acts in the first few minutes, hours, and days to control this poxviral infection until the adaptive immune response can react, and loss of this system results in lethal infection.
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using biomarkers to stage disease progression in a lethal Mousepox model treated with cmx001
Antiviral Therapy, 2008Co-Authors: Scott Parker, George R. Painter, Jill Schriewer, Christina Oberle, Alice Robertson, Randall Lanier, Mark R L BullerAbstract:Background The emergence of human monkeypox and the potential use of recombinant variola and monkeypox viruses as biological terrorist agents have necessitated the development of therapeutic and prophylactic therapies. The primary, or index, cases of smallpox and/or human monkeypox will likely be identified by a characteristic rash. Effective biomarkers will be required to monitor disease progression, guide the choice of therapeutic intervention strategies and evaluate their efficacies. To address this we have evaluated several biomarkers of disease in a lethal Mousepox model.
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biosynthesis of the ifn γ binding protein of ectromelia virus the causative agent of Mousepox
Virology, 2005Co-Authors: Hongdong Bai, Nanhai Chen, Mark R L Buller, Michael Green, Anthony A NuaraAbstract:Abstract Ectromelia virus (ECTV), the causative agent of Mousepox, expresses an extracellular interferon-γ binding protein (IFN-γBP) with homology to the ligand binding domains of the IFN-γ high affinity receptor (IFN-γR1). Unlike the cellular receptor, the IFN-γBP binds IFN-γ from several species. The IFN-γBP is synthesized early after infection, accumulating in the extracellular milieu as dimers composed of two protein species with M r of 34.6 or 33.0 kDa. Homodimers are covalently linked by an interchain disulphide bond at position 216. The IFN-γBP has complex N-linked oligosaccharides at positions 41 and 149 as determined by site-directed mutagenesis and glycosidase treatment. Glycosylation at position 41 is required for secretion from mammalian cells and may play a role in the activity of the IFN-γBP. Glycosylation at position 149 is not required for secretion, and the lack of glycosylation at this site does not diminish ligand binding as measured by surface plasmon resonance (SPR) and ELISA.
Hermann Meyer - One of the best experts on this subject based on the ideXlab platform.
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Real-Time PCR System for Detection of Orthopoxviruses and Simultaneous Identification of Smallpox Virus
Journal of clinical microbiology, 2004Co-Authors: Victoria A. Olson, Thomas Laue, Miriam Laker, I. V. Babkin, Christian Drosten, Sergei N. Shchelkunov, Matthias Niedrig, Hermann MeyerAbstract:A screening assay for real-time LightCycler (Roche Applied Science, Mannheim, Germany) PCR identification of smallpox virus DNA was developed and compiled in a kit system under good manufacturing practice conditions with standardized reagents. In search of a sequence region unique to smallpox virus, the nucleotide sequence of the 14-kDa fusion protein gene of each of 14 variola virus isolates of the Russian World Health Organization smallpox virus repository was determined and compared to published sequences. PCR primers were designed to detect all Eurasian-African species of the genus Orthopoxvirus. A single nucleotide mismatch resulting in a unique amino acid substitution in smallpox virus was used to design a hybridization probe pair with a specific sensor probe that allows reliable differentiation of smallpox virus from other orthopoxviruses by melting-curve analysis. The applicability was demonstrated by successful amplification of 120 strains belonging to the orthopoxvirus species variola, vaccinia, camelpox, Mousepox, cowpox, and monkeypox virus. The melting temperatures (Tms) determined for 46 strains of variola virus (Tms, 55.9 to 57.8°C) differed significantly (P = 0.005) from those obtained for 11 strains of vaccinia virus (Tms, 61.7 to 62.7°C), 15 strains of monkeypox virus (Tms, 61.9 to 62.2°C), 40 strains of cowpox virus (Tms, 61.3 to 63.7°C), 8 strains of Mousepox virus (Tm, 61.9°C), and 8 strains of camelpox virus (Tms, 64.0 to 65.0°C). As most of the smallpox virus samples were derived from infected cell cultures and tissues, smallpox virus DNA could be detected in a background of human DNA. By applying probit regression analysis, the analytical sensitivity was determined to be 4 copies of smallpox virus target DNA per sample. The DNAs of several human herpesviruses as well as poxviruses other than orthopoxviruses were not detected by this method. The assay proved to be a reliable technique for the detection of orthopoxviruses, with the advantage that it can simultaneously identify variola virus.
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specific detection of Mousepox virus by polymerase chain reaction
Laboratory Animals, 1997Co-Authors: Heinrich Neubauer, Martin Pfeffer, Hermann MeyerAbstract:Polymerase chain reaction was applied to the rapid identification and detection of Mousepox virus. This was accomplished by selection of primers targeting the A-type inclusion body protein gene. By investigating 20 strains belonging to five different species of the genus Orthopoxvirus, amplification was achieved only with the seven Mousepox virus strains examined. The size of the resulting DNA fragment accounted for 116 base pairs and contained a recognition site for the restriction enzyme HindII, thus confirming its viral origin. Amplification of Mousepox virus specific sequences was also possible from infected mouse lung tissue and serum.
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Sequence alterations within and downstream of the A-type inclusion protein genes allow differentiation of Orthopoxvirus species by polymerase chain reaction.
Journal of General Virology, 1994Co-Authors: Hermann Meyer, Martin Pfeffer, Hanns-joachim RzihaAbstract:A PCR protocol was established that not only allows the detection of, but also the differentiation of species of the genus Orthopoxvirus. This assay was accomplished by the selection of oligonucleotides located within the gene that encodes the A-type inclusion protein of cowpox virus. The primer pair flanked a region exhibiting distinct and specific DNA deletions in the corresponding sequences of vaccinia, Mousepox, monkeypox and camelpox virus. For this reason, PCR resulted in DNA fragments of different sizes. The presented PCR protocol, combined with BglII restriction digests, allowed the unequivocal assignment of 42 orthopoxvirus (OPV) strains and isolates to the correct OPV species. The resulting classification corresponded exactly with known biological data for the OPV strains investigated. Furthermore, 13 out of 22 cowpox virus isolates could be subtyped by the presence or absence of a small BglII fragment. DNA sequencing showed that the lack of this BglII fragment was caused by a deletion of 72 nucleotides.
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characterization of the gene encoding the a type inclusion body protein of Mousepox virus
Virus Genes, 1994Co-Authors: Nikolaus Osterrieder, Hermann Meyer, Martin PfefferAbstract:The gene of the Mousepox virus strain MP-1 coding for the protein of A-type inclusions was identified and sequenced. The gene maps in theHindIII-A fragment at the same position as the cowpoxvirus Brighton 160 kD gene (1) and the closely related 94 kD LS gene of vaccinia virus strain Western Reserve (2,3). The encoded protein consists of 1049 amino acids with a predicted molecular weight of 122.5 kD, which corresponds well to the apparent molecular weight of 130 kD estimated after polyacrylamide gel electrophoresis and Western blotting. The protein is a characteristic feature of Mousepox virus and could be demonstrated for five independently isolated strains. The MP-1 ATI protein displays a similarity of 82.3% to the cowpox virus Brighton 160 kD protein, the first 340 amino acids being almost identical. However, two major deletions of 55 and 92 amino acids were observed from amino acid positions 671 to 732 and 794 to 885, respectively. Furthermore, the C-terminal residues (position 998–1049 of the MP-1 sequence) did not match at satisfactory levels with cowpox nor with vaccinia virus sequences. According to Western blot and protein alignment data as well as hydropathy predictions, the 130 and 160 kD proteins closely resemble each other, indicating similar structure and function.
R. Mark L. Buller - One of the best experts on this subject based on the ideXlab platform.
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Ectromelia virus infections of mice as a model to support the licensure of anti-orthopoxvirus therapeutics.
Viruses, 2010Co-Authors: Scott Parker, Akbar M. Siddiqui, George R. Painter, Jill Schriewer, R. Mark L. BullerAbstract:The absence of herd immunity to orthopoxviruses and the concern that variola or monkeypox viruses could be used for bioterroristic activities has stimulated the development of therapeutics and safer prophylactics. One major limitation in this process is the lack of accessible human orthopoxvirus infections for clinical efficacy trials; however, drug licensure can be based on orthopoxvirus animal challenge models as described in the “Animal Efficacy Rule”. One such challenge model uses ectromelia virus, an orthopoxvirus, whose natural host is the mouse and is the etiological agent of Mousepox. The genetic similarity of ectromelia virus to variola and monkeypox viruses, the common features of the resulting disease, and the convenience of the mouse as a laboratory animal underscores its utility in the study of orthopoxvirus pathogenesis and in the development of therapeutics and prophylactics. In this review we outline how Mousepox has been used as a model for smallpox. We also discuss Mousepox in the context of mouse strain, route of infection, infectious dose, disease progression, and recovery from infection.
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Ectromelia virus: the causative agent of Mousepox.
Journal of General Virology, 2005Co-Authors: David J. Esteban, R. Mark L. BullerAbstract:Ectromelia virus (ECTV) is an orthopoxvirus whose natural host is the mouse; it is related closely to Variola virus, the causative agent of smallpox, and Monkeypox virus, the cause of an emerging zoonosis. The recent sequencing of its genome, along with an effective animal model, makes ECTV an attractive model for the study of poxvirus pathogenesis, antiviral and vaccine testing and viral immune and inflammatory responses. This review discusses the pathogenesis of Mousepox, modulation of the immune response by the virus and the cytokine and cellular components of the skin and systemic immune system that are critical to recovery from infection.
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The genomic sequence of ectromelia virus, the causative agent of Mousepox.
Virology, 2003Co-Authors: Nanhai Chen, R. Mark L. Buller, Maria I. Danila, Zehua Feng, Chunlin Wang, Xiaosi Han, Elliot J. Lefkowitz, Chris UptonAbstract:Ectromelia virus is the causative agent of Mousepox, an acute exanthematous disease of mouse colonies in Europe, Japan, China, and the U.S. The Moscow, Hampstead, and NIH79 strains are the most thoroughly studied with the Moscow strain being the most infectious and virulent for the mouse. In the late 1940s Mousepox was proposed as a model for the study of the pathogenesis of smallpox and generalized vaccinia in humans. Studies in the last five decades from a succession of investigators have resulted in a detailed description of the virologic and pathologic disease course in genetically susceptible and resistant inbred and out-bred mice. We report the DNA sequence of the left-hand end, the predicted right-hand terminal repeat, and central regions of the genome of the Moscow strain of ectromelia virus (approximately 177,500 bp), which together with the previously sequenced right-hand end, yields a genome of 209,771 bp. We identified 175 potential genes specifying proteins of between 53 and 1924 amino acids, and 29 regions containing sequences related to genes predicted in other poxviruses, but unlikely to encode for functional proteins in ectromelia virus. The translated protein sequences were compared with the protein database for structure/function relationships, and these analyses were used to investigate poxvirus evolution and to attempt to explain at the cellular and molecular level the well-characterized features of the ectromelia virus natural life cycle.
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Analysis of host response modifier ORFs of ectromelia virus, the causative agent of Mousepox.
Virus research, 2000Co-Authors: Nanhai Chen, R. Mark L. Buller, Erika M. Wall, Chris UptonAbstract:From the right-hand end of the ectromelia virus (strain Moscow) genome, 32318 bps have been sequenced, and characterized to include a total of 18 open reading frames (ORFs) and six regions which apparently no longer code for functional proteins. At least six of the ORFs appear to be involved in blocking the inflammatory/immune host response to infection, and therefore probably contribute significantly to the virulence of this virus in its natural host, the mouse. One of these genes encoded an isolog of the poxvirus chemokine binding protein, and was shown to be the most abundant protein secreted from ectromelia virus infected cells. Two regions were found to have significant similarity to poxvirus genes encoding tumor necrosis factor (TNF) binding proteins. Both are distinct from cytokine response modifier (crm)B and crmC but only one is predicted to encode a functional TNF binding protein. A novel similarity between the C-terminal domain of poxvirus TNF binding proteins and several other poxvirus proteins is also presented. The results are discussed in the context of ectromelia virus pathogenesis of mice.