The Experts below are selected from a list of 69 Experts worldwide ranked by ideXlab platform

Slobodan Paessler - One of the best experts on this subject based on the ideXlab platform.

  • the ectodomain of glycoprotein from the candid 1 vaccine strain of junin virus rendered machupo virus partially attenuated in mice lacking ifn αβ γ receptor
    PLOS Neglected Tropical Diseases, 2016
    Co-Authors: Takaaki Koma, Cheng Huang, Judith F. Aronson, Aida G Walker, Milagros Miller, Jeanon N Smith, Michael Patterson, Slobodan Paessler
    Abstract:

    Machupo virus (MACV), a New World arenavirus, is the etiological agent of Bolivian Hemorrhagic Fever (BHF). Junin virus (JUNV), a close relative, causes Argentine Hemorrhagic Fever (AHF). Previously, we reported that a recombinant, chimeric MACV (rMACV/Cd#1-GPC) expressing glycoprotein from the Candid#1 (Cd#1) vaccine strain of JUNV is completely attenuated in a murine model and protects animals from lethal challenge with MACV. A rMACV with a single F438I substitution in the transmembrane domain (TMD) of GPC, which is equivalent to the F427I attenuating mutation in Cd#1 GPC, was attenuated in a murine model but genetically unstable. In addition, the TMD mutation alone was not sufficient to fully attenuate JUNV, indicating that other domains of the GPC may also contribute to the attenuation. To investigate the requirement of different domains of Cd#1 GPC for successful attenuation of MACV, we rescued several rMACVs expressing the ectodomain of GPC from Cd#1 either alone (MCg1), along with the TMD F438I substitution (MCg2), or with the TMD of Cd#1 (MCg3). All rMACVs exhibited similar growth curves in cultured cells. In mice, the MCg1 displayed significant reduction in lethality as compared with rMACV. The MCg1 was detected in brains and spleens of MCg1-infected mice and the infection was associated with tissue inflammation. On the other hand, all animals survived MCg2 and MCg3 infection without detectable levels of virus in various organs while producing neutralizing antibody against Cd#1. Overall our data suggest the indispensable role of each GPC domain in the full attenuation and immunogenicity of rMACV/Cd#1 GPC.

  • machupo virus expressing gpc of the candid 1 vaccine strain of junin virus is highly attenuated and immunogenic
    Journal of Virology, 2016
    Co-Authors: Takaaki Koma, Cheng Huang, Aida G Walker, Milagros Miller, Jeanon N Smith, Michael Patterson, Alexey Seregin, Payal D Maharaj, Steven Hallam, Slobodan Paessler
    Abstract:

    ABSTRACT Machupo virus (MACV) is the causative agent of Bolivian Hemorrhagic Fever. Our previous study demonstrated that a MACV strain with a single amino acid substitution (F438I) in the transmembrane domain of glycoprotein is attenuated but genetically unstable in mice. MACV is closely related to Junin virus (JUNV), the causative agent of Argentine Hemorrhagic Fever. Others and our group have identified the glycoprotein to be the major viral factor determining JUNV attenuation. In this study, we tested the compatibility of the glycoprotein of the Candid#1 live-attenuated vaccine strain of JUNV in MACV replication and its ability to attenuate MACV in vivo . Recombinant MACV with the Candid#1 glycoprotein (rMACV/Cd#1-GPC) exhibited growth properties similar to those of Candid#1 and was genetically stable in vitro . In a mouse model of lethal infection, rMACV/Cd#1-GPC was fully attenuated, more immunogenic than Candid#1, and fully protective against MACV infection. Therefore, the MACV strain expressing the glycoprotein of Candid#1 is safe, genetically stable, and highly protective against MACV infection in a mouse model. IMPORTANCE Currently, there are no FDA-approved vaccines and/or treatments for Bolivian Hemorrhagic Fever, which is a fatal human disease caused by MACV. The development of antiviral strategies to combat viral Hemorrhagic Fevers, including Bolivian Hemorrhagic Fever, is one of the top priorities of the Implementation Plan of the U.S. Department of Health and Human Services Public Health Emergency Medical Countermeasures Enterprise. Here, we demonstrate for the first time that MACV expressing glycoprotein of Candid#1 is a safe, genetically stable, highly immunogenic, and protective vaccine candidate against Bolivian Hemorrhagic Fever.

  • The Ectodomain of Glycoprotein from the Candid#1 Vaccine Strain of Junin Virus Rendered Machupo Virus Partially Attenuated in Mice Lacking IFN-αβ/γ Receptor.
    Public Library of Science (PLoS), 2016
    Co-Authors: Takaaki Koma, Cheng Huang, Judith F. Aronson, Aida G Walker, Milagros Miller, Jeanon N Smith, Michael Patterson, Slobodan Paessler
    Abstract:

    Machupo virus (MACV), a New World arenavirus, is the etiological agent of Bolivian Hemorrhagic Fever (BHF). Junin virus (JUNV), a close relative, causes Argentine Hemorrhagic Fever (AHF). Previously, we reported that a recombinant, chimeric MACV (rMACV/Cd#1-GPC) expressing glycoprotein from the Candid#1 (Cd#1) vaccine strain of JUNV is completely attenuated in a murine model and protects animals from lethal challenge with MACV. A rMACV with a single F438I substitution in the transmembrane domain (TMD) of GPC, which is equivalent to the F427I attenuating mutation in Cd#1 GPC, was attenuated in a murine model but genetically unstable. In addition, the TMD mutation alone was not sufficient to fully attenuate JUNV, indicating that other domains of the GPC may also contribute to the attenuation. To investigate the requirement of different domains of Cd#1 GPC for successful attenuation of MACV, we rescued several rMACVs expressing the ectodomain of GPC from Cd#1 either alone (MCg1), along with the TMD F438I substitution (MCg2), or with the TMD of Cd#1 (MCg3). All rMACVs exhibited similar growth curves in cultured cells. In mice, the MCg1 displayed significant reduction in lethality as compared with rMACV. The MCg1 was detected in brains and spleens of MCg1-infected mice and the infection was associated with tissue inflammation. On the other hand, all animals survived MCg2 and MCg3 infection without detectable levels of virus in various organs while producing neutralizing antibody against Cd#1. Overall our data suggest the indispensable role of each GPC domain in the full attenuation and immunogenicity of rMACV/Cd#1 GPC

  • epidemiology and pathogenesis of Bolivian Hemorrhagic Fever
    Current Opinion in Virology, 2014
    Co-Authors: Michael Patterson, Ashley M Grant, Slobodan Paessler
    Abstract:

    The etiologic agent of Bolivian Hemorrhagic Fever (BHF), Machupo virus (MACV) is reported to have a mortality rate of 25–35%. First identified in 1959, BHF was the cause of a localized outbreak in San Joaquin until rodent population controls were implemented in 1964. The rodent Calomys collosus was identified as the primary vector and reservoir for the virus. Multiple animal models were considered during the 1970s with the most human-like disease identified in Rhesus macaques but minimal characterization of the pathogenesis has been published since. A reemergence of reported BHF cases has been reported in recent years, which necessitates the further study and development of a vaccine to prevent future outbreaks.

Michael Patterson - One of the best experts on this subject based on the ideXlab platform.

  • Rescue of a Recombinant Machupo Virus from Cloned cDNAs and In Vivo Characterization in Interferon (/) Receptor Double Knockout Mice
    2016
    Co-Authors: Michael Patterson, Cheng Huang, Milagros Miller, Alexey Seregin, Olga A. Kolokoltsova, Allison Poussard, Jennifer Smith, Jeanon Smith, Nadezhda Yun, Ashley Grant
    Abstract:

    Machupo virus (MACV) is the etiological agent of Bolivian Hemorrhagic Fever (BHF), a reemerging and neglected tropical dis-ease associated with highmortality. The prototypical strain of MACV, Carvallo, was isolated from a human patient in 1963, but minimal in vitro and in vivo characterization has been reported. To this end, we utilized reverse genetics to rescue a pathogenic MACV from cloned cDNAs. The recombinant MACV (rMACV) had in vitro growth properties similar to those of the parental MACV. Both viruses caused similar disease development in alpha/beta and gamma interferon receptor knockout mice, including neurological disease development and highmortality. In addition, we have identified a novel murine model with mortality and neurological disease similar to BHF disease reported in humans and nonhuman primates. Amember of the family Arenaviridae, Machupo virus (MACV)is an enveloped, bisegmented negative-stranded RNA virus. Arenaviruses utilize an ambisense coding strategy to direct viral gene transcription from two genomic segments, the large segment (L, ca. 7.2 kb) and the small segment (S, ca. 3.3 kb). Each segment carries two viral genes; S encodes the glycoprotein precursor (GPC) and the nucleoprotein (NP), while L encodes the RNA-dependent RNA polymerase (L polymerase) and the small RING finger protein Z. The GPC is posttranslationally cleaved by th

  • the ectodomain of glycoprotein from the candid 1 vaccine strain of junin virus rendered machupo virus partially attenuated in mice lacking ifn αβ γ receptor
    PLOS Neglected Tropical Diseases, 2016
    Co-Authors: Takaaki Koma, Cheng Huang, Judith F. Aronson, Aida G Walker, Milagros Miller, Jeanon N Smith, Michael Patterson, Slobodan Paessler
    Abstract:

    Machupo virus (MACV), a New World arenavirus, is the etiological agent of Bolivian Hemorrhagic Fever (BHF). Junin virus (JUNV), a close relative, causes Argentine Hemorrhagic Fever (AHF). Previously, we reported that a recombinant, chimeric MACV (rMACV/Cd#1-GPC) expressing glycoprotein from the Candid#1 (Cd#1) vaccine strain of JUNV is completely attenuated in a murine model and protects animals from lethal challenge with MACV. A rMACV with a single F438I substitution in the transmembrane domain (TMD) of GPC, which is equivalent to the F427I attenuating mutation in Cd#1 GPC, was attenuated in a murine model but genetically unstable. In addition, the TMD mutation alone was not sufficient to fully attenuate JUNV, indicating that other domains of the GPC may also contribute to the attenuation. To investigate the requirement of different domains of Cd#1 GPC for successful attenuation of MACV, we rescued several rMACVs expressing the ectodomain of GPC from Cd#1 either alone (MCg1), along with the TMD F438I substitution (MCg2), or with the TMD of Cd#1 (MCg3). All rMACVs exhibited similar growth curves in cultured cells. In mice, the MCg1 displayed significant reduction in lethality as compared with rMACV. The MCg1 was detected in brains and spleens of MCg1-infected mice and the infection was associated with tissue inflammation. On the other hand, all animals survived MCg2 and MCg3 infection without detectable levels of virus in various organs while producing neutralizing antibody against Cd#1. Overall our data suggest the indispensable role of each GPC domain in the full attenuation and immunogenicity of rMACV/Cd#1 GPC.

  • machupo virus expressing gpc of the candid 1 vaccine strain of junin virus is highly attenuated and immunogenic
    Journal of Virology, 2016
    Co-Authors: Takaaki Koma, Cheng Huang, Aida G Walker, Milagros Miller, Jeanon N Smith, Michael Patterson, Alexey Seregin, Payal D Maharaj, Steven Hallam, Slobodan Paessler
    Abstract:

    ABSTRACT Machupo virus (MACV) is the causative agent of Bolivian Hemorrhagic Fever. Our previous study demonstrated that a MACV strain with a single amino acid substitution (F438I) in the transmembrane domain of glycoprotein is attenuated but genetically unstable in mice. MACV is closely related to Junin virus (JUNV), the causative agent of Argentine Hemorrhagic Fever. Others and our group have identified the glycoprotein to be the major viral factor determining JUNV attenuation. In this study, we tested the compatibility of the glycoprotein of the Candid#1 live-attenuated vaccine strain of JUNV in MACV replication and its ability to attenuate MACV in vivo . Recombinant MACV with the Candid#1 glycoprotein (rMACV/Cd#1-GPC) exhibited growth properties similar to those of Candid#1 and was genetically stable in vitro . In a mouse model of lethal infection, rMACV/Cd#1-GPC was fully attenuated, more immunogenic than Candid#1, and fully protective against MACV infection. Therefore, the MACV strain expressing the glycoprotein of Candid#1 is safe, genetically stable, and highly protective against MACV infection in a mouse model. IMPORTANCE Currently, there are no FDA-approved vaccines and/or treatments for Bolivian Hemorrhagic Fever, which is a fatal human disease caused by MACV. The development of antiviral strategies to combat viral Hemorrhagic Fevers, including Bolivian Hemorrhagic Fever, is one of the top priorities of the Implementation Plan of the U.S. Department of Health and Human Services Public Health Emergency Medical Countermeasures Enterprise. Here, we demonstrate for the first time that MACV expressing glycoprotein of Candid#1 is a safe, genetically stable, highly immunogenic, and protective vaccine candidate against Bolivian Hemorrhagic Fever.

  • The Ectodomain of Glycoprotein from the Candid#1 Vaccine Strain of Junin Virus Rendered Machupo Virus Partially Attenuated in Mice Lacking IFN-αβ/γ Receptor.
    Public Library of Science (PLoS), 2016
    Co-Authors: Takaaki Koma, Cheng Huang, Judith F. Aronson, Aida G Walker, Milagros Miller, Jeanon N Smith, Michael Patterson, Slobodan Paessler
    Abstract:

    Machupo virus (MACV), a New World arenavirus, is the etiological agent of Bolivian Hemorrhagic Fever (BHF). Junin virus (JUNV), a close relative, causes Argentine Hemorrhagic Fever (AHF). Previously, we reported that a recombinant, chimeric MACV (rMACV/Cd#1-GPC) expressing glycoprotein from the Candid#1 (Cd#1) vaccine strain of JUNV is completely attenuated in a murine model and protects animals from lethal challenge with MACV. A rMACV with a single F438I substitution in the transmembrane domain (TMD) of GPC, which is equivalent to the F427I attenuating mutation in Cd#1 GPC, was attenuated in a murine model but genetically unstable. In addition, the TMD mutation alone was not sufficient to fully attenuate JUNV, indicating that other domains of the GPC may also contribute to the attenuation. To investigate the requirement of different domains of Cd#1 GPC for successful attenuation of MACV, we rescued several rMACVs expressing the ectodomain of GPC from Cd#1 either alone (MCg1), along with the TMD F438I substitution (MCg2), or with the TMD of Cd#1 (MCg3). All rMACVs exhibited similar growth curves in cultured cells. In mice, the MCg1 displayed significant reduction in lethality as compared with rMACV. The MCg1 was detected in brains and spleens of MCg1-infected mice and the infection was associated with tissue inflammation. On the other hand, all animals survived MCg2 and MCg3 infection without detectable levels of virus in various organs while producing neutralizing antibody against Cd#1. Overall our data suggest the indispensable role of each GPC domain in the full attenuation and immunogenicity of rMACV/Cd#1 GPC

  • epidemiology and pathogenesis of Bolivian Hemorrhagic Fever
    Current Opinion in Virology, 2014
    Co-Authors: Michael Patterson, Ashley M Grant, Slobodan Paessler
    Abstract:

    The etiologic agent of Bolivian Hemorrhagic Fever (BHF), Machupo virus (MACV) is reported to have a mortality rate of 25–35%. First identified in 1959, BHF was the cause of a localized outbreak in San Joaquin until rodent population controls were implemented in 1964. The rodent Calomys collosus was identified as the primary vector and reservoir for the virus. Multiple animal models were considered during the 1970s with the most human-like disease identified in Rhesus macaques but minimal characterization of the pathogenesis has been published since. A reemergence of reported BHF cases has been reported in recent years, which necessitates the further study and development of a vaccine to prevent future outbreaks.

Takaaki Koma - One of the best experts on this subject based on the ideXlab platform.

  • the ectodomain of glycoprotein from the candid 1 vaccine strain of junin virus rendered machupo virus partially attenuated in mice lacking ifn αβ γ receptor
    PLOS Neglected Tropical Diseases, 2016
    Co-Authors: Takaaki Koma, Cheng Huang, Judith F. Aronson, Aida G Walker, Milagros Miller, Jeanon N Smith, Michael Patterson, Slobodan Paessler
    Abstract:

    Machupo virus (MACV), a New World arenavirus, is the etiological agent of Bolivian Hemorrhagic Fever (BHF). Junin virus (JUNV), a close relative, causes Argentine Hemorrhagic Fever (AHF). Previously, we reported that a recombinant, chimeric MACV (rMACV/Cd#1-GPC) expressing glycoprotein from the Candid#1 (Cd#1) vaccine strain of JUNV is completely attenuated in a murine model and protects animals from lethal challenge with MACV. A rMACV with a single F438I substitution in the transmembrane domain (TMD) of GPC, which is equivalent to the F427I attenuating mutation in Cd#1 GPC, was attenuated in a murine model but genetically unstable. In addition, the TMD mutation alone was not sufficient to fully attenuate JUNV, indicating that other domains of the GPC may also contribute to the attenuation. To investigate the requirement of different domains of Cd#1 GPC for successful attenuation of MACV, we rescued several rMACVs expressing the ectodomain of GPC from Cd#1 either alone (MCg1), along with the TMD F438I substitution (MCg2), or with the TMD of Cd#1 (MCg3). All rMACVs exhibited similar growth curves in cultured cells. In mice, the MCg1 displayed significant reduction in lethality as compared with rMACV. The MCg1 was detected in brains and spleens of MCg1-infected mice and the infection was associated with tissue inflammation. On the other hand, all animals survived MCg2 and MCg3 infection without detectable levels of virus in various organs while producing neutralizing antibody against Cd#1. Overall our data suggest the indispensable role of each GPC domain in the full attenuation and immunogenicity of rMACV/Cd#1 GPC.

  • machupo virus expressing gpc of the candid 1 vaccine strain of junin virus is highly attenuated and immunogenic
    Journal of Virology, 2016
    Co-Authors: Takaaki Koma, Cheng Huang, Aida G Walker, Milagros Miller, Jeanon N Smith, Michael Patterson, Alexey Seregin, Payal D Maharaj, Steven Hallam, Slobodan Paessler
    Abstract:

    ABSTRACT Machupo virus (MACV) is the causative agent of Bolivian Hemorrhagic Fever. Our previous study demonstrated that a MACV strain with a single amino acid substitution (F438I) in the transmembrane domain of glycoprotein is attenuated but genetically unstable in mice. MACV is closely related to Junin virus (JUNV), the causative agent of Argentine Hemorrhagic Fever. Others and our group have identified the glycoprotein to be the major viral factor determining JUNV attenuation. In this study, we tested the compatibility of the glycoprotein of the Candid#1 live-attenuated vaccine strain of JUNV in MACV replication and its ability to attenuate MACV in vivo . Recombinant MACV with the Candid#1 glycoprotein (rMACV/Cd#1-GPC) exhibited growth properties similar to those of Candid#1 and was genetically stable in vitro . In a mouse model of lethal infection, rMACV/Cd#1-GPC was fully attenuated, more immunogenic than Candid#1, and fully protective against MACV infection. Therefore, the MACV strain expressing the glycoprotein of Candid#1 is safe, genetically stable, and highly protective against MACV infection in a mouse model. IMPORTANCE Currently, there are no FDA-approved vaccines and/or treatments for Bolivian Hemorrhagic Fever, which is a fatal human disease caused by MACV. The development of antiviral strategies to combat viral Hemorrhagic Fevers, including Bolivian Hemorrhagic Fever, is one of the top priorities of the Implementation Plan of the U.S. Department of Health and Human Services Public Health Emergency Medical Countermeasures Enterprise. Here, we demonstrate for the first time that MACV expressing glycoprotein of Candid#1 is a safe, genetically stable, highly immunogenic, and protective vaccine candidate against Bolivian Hemorrhagic Fever.

  • The Ectodomain of Glycoprotein from the Candid#1 Vaccine Strain of Junin Virus Rendered Machupo Virus Partially Attenuated in Mice Lacking IFN-αβ/γ Receptor.
    Public Library of Science (PLoS), 2016
    Co-Authors: Takaaki Koma, Cheng Huang, Judith F. Aronson, Aida G Walker, Milagros Miller, Jeanon N Smith, Michael Patterson, Slobodan Paessler
    Abstract:

    Machupo virus (MACV), a New World arenavirus, is the etiological agent of Bolivian Hemorrhagic Fever (BHF). Junin virus (JUNV), a close relative, causes Argentine Hemorrhagic Fever (AHF). Previously, we reported that a recombinant, chimeric MACV (rMACV/Cd#1-GPC) expressing glycoprotein from the Candid#1 (Cd#1) vaccine strain of JUNV is completely attenuated in a murine model and protects animals from lethal challenge with MACV. A rMACV with a single F438I substitution in the transmembrane domain (TMD) of GPC, which is equivalent to the F427I attenuating mutation in Cd#1 GPC, was attenuated in a murine model but genetically unstable. In addition, the TMD mutation alone was not sufficient to fully attenuate JUNV, indicating that other domains of the GPC may also contribute to the attenuation. To investigate the requirement of different domains of Cd#1 GPC for successful attenuation of MACV, we rescued several rMACVs expressing the ectodomain of GPC from Cd#1 either alone (MCg1), along with the TMD F438I substitution (MCg2), or with the TMD of Cd#1 (MCg3). All rMACVs exhibited similar growth curves in cultured cells. In mice, the MCg1 displayed significant reduction in lethality as compared with rMACV. The MCg1 was detected in brains and spleens of MCg1-infected mice and the infection was associated with tissue inflammation. On the other hand, all animals survived MCg2 and MCg3 infection without detectable levels of virus in various organs while producing neutralizing antibody against Cd#1. Overall our data suggest the indispensable role of each GPC domain in the full attenuation and immunogenicity of rMACV/Cd#1 GPC

Milagros Miller - One of the best experts on this subject based on the ideXlab platform.

  • Rescue of a Recombinant Machupo Virus from Cloned cDNAs and In Vivo Characterization in Interferon (/) Receptor Double Knockout Mice
    2016
    Co-Authors: Michael Patterson, Cheng Huang, Milagros Miller, Alexey Seregin, Olga A. Kolokoltsova, Allison Poussard, Jennifer Smith, Jeanon Smith, Nadezhda Yun, Ashley Grant
    Abstract:

    Machupo virus (MACV) is the etiological agent of Bolivian Hemorrhagic Fever (BHF), a reemerging and neglected tropical dis-ease associated with highmortality. The prototypical strain of MACV, Carvallo, was isolated from a human patient in 1963, but minimal in vitro and in vivo characterization has been reported. To this end, we utilized reverse genetics to rescue a pathogenic MACV from cloned cDNAs. The recombinant MACV (rMACV) had in vitro growth properties similar to those of the parental MACV. Both viruses caused similar disease development in alpha/beta and gamma interferon receptor knockout mice, including neurological disease development and highmortality. In addition, we have identified a novel murine model with mortality and neurological disease similar to BHF disease reported in humans and nonhuman primates. Amember of the family Arenaviridae, Machupo virus (MACV)is an enveloped, bisegmented negative-stranded RNA virus. Arenaviruses utilize an ambisense coding strategy to direct viral gene transcription from two genomic segments, the large segment (L, ca. 7.2 kb) and the small segment (S, ca. 3.3 kb). Each segment carries two viral genes; S encodes the glycoprotein precursor (GPC) and the nucleoprotein (NP), while L encodes the RNA-dependent RNA polymerase (L polymerase) and the small RING finger protein Z. The GPC is posttranslationally cleaved by th

  • the ectodomain of glycoprotein from the candid 1 vaccine strain of junin virus rendered machupo virus partially attenuated in mice lacking ifn αβ γ receptor
    PLOS Neglected Tropical Diseases, 2016
    Co-Authors: Takaaki Koma, Cheng Huang, Judith F. Aronson, Aida G Walker, Milagros Miller, Jeanon N Smith, Michael Patterson, Slobodan Paessler
    Abstract:

    Machupo virus (MACV), a New World arenavirus, is the etiological agent of Bolivian Hemorrhagic Fever (BHF). Junin virus (JUNV), a close relative, causes Argentine Hemorrhagic Fever (AHF). Previously, we reported that a recombinant, chimeric MACV (rMACV/Cd#1-GPC) expressing glycoprotein from the Candid#1 (Cd#1) vaccine strain of JUNV is completely attenuated in a murine model and protects animals from lethal challenge with MACV. A rMACV with a single F438I substitution in the transmembrane domain (TMD) of GPC, which is equivalent to the F427I attenuating mutation in Cd#1 GPC, was attenuated in a murine model but genetically unstable. In addition, the TMD mutation alone was not sufficient to fully attenuate JUNV, indicating that other domains of the GPC may also contribute to the attenuation. To investigate the requirement of different domains of Cd#1 GPC for successful attenuation of MACV, we rescued several rMACVs expressing the ectodomain of GPC from Cd#1 either alone (MCg1), along with the TMD F438I substitution (MCg2), or with the TMD of Cd#1 (MCg3). All rMACVs exhibited similar growth curves in cultured cells. In mice, the MCg1 displayed significant reduction in lethality as compared with rMACV. The MCg1 was detected in brains and spleens of MCg1-infected mice and the infection was associated with tissue inflammation. On the other hand, all animals survived MCg2 and MCg3 infection without detectable levels of virus in various organs while producing neutralizing antibody against Cd#1. Overall our data suggest the indispensable role of each GPC domain in the full attenuation and immunogenicity of rMACV/Cd#1 GPC.

  • machupo virus expressing gpc of the candid 1 vaccine strain of junin virus is highly attenuated and immunogenic
    Journal of Virology, 2016
    Co-Authors: Takaaki Koma, Cheng Huang, Aida G Walker, Milagros Miller, Jeanon N Smith, Michael Patterson, Alexey Seregin, Payal D Maharaj, Steven Hallam, Slobodan Paessler
    Abstract:

    ABSTRACT Machupo virus (MACV) is the causative agent of Bolivian Hemorrhagic Fever. Our previous study demonstrated that a MACV strain with a single amino acid substitution (F438I) in the transmembrane domain of glycoprotein is attenuated but genetically unstable in mice. MACV is closely related to Junin virus (JUNV), the causative agent of Argentine Hemorrhagic Fever. Others and our group have identified the glycoprotein to be the major viral factor determining JUNV attenuation. In this study, we tested the compatibility of the glycoprotein of the Candid#1 live-attenuated vaccine strain of JUNV in MACV replication and its ability to attenuate MACV in vivo . Recombinant MACV with the Candid#1 glycoprotein (rMACV/Cd#1-GPC) exhibited growth properties similar to those of Candid#1 and was genetically stable in vitro . In a mouse model of lethal infection, rMACV/Cd#1-GPC was fully attenuated, more immunogenic than Candid#1, and fully protective against MACV infection. Therefore, the MACV strain expressing the glycoprotein of Candid#1 is safe, genetically stable, and highly protective against MACV infection in a mouse model. IMPORTANCE Currently, there are no FDA-approved vaccines and/or treatments for Bolivian Hemorrhagic Fever, which is a fatal human disease caused by MACV. The development of antiviral strategies to combat viral Hemorrhagic Fevers, including Bolivian Hemorrhagic Fever, is one of the top priorities of the Implementation Plan of the U.S. Department of Health and Human Services Public Health Emergency Medical Countermeasures Enterprise. Here, we demonstrate for the first time that MACV expressing glycoprotein of Candid#1 is a safe, genetically stable, highly immunogenic, and protective vaccine candidate against Bolivian Hemorrhagic Fever.

  • The Ectodomain of Glycoprotein from the Candid#1 Vaccine Strain of Junin Virus Rendered Machupo Virus Partially Attenuated in Mice Lacking IFN-αβ/γ Receptor.
    Public Library of Science (PLoS), 2016
    Co-Authors: Takaaki Koma, Cheng Huang, Judith F. Aronson, Aida G Walker, Milagros Miller, Jeanon N Smith, Michael Patterson, Slobodan Paessler
    Abstract:

    Machupo virus (MACV), a New World arenavirus, is the etiological agent of Bolivian Hemorrhagic Fever (BHF). Junin virus (JUNV), a close relative, causes Argentine Hemorrhagic Fever (AHF). Previously, we reported that a recombinant, chimeric MACV (rMACV/Cd#1-GPC) expressing glycoprotein from the Candid#1 (Cd#1) vaccine strain of JUNV is completely attenuated in a murine model and protects animals from lethal challenge with MACV. A rMACV with a single F438I substitution in the transmembrane domain (TMD) of GPC, which is equivalent to the F427I attenuating mutation in Cd#1 GPC, was attenuated in a murine model but genetically unstable. In addition, the TMD mutation alone was not sufficient to fully attenuate JUNV, indicating that other domains of the GPC may also contribute to the attenuation. To investigate the requirement of different domains of Cd#1 GPC for successful attenuation of MACV, we rescued several rMACVs expressing the ectodomain of GPC from Cd#1 either alone (MCg1), along with the TMD F438I substitution (MCg2), or with the TMD of Cd#1 (MCg3). All rMACVs exhibited similar growth curves in cultured cells. In mice, the MCg1 displayed significant reduction in lethality as compared with rMACV. The MCg1 was detected in brains and spleens of MCg1-infected mice and the infection was associated with tissue inflammation. On the other hand, all animals survived MCg2 and MCg3 infection without detectable levels of virus in various organs while producing neutralizing antibody against Cd#1. Overall our data suggest the indispensable role of each GPC domain in the full attenuation and immunogenicity of rMACV/Cd#1 GPC

Cheng Huang - One of the best experts on this subject based on the ideXlab platform.

  • Rescue of a Recombinant Machupo Virus from Cloned cDNAs and In Vivo Characterization in Interferon (/) Receptor Double Knockout Mice
    2016
    Co-Authors: Michael Patterson, Cheng Huang, Milagros Miller, Alexey Seregin, Olga A. Kolokoltsova, Allison Poussard, Jennifer Smith, Jeanon Smith, Nadezhda Yun, Ashley Grant
    Abstract:

    Machupo virus (MACV) is the etiological agent of Bolivian Hemorrhagic Fever (BHF), a reemerging and neglected tropical dis-ease associated with highmortality. The prototypical strain of MACV, Carvallo, was isolated from a human patient in 1963, but minimal in vitro and in vivo characterization has been reported. To this end, we utilized reverse genetics to rescue a pathogenic MACV from cloned cDNAs. The recombinant MACV (rMACV) had in vitro growth properties similar to those of the parental MACV. Both viruses caused similar disease development in alpha/beta and gamma interferon receptor knockout mice, including neurological disease development and highmortality. In addition, we have identified a novel murine model with mortality and neurological disease similar to BHF disease reported in humans and nonhuman primates. Amember of the family Arenaviridae, Machupo virus (MACV)is an enveloped, bisegmented negative-stranded RNA virus. Arenaviruses utilize an ambisense coding strategy to direct viral gene transcription from two genomic segments, the large segment (L, ca. 7.2 kb) and the small segment (S, ca. 3.3 kb). Each segment carries two viral genes; S encodes the glycoprotein precursor (GPC) and the nucleoprotein (NP), while L encodes the RNA-dependent RNA polymerase (L polymerase) and the small RING finger protein Z. The GPC is posttranslationally cleaved by th

  • the ectodomain of glycoprotein from the candid 1 vaccine strain of junin virus rendered machupo virus partially attenuated in mice lacking ifn αβ γ receptor
    PLOS Neglected Tropical Diseases, 2016
    Co-Authors: Takaaki Koma, Cheng Huang, Judith F. Aronson, Aida G Walker, Milagros Miller, Jeanon N Smith, Michael Patterson, Slobodan Paessler
    Abstract:

    Machupo virus (MACV), a New World arenavirus, is the etiological agent of Bolivian Hemorrhagic Fever (BHF). Junin virus (JUNV), a close relative, causes Argentine Hemorrhagic Fever (AHF). Previously, we reported that a recombinant, chimeric MACV (rMACV/Cd#1-GPC) expressing glycoprotein from the Candid#1 (Cd#1) vaccine strain of JUNV is completely attenuated in a murine model and protects animals from lethal challenge with MACV. A rMACV with a single F438I substitution in the transmembrane domain (TMD) of GPC, which is equivalent to the F427I attenuating mutation in Cd#1 GPC, was attenuated in a murine model but genetically unstable. In addition, the TMD mutation alone was not sufficient to fully attenuate JUNV, indicating that other domains of the GPC may also contribute to the attenuation. To investigate the requirement of different domains of Cd#1 GPC for successful attenuation of MACV, we rescued several rMACVs expressing the ectodomain of GPC from Cd#1 either alone (MCg1), along with the TMD F438I substitution (MCg2), or with the TMD of Cd#1 (MCg3). All rMACVs exhibited similar growth curves in cultured cells. In mice, the MCg1 displayed significant reduction in lethality as compared with rMACV. The MCg1 was detected in brains and spleens of MCg1-infected mice and the infection was associated with tissue inflammation. On the other hand, all animals survived MCg2 and MCg3 infection without detectable levels of virus in various organs while producing neutralizing antibody against Cd#1. Overall our data suggest the indispensable role of each GPC domain in the full attenuation and immunogenicity of rMACV/Cd#1 GPC.

  • machupo virus expressing gpc of the candid 1 vaccine strain of junin virus is highly attenuated and immunogenic
    Journal of Virology, 2016
    Co-Authors: Takaaki Koma, Cheng Huang, Aida G Walker, Milagros Miller, Jeanon N Smith, Michael Patterson, Alexey Seregin, Payal D Maharaj, Steven Hallam, Slobodan Paessler
    Abstract:

    ABSTRACT Machupo virus (MACV) is the causative agent of Bolivian Hemorrhagic Fever. Our previous study demonstrated that a MACV strain with a single amino acid substitution (F438I) in the transmembrane domain of glycoprotein is attenuated but genetically unstable in mice. MACV is closely related to Junin virus (JUNV), the causative agent of Argentine Hemorrhagic Fever. Others and our group have identified the glycoprotein to be the major viral factor determining JUNV attenuation. In this study, we tested the compatibility of the glycoprotein of the Candid#1 live-attenuated vaccine strain of JUNV in MACV replication and its ability to attenuate MACV in vivo . Recombinant MACV with the Candid#1 glycoprotein (rMACV/Cd#1-GPC) exhibited growth properties similar to those of Candid#1 and was genetically stable in vitro . In a mouse model of lethal infection, rMACV/Cd#1-GPC was fully attenuated, more immunogenic than Candid#1, and fully protective against MACV infection. Therefore, the MACV strain expressing the glycoprotein of Candid#1 is safe, genetically stable, and highly protective against MACV infection in a mouse model. IMPORTANCE Currently, there are no FDA-approved vaccines and/or treatments for Bolivian Hemorrhagic Fever, which is a fatal human disease caused by MACV. The development of antiviral strategies to combat viral Hemorrhagic Fevers, including Bolivian Hemorrhagic Fever, is one of the top priorities of the Implementation Plan of the U.S. Department of Health and Human Services Public Health Emergency Medical Countermeasures Enterprise. Here, we demonstrate for the first time that MACV expressing glycoprotein of Candid#1 is a safe, genetically stable, highly immunogenic, and protective vaccine candidate against Bolivian Hemorrhagic Fever.

  • The Ectodomain of Glycoprotein from the Candid#1 Vaccine Strain of Junin Virus Rendered Machupo Virus Partially Attenuated in Mice Lacking IFN-αβ/γ Receptor.
    Public Library of Science (PLoS), 2016
    Co-Authors: Takaaki Koma, Cheng Huang, Judith F. Aronson, Aida G Walker, Milagros Miller, Jeanon N Smith, Michael Patterson, Slobodan Paessler
    Abstract:

    Machupo virus (MACV), a New World arenavirus, is the etiological agent of Bolivian Hemorrhagic Fever (BHF). Junin virus (JUNV), a close relative, causes Argentine Hemorrhagic Fever (AHF). Previously, we reported that a recombinant, chimeric MACV (rMACV/Cd#1-GPC) expressing glycoprotein from the Candid#1 (Cd#1) vaccine strain of JUNV is completely attenuated in a murine model and protects animals from lethal challenge with MACV. A rMACV with a single F438I substitution in the transmembrane domain (TMD) of GPC, which is equivalent to the F427I attenuating mutation in Cd#1 GPC, was attenuated in a murine model but genetically unstable. In addition, the TMD mutation alone was not sufficient to fully attenuate JUNV, indicating that other domains of the GPC may also contribute to the attenuation. To investigate the requirement of different domains of Cd#1 GPC for successful attenuation of MACV, we rescued several rMACVs expressing the ectodomain of GPC from Cd#1 either alone (MCg1), along with the TMD F438I substitution (MCg2), or with the TMD of Cd#1 (MCg3). All rMACVs exhibited similar growth curves in cultured cells. In mice, the MCg1 displayed significant reduction in lethality as compared with rMACV. The MCg1 was detected in brains and spleens of MCg1-infected mice and the infection was associated with tissue inflammation. On the other hand, all animals survived MCg2 and MCg3 infection without detectable levels of virus in various organs while producing neutralizing antibody against Cd#1. Overall our data suggest the indispensable role of each GPC domain in the full attenuation and immunogenicity of rMACV/Cd#1 GPC