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  1. Article ; Online: Characterization of Live-Attenuated Powassan Virus Vaccine Candidates Identifies an Efficacious Prime-Boost Strategy for Mitigating Powassan Virus Disease in a Murine Model

    Andrew M. Cheung / Elaine Z. Yip / Alison W. Ashbrook / Niluka Goonawardane / Corrine Quirk / Charles M. Rice / Margaret R. MacDonald / Hans-Heinrich Hoffmann

    Vaccines, Vol 11, Iss 612, p

    2023  Volume 612

    Abstract: Powassan virus (POWV) is an emerging tick-borne virus and cause of lethal encephalitis in humans. The lack of treatment or prevention strategies for POWV disease underscores the need for an effective POWV vaccine. Here, we took two independent approaches ...

    Abstract Powassan virus (POWV) is an emerging tick-borne virus and cause of lethal encephalitis in humans. The lack of treatment or prevention strategies for POWV disease underscores the need for an effective POWV vaccine. Here, we took two independent approaches to develop vaccine candidates. First, we recoded the POWV genome to increase the dinucleotide frequencies of CpG and UpA to potentially attenuate the virus by raising its susceptibility to host innate immune factors, such as the zinc-finger antiviral protein (ZAP). Secondly, we took advantage of the live-attenuated yellow fever virus vaccine 17D strain (YFV-17D) as a vector to express the structural genes pre-membrane (prM) and envelope (E) of POWV. The chimeric YFV-17D-POWV vaccine candidate was further attenuated for in vivo application by removing an N-linked glycosylation site within the nonstructural protein (NS)1 of YFV-17D. This live-attenuated chimeric vaccine candidate significantly protected mice from POWV disease, conferring a 70% survival rate after lethal challenge when administered in a homologous two-dose regimen. Importantly, when given in a heterologous prime-boost vaccination scheme, in which vaccination with the initial chimeric virus was followed by a protein boost with the envelope protein domain III (EDIII), 100% of the mice were protected without showing any signs of morbidity. Combinations of this live-attenuated chimeric YFV-17D-POWV vaccine candidate with an EDIII protein boost warrant further studies for the development of an effective vaccine strategy for the prevention of POWV disease.
    Keywords Powassan virus ; deer tick virus ; live-attenuated vaccine ; yellow fever 17D virus vaccine ; CpG and UpA dinucleotides ; zinc finger antiviral protein (ZAP) ; Medicine ; R
    Subject code 570
    Language English
    Publishing date 2023-03-01T00:00:00Z
    Publisher MDPI AG
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  2. Article ; Online: Metabolites with SARS-CoV-2 Inhibitory Activity Identified from Human Microbiome Commensals

    Frank J. Piscotta / Hans-Heinrich Hoffmann / Young Joo Choi / Gabriel I. Small / Alison W. Ashbrook / Bimal Koirala / Elizabeth A. Campbell / Seth A. Darst / Charles M. Rice / Sean F. Brady

    mSphere, Vol 6, Iss

    2021  Volume 6

    Abstract: ABSTRACT The COVID-19 pandemic has highlighted the need to identify additional antiviral small molecules to complement existing therapies. Although increasing evidence suggests that metabolites produced by the human microbiome have diverse biological ... ...

    Abstract ABSTRACT The COVID-19 pandemic has highlighted the need to identify additional antiviral small molecules to complement existing therapies. Although increasing evidence suggests that metabolites produced by the human microbiome have diverse biological activities, their antiviral properties remain poorly explored. Using a cell-based SARS-CoV-2 infection assay, we screened culture broth extracts from a collection of phylogenetically diverse human-associated bacteria for the production of small molecules with antiviral activity. Bioassay-guided fractionation uncovered three bacterial metabolites capable of inhibiting SARS-CoV-2 infection. This included the nucleoside analogue N6-(Δ2-isopentenyl)adenosine, the 5-hydroxytryptamine receptor agonist tryptamine, and the pyrazine 2,5-bis(3-indolylmethyl)pyrazine. The most potent of these, N6-(Δ2-isopentenyl)adenosine, had a 50% inhibitory concentration (IC50) of 2 μM. These natural antiviral compounds exhibit structural and functional similarities to synthetic drugs that have been clinically examined for use against COVID-19. Our discovery of structurally diverse metabolites with anti-SARS-CoV-2 activity from screening a small fraction of the bacteria reported to be associated with the human microbiome suggests that continued exploration of phylogenetically diverse human-associated bacteria is likely to uncover additional small molecules that inhibit SARS-CoV-2 as well as other viral infections. IMPORTANCE The continued prevalence of COVID-19 and the emergence of new variants has once again put the spotlight on the need for the identification of SARS-CoV-2 antivirals. The human microbiome produces an array of small molecules with bioactivities (e.g., host receptor ligands), but its ability to produce antiviral small molecules is relatively underexplored. Here, using a cell-based screening platform, we describe the isolation of three microbiome-derived metabolites that are able to prevent SARS-CoV-2 infection in vitro. These molecules display structural similarities to ...
    Keywords biochemistry ; molecular biology ; virology ; Microbiology ; QR1-502
    Subject code 572
    Language English
    Publishing date 2021-12-01T00:00:00Z
    Publisher American Society for Microbiology
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  3. Article ; Online: Defining the proteolytic landscape during enterovirus infection.

    Mohsan Saeed / Sebastian Kapell / Nicholas T Hertz / Xianfang Wu / Kierstin Bell / Alison W Ashbrook / Milica Tesic Mark / Henry A Zebroski / Maxwell L Neal / Malin Flodström-Tullberg / Margaret R MacDonald / John D Aitchison / Henrik Molina / Charles M Rice

    PLoS Pathogens, Vol 16, Iss 9, p e

    2020  Volume 1008927

    Abstract: Viruses cleave cellular proteins to remodel the host proteome. The study of these cleavages has revealed mechanisms of immune evasion, resource exploitation, and pathogenesis. However, the full extent of virus-induced proteolysis in infected cells is ... ...

    Abstract Viruses cleave cellular proteins to remodel the host proteome. The study of these cleavages has revealed mechanisms of immune evasion, resource exploitation, and pathogenesis. However, the full extent of virus-induced proteolysis in infected cells is unknown, mainly because until recently the technology for a global view of proteolysis within cells was lacking. Here, we report the first comprehensive catalog of proteins cleaved upon enterovirus infection and identify the sites within proteins where the cleavages occur. We employed multiple strategies to confirm protein cleavages and assigned them to one of the two enteroviral proteases. Detailed characterization of one substrate, LSM14A, a p body protein with a role in antiviral immunity, showed that cleavage of this protein disrupts its antiviral function. This study yields a new depth of information about the host interface with a group of viruses that are both important biological tools and significant agents of disease.
    Keywords Immunologic diseases. Allergy ; RC581-607 ; Biology (General) ; QH301-705.5
    Subject code 570
    Language English
    Publishing date 2020-09-01T00:00:00Z
    Publisher Public Library of Science (PLoS)
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  4. Article ; Online: Antagonism of the Sodium-Potassium ATPase Impairs Chikungunya Virus Infection

    Alison W. Ashbrook / Anthony J. Lentscher / Paula F. Zamora / Laurie A. Silva / Nicholas A. May / Joshua A. Bauer / Thomas E. Morrison / Terence S. Dermody

    mBio, Vol 7, Iss 3, p e00693-

    2016  Volume 16

    Abstract: Chikungunya virus (CHIKV) is a reemerging alphavirus that has caused epidemics of fever, arthralgia, and rash worldwide. There are currently no licensed vaccines or antiviral therapies available for the prevention or treatment of CHIKV disease. We ... ...

    Abstract Chikungunya virus (CHIKV) is a reemerging alphavirus that has caused epidemics of fever, arthralgia, and rash worldwide. There are currently no licensed vaccines or antiviral therapies available for the prevention or treatment of CHIKV disease. We conducted a high-throughput, chemical compound screen that identified digoxin, a cardiac glycoside that blocks the sodium-potassium ATPase, as a potent inhibitor of CHIKV infection. Treatment of human cells with digoxin or a related cardiac glycoside, ouabain, resulted in a dose-dependent decrease in infection by CHIKV. Inhibition by digoxin was cell type-specific, as digoxin treatment of either murine or mosquito cells did not diminish CHIKV infection. Digoxin displayed antiviral activity against other alphaviruses, including Ross River virus and Sindbis virus, as well as mammalian reovirus and vesicular stomatitis virus. The digoxin-mediated block to CHIKV and reovirus infection occurred at one or more postentry steps, as digoxin inhibition was not bypassed by fusion of CHIKV at the plasma membrane or infection with cell surface-penetrating reovirus entry intermediates. Selection of digoxin-resistant CHIKV variants identified multiple mutations in the nonstructural proteins required for replication complex formation and synthesis of viral RNA. These data suggest a role for the sodium-potassium ATPase in promoting postentry steps of CHIKV replication and provide rationale for modulation of this pathway as a broad-spectrum antiviral strategy.
    Keywords Science ; Q ; Microbiology ; QR1-502
    Subject code 570
    Language English
    Publishing date 2016-05-01T00:00:00Z
    Publisher American Society for Microbiology
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  5. Article ; Online: Pathogenic Chikungunya Virus Evades B Cell Responses to Establish Persistence

    David W. Hawman / Julie M. Fox / Alison W. Ashbrook / Nicholas A. May / Kristin M.S. Schroeder / Raul M. Torres / James E. Crowe Jr. / Terence S. Dermody / Michael S. Diamond / Thomas E. Morrison

    Cell Reports, Vol 16, Iss 5, Pp 1326-

    2016  Volume 1338

    Abstract: Chikungunya virus (CHIKV) and related alphaviruses cause epidemics of acute and chronic musculoskeletal disease. To investigate the mechanisms underlying the failure of immune clearance of CHIKV, we studied mice infected with an attenuated CHIKV strain ( ... ...

    Abstract Chikungunya virus (CHIKV) and related alphaviruses cause epidemics of acute and chronic musculoskeletal disease. To investigate the mechanisms underlying the failure of immune clearance of CHIKV, we studied mice infected with an attenuated CHIKV strain (181/25) and the pathogenic parental strain (AF15561), which differ by five amino acids. Whereas AF15561 infection of wild-type mice results in viral persistence in joint tissues, 181/25 is cleared. In contrast, 181/25 infection of μMT mice lacking mature B cells results in viral persistence in joint tissues, suggesting that virus-specific antibody is required for clearance of infection. Mapping studies demonstrated that a highly conserved glycine at position 82 in the A domain of the E2 glycoprotein impedes clearance and neutralization of multiple CHIKV strains. Remarkably, murine and human antibodies targeting E2 domain B failed to neutralize pathogenic CHIKV strains efficiently. Our data suggest that pathogenic CHIKV strains evade E2 domain-B-neutralizing antibodies to establish persistence.
    Keywords Biology (General) ; QH301-705.5
    Subject code 570
    Language English
    Publishing date 2016-08-01T00:00:00Z
    Publisher Elsevier
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  6. Article ; Online: Male germ cells support long-term propagation of Zika virus

    Christopher L. Robinson / Angie C. N. Chong / Alison W. Ashbrook / Ginnie Jeng / Julia Jin / Haiqi Chen / Elizabeth I. Tang / Laura A. Martin / Rosa S. Kim / Reyn M. Kenyon / Eileen Do / Joseph M. Luna / Mohsan Saeed / Lori Zeltser / Harold Ralph / Vanessa L. Dudley / Marc Goldstein / Charles M. Rice / C. Yan Cheng /
    Marco Seandel / Shuibing Chen

    Nature Communications, Vol 9, Iss 1, Pp 1-

    2018  Volume 11

    Abstract: Zika virus (ZIKV) can persist for months in semen and sperm. Here, the authors show that germ cells, compared to other cell types in the reproductive tract, are most susceptible to ZIKV and produce high levels of progeny virus, which coincides with ... ...

    Abstract Zika virus (ZIKV) can persist for months in semen and sperm. Here, the authors show that germ cells, compared to other cell types in the reproductive tract, are most susceptible to ZIKV and produce high levels of progeny virus, which coincides with decreased expression of the interferon-stimulated gene Ifi44l.
    Keywords Science ; Q
    Language English
    Publishing date 2018-05-01T00:00:00Z
    Publisher Nature Publishing Group
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  7. Article ; Online: Male germ cells support long-term propagation of Zika virus

    Christopher L. Robinson / Angie C. N. Chong / Alison W. Ashbrook / Ginnie Jeng / Julia Jin / Haiqi Chen / Elizabeth I. Tang / Laura A. Martin / Rosa S. Kim / Reyn M. Kenyon / Eileen Do / Joseph M. Luna / Mohsan Saeed / Lori Zeltser / Harold Ralph / Vanessa L. Dudley / Marc Goldstein / Charles M. Rice / C. Yan Cheng /
    Marco Seandel / Shuibing Chen

    Nature Communications, Vol 9, Iss 1, Pp 1-

    2018  Volume 11

    Abstract: Zika virus (ZIKV) can persist for months in semen and sperm. Here, the authors show that germ cells, compared to other cell types in the reproductive tract, are most susceptible to ZIKV and produce high levels of progeny virus, which coincides with ... ...

    Abstract Zika virus (ZIKV) can persist for months in semen and sperm. Here, the authors show that germ cells, compared to other cell types in the reproductive tract, are most susceptible to ZIKV and produce high levels of progeny virus, which coincides with decreased expression of the interferon-stimulated gene Ifi44l.
    Keywords Science ; Q
    Language English
    Publishing date 2018-05-01T00:00:00Z
    Publisher Nature Portfolio
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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