YEARS

2007-2016

AUTHORS

Hyeryun Choe

TITLE

A Cellular Receptor for New World Arenaviruses

ABSTRACT

DESCRIPTION (provided by applicant): Five New World arenaviruses cause fatal hemorrhagic fevers in humans. In the last funding cycle we identified the common cellular receptor for these viruses, human transferrin receptor 1 (TfR1). We also localized the TfR1 domain which these viruses bind, and identified key commonalities between the human TfR1 and TfR1 orthologs of their host species that made possible efficient transmission to humans. We further showed that two non-pathogenic viruses, closely related to human hemorrhagic fever arenaviruses, efficiently used the TfR1 orthologs of their respective host species, but did not bind or use human TfR1. These viruses nonetheless efficiently enter human cells through a TfR1- independent mechanism. In addition to these studies, we collaborated to determine the structure of the entry glycoprotein GP1 of the Machupo virus, complexed to human TfR1. Collectively our previous studies made clear that (1) ability to use human TfR1, not the ability to infect human cells, is the key determinant in whether a New World arenavirus will cause a human hemorrhagic fever, (2) gain of use of human TfR1 by non-pathogenic viruses will require only modest changes in the receptor-binding regions of their entry glycoproteins, GP. Our current studies seek to answer two questions raised by these studies. First, how likely is it that non- pathogenic arenaviruses circulating in North and South America include quasispecies that can use human TfR1? To address this question we have developed a GP library-based approach for assessing the relative likelihood that a given arenavirus variant will gain the ability to use human TfR1. We will also solve the structures of additional GP1/TfR1 complexes to provide a framework for interpreting the results of our library-based studies. Second, what is the physiological basis for the close relationship between human TfR1 use and hemorrhagic fever? We explore the hypothesis that TfR1 upregulation in response to infection, and in particular as a consequence of iron sequestration, plays a pivotal role in amplifying viral replication. To test this hypothesis we will develop a novel murine model of New World arenaviral infection. Collectively our studies will highlight circulating arenaviruses that may be of special concern, establish a novel model of infection, and illuminate a destructive feedback mechanism contributing to arenaviral hemorrhagic fevers.

FUNDED PUBLICATIONS

  • TIM-family proteins promote infection of multiple enveloped viruses through virion-associated phosphatidylserine.
  • Receptor determinants of zoonotic transmission of New World hemorrhagic fever arenaviruses.
  • Transferrin receptor 1 is a cellular receptor for New World haemorrhagic fever arenaviruses.
  • Transferrin receptor 1 in the zoonosis and pathogenesis of New World hemorrhagic fever arenaviruses.
  • Structural basis for receptor recognition by New World hemorrhagic fever arenaviruses
  • Transferrin receptor 1 is a cellular receptor for New World haemorrhagic fever arenaviruses
  • An antibody recognizing the apical domain of human transferrin receptor 1 efficiently inhibits the entry of all new world hemorrhagic Fever arenaviruses.
  • Structural basis for receptor recognition by New World hemorrhagic fever arenaviruses.
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    25 TRIPLES      17 PREDICATES      26 URIs      9 LITERALS

    Subject Predicate Object
    1 grants:bb297fecfafd7234207082b6fcb9242a sg:abstract DESCRIPTION (provided by applicant): Five New World arenaviruses cause fatal hemorrhagic fevers in humans. In the last funding cycle we identified the common cellular receptor for these viruses, human transferrin receptor 1 (TfR1). We also localized the TfR1 domain which these viruses bind, and identified key commonalities between the human TfR1 and TfR1 orthologs of their host species that made possible efficient transmission to humans. We further showed that two non-pathogenic viruses, closely related to human hemorrhagic fever arenaviruses, efficiently used the TfR1 orthologs of their respective host species, but did not bind or use human TfR1. These viruses nonetheless efficiently enter human cells through a TfR1- independent mechanism. In addition to these studies, we collaborated to determine the structure of the entry glycoprotein GP1 of the Machupo virus, complexed to human TfR1. Collectively our previous studies made clear that (1) ability to use human TfR1, not the ability to infect human cells, is the key determinant in whether a New World arenavirus will cause a human hemorrhagic fever, (2) gain of use of human TfR1 by non-pathogenic viruses will require only modest changes in the receptor-binding regions of their entry glycoproteins, GP. Our current studies seek to answer two questions raised by these studies. First, how likely is it that non- pathogenic arenaviruses circulating in North and South America include quasispecies that can use human TfR1? To address this question we have developed a GP library-based approach for assessing the relative likelihood that a given arenavirus variant will gain the ability to use human TfR1. We will also solve the structures of additional GP1/TfR1 complexes to provide a framework for interpreting the results of our library-based studies. Second, what is the physiological basis for the close relationship between human TfR1 use and hemorrhagic fever? We explore the hypothesis that TfR1 upregulation in response to infection, and in particular as a consequence of iron sequestration, plays a pivotal role in amplifying viral replication. To test this hypothesis we will develop a novel murine model of New World arenaviral infection. Collectively our studies will highlight circulating arenaviruses that may be of special concern, establish a novel model of infection, and illuminate a destructive feedback mechanism contributing to arenaviral hemorrhagic fevers.
    2 sg:endYear 2016
    3 sg:fundingAmount 3409120.0
    4 sg:fundingCurrency USD
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    18 sg:language English
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    20 sg:scigraphId bb297fecfafd7234207082b6fcb9242a
    21 sg:startYear 2007
    22 sg:title A Cellular Receptor for New World Arenaviruses
    23 sg:webpage http://projectreporter.nih.gov/project_info_description.cfm?aid=8712336
    24 rdf:type sg:Grant
    25 rdfs:label Grant: A Cellular Receptor for New World Arenaviruses
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