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.

Public Health Relevance

We have identified the receptor for the five known New World hemorrhagic fever arenaviruses. Use of this receptor is closely linked to severe human disease. Here we seek to understand this link, and develop methods for predicting whether related viruses might gain the ability to use this receptor.

Agency
National Institute of Health (NIH)
Type
Research Project (R01)
Project #
5R01AI074879-09
Application #
8712336
Study Section
Virology - A Study Section (VIRA)
Program Officer
Repik, Patricia M
Project Start
Project End
Budget Start
Budget End
Support Year
9
Fiscal Year
2014
Total Cost
Indirect Cost
Name
Scripps Florida
Department
Type
DUNS #
City
Jupiter
State
FL
Country
United States
Zip Code
33458
Jemielity, Stephanie; Wang, Jinyize J; Chan, Ying Kai et al. (2013) TIM-family proteins promote infection of multiple enveloped viruses through virion-associated phosphatidylserine. PLoS Pathog 9:e1003232
Helguera, Gustavo; Jemielity, Stephanie; Abraham, Jonathan et al. (2012) An antibody recognizing the apical domain of human transferrin receptor 1 efficiently inhibits the entry of all new world hemorrhagic Fever arenaviruses. J Virol 86:4024-8
Choe, Hyeryun; Jemielity, Stephanie; Abraham, Jonathan et al. (2011) Transferrin receptor 1 in the zoonosis and pathogenesis of New World hemorrhagic fever arenaviruses. Curr Opin Microbiol 14:476-82
Abraham, Jonathan; Corbett, Kevin D; Farzan, Michael et al. (2010) Structural basis for receptor recognition by New World hemorrhagic fever arenaviruses. Nat Struct Mol Biol 17:438-44