The South American arenaviruses Junin, Machupo, and Guanarito are the causative agents of hemorrhagic fevers with high morbidity and mortality in humans. They are considered category A infectious agents and represent a major threat for human health. Since the binding of a virus to its cellular receptor is the first step in virus infection, it represents a key determinant for the epidemiology and pathogenesis of a virus and provides a primary target for the development of anti-viral drugs. The cellular receptor for Old World arenaviruses and 1 subgroup of the New World arenaviruses (Clade C) has recently been identified as alpha-dystroglycan. In contrast, the receptors of the South American hemorrhagic fever viruses, which belong to the Clade B New World arenaviruses, are currently unknown. Considering the pivotal role of the virus-receptor interaction for infection and tissue tropism, the identification of the cellular receptors used by these viruses will substantially contribute to the understanding of their pathogenesis and also provide promising new targets for anti-viral strategies. Among the human pathogenic New World arenaviruses, Junin virus, the causative agent of Argentine hemorrhagic fever affects by far the largest number of people. The present application aims therefore at the identification of cellular receptor molecules of Junin virus. In a first approach to identify candidate receptors, a receptor-deficient cell line will be genetically complemented with cDNA expression libraries generated from human cell lines that are susceptible to infection. Cells transfected with candidate receptor cDNAs will become susceptible to the infection with recombinant retroviruses containing the glycoprotein of Junin virus. Infected cells will be selected using an antibiotic resistance gene and a green fluorescent protein reporter present in the genome of the recombinant retroviruses. Candidate cDNAs will be amplified by PCR, sequenced, and identified using human genomic databases. Preliminary characterization of the cellular receptor(s) of Junin virus demonstrated that they are either protein(s) or protein-bound entities. In a complementary approach, biochemical techniques, combined with mass spectrometry, will therefore be used for the identification of candidate receptors for this important human pathogen. ? ? ?
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| Rojek, Jillian M; Lee, Andrew M; Nguyen, NgocThao et al. (2008) Site 1 protease is required for proteolytic processing of the glycoproteins of the South American hemorrhagic fever viruses Junin, Machupo, and Guanarito. J Virol 82:6045-51 |
| Rojek, Jillian M; Sanchez, Ana B; Nguyen, Ngoc Thao et al. (2008) Different mechanisms of cell entry by human-pathogenic Old World and New World arenaviruses. J Virol 82:7677-87 |
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| Rojek, Jillian M; Perez, Mar; Kunz, Stefan (2008) Cellular entry of lymphocytic choriomeningitis virus. J Virol 82:1505-17 |
