We request supplemental funds to foster cooperative research under the Emerging Diseases Research Network Plan involving Stuart Nichol of the Special Pathogens Branch at CDC, Richard Compans' laboratory at Emory and our group at Scripps to define and manipulate the host cell surface receptor utilized by lymphocytic choriomeningitis virus (LCMV), Lassa fever virus (LFV) and other newly emerging arenaviruses. A candidate cell surface receptor (120 to 140 kD virus binding protein) for LCMV (J. Virol. 66:7270, 1992) and LFV (unpublished) has been identified and defined. This receptor is utilized by strains of LCMV that primarily cause immunosuppression (ARM 53b Clone 13, WE 54, Traub) and show heightened tropism for the major professional antigen presenting dendritic cell when compared to other LCMV strains (ARM 53b, E350, Pasteur, WE Clone 2. 2). Pertinent to this application is our preliminary observations with Stuart Nichol that LFV, Josiah and Nigeria strains as well as Mopeia use the 120-140 kD cellular binding protein but that New World nonhuman infecting arenaviruses Tacaribe and Pichinde do not. This proposal allows study of human pathogenic and newly emerging arenaviruses to determine first whether LCMV and LFV use the same receptor. This is to be accomplished initially by competitive blocking assays for the cell binding protein and then by biochemical characterization of the cellular binding protein used by these viruses. Second, we will determine whether LFV and other arenaviruses enter and exit the cell by the apical, basal or both apical and basal routes of the plasma membrane and correlate their pathway with the presence of the cellular binding protein. Third, we will correlate binding of other newly emerging human arenaviruses to the cellular binding protein in anticipation of classifying arenaviruses into different groups and better understanding its pathogenesis. The eventual goal is to understand and then manipulate, for the profit of the host, the early events of arenavirus entry into cells.
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