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 A candidate cell surface receptor (120 to 140 kD virus binding protein) for LCMV (J. Virol. 66:7270, 1992) and LFV (unpublished) has been identified and defined.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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI009484-33
Application #
6510185
Study Section
Experimental Virology Study Section (EVR)
Program Officer
Beisel, Christopher E
Project Start
1977-09-01
Project End
2003-06-30
Budget Start
2002-03-01
Budget End
2003-06-30
Support Year
33
Fiscal Year
2002
Total Cost
$342,676
Indirect Cost
Name
Scripps Research Institute
Department
Type
DUNS #
City
La Jolla
State
CA
Country
United States
Zip Code
92037
Oldstone, Michael B A; Ware, Brian C; Horton, Lucy E et al. (2018) Lymphocytic choriomeningitis virus Clone 13 infection causes either persistence or acute death dependent on IFN-1, cytotoxic T lymphocytes (CTLs), and host genetics. Proc Natl Acad Sci U S A 115:E7814-E7823
Marro, Brett S; Ware, Brian C; Zak, Jaroslav et al. (2017) Progression of type 1 diabetes from the prediabetic stage is controlled by interferon-? signaling. Proc Natl Acad Sci U S A 114:3708-3713
Hastie, Kathryn M; Igonet, S├ębastien; Sullivan, Brian M et al. (2016) Crystal structure of the prefusion surface glycoprotein of the prototypic arenavirus LCMV. Nat Struct Mol Biol 23:513-521
Teijaro, John R; Studer, Sean; Leaf, Nora et al. (2016) S1PR1-mediated IFNAR1 degradation modulates plasmacytoid dendritic cell interferon-? autoamplification. Proc Natl Acad Sci U S A 113:1351-6
Ng, Cherie T; Mendoza, Juan L; Garcia, K Christopher et al. (2016) Alpha and Beta Type 1 Interferon Signaling: Passage for Diverse Biologic Outcomes. Cell 164:349-52
Oldstone, Michael B A (2015) A Jekyll and Hyde Profile: Type 1 Interferon Signaling Plays a Prominent Role in the Initiation and Maintenance of a Persistent Virus Infection. J Infect Dis 212 Suppl 1:S31-6
Sullivan, Brian M; Teijaro, John R; de la Torre, Juan Carlos et al. (2015) Early virus-host interactions dictate the course of a persistent infection. PLoS Pathog 11:e1004588
Ng, Cherie T; Sullivan, Brian M; Teijaro, John R et al. (2015) Blockade of interferon Beta, but not interferon alpha, signaling controls persistent viral infection. Cell Host Microbe 17:653-61
Teijaro, John R; Walsh, Kevin B; Long, James P et al. (2014) Protection of ferrets from pulmonary injury due to H1N1 2009 influenza virus infection: immunopathology tractable by sphingosine-1-phosphate 1 receptor agonist therapy. Virology 452-453:152-7
Oldstone, Michael B A (2014) Molecular mimicry: its evolution from concept to mechanism as a cause of autoimmune diseases. Monoclon Antib Immunodiagn Immunother 33:158-65

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