This is a corrected and revised resubmission to study the structure/biology of the arenavirus receptor. We found alpha-dystroglycan (alpha-DG) was the receptor for arenaviruses (Science 282, 1998).
All specific aims proposed on the initial 5 yr grant have been accomplished. The first was to determine whether alpha-DG was a receptor for all arenaviruses. We found alpha-DG was the only receptor required for all Old World (LCMV, Lassa fever virus [LFV]) and New World Clade C viruses (Latino, Oliveros) (J. Virol. 76, 2002).
The second aim was to map the portion(s) of alpha-DG that arenaviruses and the cell's natural ligand laminin bound to. This was accomplished by constructing and using alpha-DG deletion mutants and Fc fragments transfected into alpha-DG-/- cells (JEM 192, 2000; J. Virol. 75, 2001; Virology 325, 2004; JCB 155, 2001; Cell 117, 2004).
The third aim was to study biologic consequence of virus binding to alpha-DG and extension of those findings form the bulk of this application. We found alpha-DG was expressed in the immune system almost exclusively on dendritic cells (DC) and in the peripheral nervous system on Schwann cells (SC). High affinity alpha-DG binding viruses infected (>75%) DC and their bone marrow (BM) precursors and >98% of SC while low affinity binders (bind at 2-3 logs less) infected <10% of these cells. Infected DC were neither able to arm T cells and terminate infection (JEM 192, 2000) nor expand in vivo or in vitro (JCI 113, 2004). Infected BM cells failed to develop and differentiate into DC (JCI 113, 2004; Immunity, in press, 2005). Infected SC failed to make myelin (PNAS 100, 2003). We propose identifying the signaling pathways and the molecules that alter differentiation of BM cells, dysfunction of DCs and cause the failure of SC to form myelin during viral infection. These findings have relevance for biodefense of several viruses including LFV.
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