Molecular analysis of the interaction of LCMV with its cellular receptor α-dystroglycan

alpha -Dystroglycan (DG) has been identified as the cellular receptor for lymphocytic choriomeningitis virus (LCMV) and Lassa fever virus (LFV). This subunit of DG is a highly versatile cell surface molecule that provides a molecular link between the extracellular matrix (ECM) and a beta -DG transmembrane component, which interacts with the actin-based cytoskeleton. In addition, DC exhibits a complex pattern of interaction with a wide variety of ECM and cellular proteins. In the present study, we characterized the binding of LCMV to alpha -DG and addressed the role of alpha -DG-associated host-derived proteins in virus infection. We found that the COOH-terminal region of alpha -DG's first globular domain and the NH2-terminal region of the mucin-related structures of alpha -DG together form the binding site for LCMV. The virus-alpha -DG binding unlike ECM alpha -DG interactions was not dependent on divalent cations. Despite such differences in binding, LCMV and laminin-1 use, in part, an overlapping binding site on alpha -DG, and the ability of an LCMV isolate to compete with laminin-1 for receptor binding is determined by its binding affinity to alpha -DG. This competition of the virus with ECM molecules for receptor binding likely explains the recently found correlation between the affinity of LCMV binding to alpha -DG, tissue tropism, and pathological potential. LCMV strains and variants with high binding affinity to alpha -DG but not low affinity binders are able to infect CD11c(+) dendritic cells, which express alpha -DG at their surface. Infection followed by dysfunction of these antigen-presenting cells contributes to immunosuppression and persistent viral infection in vivo.