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Lassa virus (LASV) causes severe hemorrhagic fever with high mortality, yet no vaccine currently exists. Antibodies targeting viral attachment proteins are crucial for protection against many viral infections. However, the envelope glycoprotein (GP)−1 of LASV elicits weak antibody responses due to extensive glycan shielding. Here, we explored a novel vaccine strategy to enhance humoral immunity against...
Maturation of the arenavirus GP precursor (GPC) involves proteolytic processing by cellular signal peptidase and the proprotein convertase subtilisin kexin isozyme 1 (SKI-1)/site 1 protease (S1P), yielding a tripartite complex comprised of a stable signal peptide (SSP), the receptor-binding GP1, and the fusion-active transmembrane GP2. Here we investigated the roles of SKI-1/S1P processing and SSP...
The cellular protease subtilisin kexin isozyme-1 (SKI-1)/site-1 protease (S1P) is implicated in the proteolytic processing of the viral envelope glycoprotein precursor (GPC) of arenaviruses, a step strictly required for production of infectious progeny. The small molecule SKI-1/S1P inhibitor PF-429242 was shown to have anti-viral activity against Old World arenaviruses. Here we extended these studies...
A crucial step in the arenavirus life cycle is the proteolytic processing of the viral envelope glycoprotein precursor (GPC) by the cellular proprotein convertase (PC) subtilisin kexin isozyme-1 (SKI-1)/site-1 protease (S1P). Here we conducted a systematic and quantitative analysis of SKI-1/S1P processing of peptides derived from the recognition sites of GPCs of different Old World and New World arenaviruses...
Hemorrhagic fevers caused by arenaviruses are among the most devastating emerging human diseases. Considering the number of individuals affected, the current lack of a licensed vaccine, and the limited therapeutic options, arenaviruses are arguably among the most neglected tropical pathogens and the development of efficacious anti-arenaviral drugs is of high priority. Over the past years significant...
Ten years ago, the first cellular receptor for the prototypic arenavirus lymphocytic choriomeningitis virus (LCMV) and the highly pathogenic Lassa virus (LASV) was identified as α-dystroglycan (α-DG), a versatile receptor for proteins of the extracellular matrix (ECM). Biochemical analysis of the interaction of α-DG with arenaviruses and ECM proteins revealed a strikingly similar mechanism of receptor...
The prototypic arenavirus lymphocytic choriomeningitis virus (LCMV) represents a powerful experimental model for the study of the basic virology and pathogenesis of arenaviruses. In the present study, we used the LCMV model to evaluate the anti-viral potential of phosphorothioate oligonucleotides against arenaviruses. Our findings indicate that amphipathic DNA polymers (APs) are potent inhibitors...
We have previously shown that mutations of CD14 or TLR4 impair type I interferon (IFN) production and macrophage survival during infection with vesicular stomatitis virus (VSV). We now report that VSV glycoprotein G (gpG) is essential for the induction of a previously unrecognized CD14/TLR4-dependent response pathway in which the adapter TRAM has predominant importance, absent any need for MyD88 or...
The New World arenaviruses Junin, Machupo, and Guanarito are the causative agents of hemorrhagic fevers (HF) with high mortality in humans. The cellular receptor for Old World arenaviruses and one subgroup of the New World arenaviruses (Clade C) have been identified as α-dystroglycan (α-DG). In contrast, the receptor(s) of the South American HF viruses, which belong to the Clade B New World arenaviruses,...
Long-term infections with viruses permit the generation of variants that evolve specific growth advantages in certain tissues and may show altered disease potentials. The selection of such variants is influenced by the host tissue and often involves virus-receptor interactions. Here we report studies of receptor usage by several lymphocytic choriomeningitis virus (LCMV) isolates that expressed different...
We report the electron microscopic structure of an α-dystroglycan (α-DG) fragment (DGEKFc4) that contains binding sites for lymphocytic choriomeningitis virus (LCMV) and the extracellular matrix (ECM) molecule laminin. In electron microscopic images, DGEKFc4 appears as dumbbell-shaped rods with a length of 7.5 +/- 0.5 nM and width of 3 +/- 0.3 nM. The C-terminal human Fc allows binding of anti-human...
Dystroglycan (DG) is a highly versatile cell surface molecule that provides a molecular link between the extracellular matrix (ECM) and the actin-based cytoskeleton. Encoded by a single gene, DG is posttranslationally processed to form α-DG, a peripheral protein identified as the cellular receptor for lymphocytic choriomeningitis virus (LCMV) and Lassa fever virus (LFV), and the membrane-spanning...
The glycoprotein (GP) of lymphocytic choriomeningitis virus (LCMV) serves as virus attachment protein to its receptor on host cells and is a key determinant for cell tropism, pathogenesis, and epidemiology of the virus. The GP of LCMV is posttranslationally cleaved by the subtilase SKI-1/S1P into two subunits, the peripheral GP1, which is implicated in receptor binding, and the transmembrane GP2 that...
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