Speaker: Dr. Stefan Kunz
Institut de Microbiologie, Centre
Hospitalier Universitaire Vaudois
Lausanne, Switzerland

Host

Núria Verdaguer
IBMB-CSIC

Wednesday, 1 October 2008, 9:30h Aula Fèlix Serratosa

Abstract

Several arenaviruses cause severe hemorrhagic fevers with high mortality in humans. The most prevalent human pathogen among the arenaviruses is the Old World arenavirus Lassa virus with over 500, 000 infections and thousands of death annually. In the Americas, the South American hemorrhagic fever viruses Junin, Machupo, and Guanarito have emerged as etiological agents of severe hemorrhagic fevers. Human pathogenic arenaviruses are highly lethal because they multiply rapidly and overwhelm the patient’s immune defense, resulting in uncontrolled fatal infection. A promising step of therapeutic intervention is therefore the first step of virus infection.

One part of our research focuses on the characterization of the cell surface receptors of pathogenic arenaviruses and the investigation of the cellular mechanisms of arenavirus entry. The cellular receptor for Lassa virus is α-dystroglycan (α-DG), a cell surface receptor for proteins of the extracellular matrix (ECM). Our recent studies showed that Lassa virus closely mimics the molecular mechanism of receptor recognition used by α-DG's ECM ligands with important implications for virus-host cell interaction and co-evolution. Upon receptor binding, LASV is internalized by endocytosis and delivered to endosomes, where pH-dependent fusion of viral envelope and cellular membrane occur. We discovered that LASV enters cells by a novel endocytotic pathway independent of clathrin and caveolin that delivers the virus to endosomes bypassing classical routes of incoming vesicular trafficking.

A major goal of our research is the development of novel anti-viral drugs able to block cell entry of human pathogenic arenaviruses. Using high-throughput screening assays for combinatorial small molecule libraries, we have identified a number of potent entry inhibitors that block entry of LASV into human cells. Our most potent lead compounds inhibit viral entry at the level of membrane fusion and are active against all major human pathogenic arenaviruses, which is remarkable considering the structural and genetic differences between these viruses.

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