Lay summary
Old World arenaviruses include the prototypic lymphocytic choriomeningitis virus (LCMV) and the highly pathogenic Lassa virus (LASV) that causes a severe hemorrhagic fever in humans and infects several thousand individuals per year in Western Africa. There is currently no vaccine available and therapeutic intervention is limited resulting in a mortality of 15-30% among hospitalized Lassa fever patients. Considering the number of people affected and the unaddressed need for better therapeutics, Lassa fever is arguably one of the most neglected tropical diseases. Cell entry of a virus is the first step of every virus infection and represents a promising target for therapeutic intervention. To invade host cell, viruses can hijack the cellular machinery that is normally responsible for the transport of nutrients and cellular cargo like membrane lipids and proteins. We and others have shown that LCMV and LASV attach to a cellular receptor, followed by internalization via a novel and unusual pathway. In this project we will investigate the largely unknown molecular mechanisms of cell entry of LASV and LCMV with the goal to identify host cell factors involved. In our first aim we will study the role of cellular proteins that are involved in the host cells' transport mechanisms to identify factors hijacked by the virus. Since cellular transport mechanisms are subject to tight regulation, we will identify signaling molecules required for viral entry. Among the first targets of LASV are antigen-presenting cells of the host's immune system, in particular dendritic cells. Infection of this crucial immune-regulatory cell population is a key event early in disease. Instead of being taken up and presented as a foreign antigen, the virus can escape from immune detection and degradation and establish a productive infection in dendritic cells, perturbing their function. Using a combination of state-of-the art methods, we will investigate how viruses can evade from the mechanisms of pathogen recognition in dendritic cells and how they manage to invade the cell without being degraded by the antigen-processing machinery. The results of our studies will illuminate basic aspects of the host cell interaction of these important human pathogens. Cellular factors essential for host cell invasion discovered in our studies will then be evaluated as novel targets for therapeutic intervention.