Dengue virus infection of dendritic cells Sensing viral replication during inflammation and immunity

Human may see themselves as superior life forms on this planet, but – even after centuries of medical progress – we are still under continuous threat from viruses. Dengue virus is a prime example that infects over 400 million people annually and for which no antiviral medicines or vaccines exist. It is transmitted by mosquitos that inject dengue virus in the skin, which is lined with dendritic cells; immune cells that detect invading pathogens and transmit information to other immune cells in lymph nodes to activate systemic immune responses. This thesis starts with an overview of the current knowledge of the immune response against dengue virus, which is followed by an investigation of the interaction between immune receptor CLEC5A and dengue virus. CLEC5A appeared to play a minor role in the immune response against dengue virus in human skin. In contrast, dendritic cells used RNA sensors RIG-I and MDA5 to detect dengue virus. This activated two signaling cascades that 1) lead to inflammatory responses with the risk of developing life-threatening dengue shock syndrome and 2) an antiviral immune response that was characterized by type I IFN and the development of specific white blood cells, called follicular T helper cells, that stimulated the production of antibodies. The research described in this thesis thereby identifies how dendritic cells induce detrimental inflammatory responses as well as protective immune responses against dengue virus, which can be used to develop novel drugs that limit the detrimental immune response and boos the protective immune response against dengue virus.