PhD ceremony Mr. J.C. Flipse: Molecular mechanisms of dengue virus infection Cell tropism, antibody-dependent enhancement, and cytokines

Dengue is the most prevalent mosquito-borne viral disease in humans. Although most infections occur in the (sub)tropical areas, recent outbreaks in Italy and Madeira indicate that the virus is spreading into Europe. Despite its relevance, no vaccine or medications are available against this virus. This is, in part, due to its complex pathogenesis. Dengue virus has four serotypes, and protection against one serotype can lead to enhanced disease after infection with another serotype. It is known that antibodies play a pivotal role in the enhanced severity, yet the underlying mechanism is unknown since the 1970’s. To unravel this mechanism, the authors followed the virus step-by-step throughout its life cycle. Surprisingly, antibodies were found to facilitate higher penetration of the virus into the cell yet combined with unaltered binding to the cell. The latter prevents that the cell is alarmed, and thus facilitates higher efficiency of infection. At last, when the cells perceive the infection, they give a disproportional response which culminates into severe disease. Besides this mechanism, the authors also describe the relevance of the cell type that is infected: dendritic cells give high virus production yet the produced virus particles are low-infectious, suggesting that these struggle to continue the infectious process. Macrophages, however, produce less virus particles yet these are more infectious. The results in this thesis provide insights for developing future treatments.