Dengue symptoms include alteration of blood coagulation and fibrinolysis, causing severe hemorrhage
and death. Here, we demonstrate that higher concentration of plasmin, the human fibrinolytic
factor, in blood meal enhances dengue virus (DENV) infection in mosquitomidgut and dissemination in
mosquitoes. We also show that mosquitoes express a plasmin-selective Kazal-type inhibitor (AaTI) in
the midgut to inhibit plasmin proteolysis and revert the enhanced infection. Using bio-layer interferometry,
we show that DENV, plasmin, and AaTI interact to form a tripartite complex. Eventually,
plasmin increases midgut internalization of dextran molecules and this is reverted by AaTI. Our study
demonstrates that (1) DENV recruits plasmin to increase local proteolytic activity in the midgut, thus
degrading the glycocalyx and enhancing DENV internalization and (2) AaTI can act as a transmissionblocking
agent by inhibiting plasmin proteolysis. Our results indicate that dengue pathogenesis
enhances DENV fitness by increasing its infectivity to mosquitoes.