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Summary: Understanding the transmission routes of arboviruses is key to determining their epidemiology. Here, we tested whether West Nile viruses (WNVs) are transmitted through mosquito excreta. First, we observed a high concentration of infectious units per excreta, although viruses were short lived. Second, we showed that virion excretion starts early after oral infection and remains constant for a long period, regardless of mosquito infection level. These results highlight the infectiousness of excreta from infected mosquitoes. Third, we found that both larvae and pupae were susceptible to infection, while pupae were highly permissive. Fourth, we established the proof-of-concept that immature mosquitoes can be infected by infectious excreta, demonstrating an excreta-mediated mode of transmission. Finally, by mathematically modeling excreta-mediated transmission in the field, we demonstrated that WNV can be transmitted within mosquito populations. Our study uncovers a route of transmission for mosquito-borne arboviruses, unveiling mechanisms of viral maintenance in mosquito reservoirs.

Summary: 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 mosquito midgut 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 transmission-blocking agent by inhibiting plasmin proteolysis. Our results indicate that dengue pathogenesis enhances DENV fitness by increasing its infectivity to mosquitoes. : Virology; Entomology Subject Areas: Virology, Entomology

Summary: ZIKA virus (ZIKV) is an emerging pathogen responsible for neurological disorders and congenital microcephaly. However, the molecular basis for ZIKV neurotropism remains poorly understood. Here, we show that Axl is expressed in human microglia and astrocytes in the developing brain and that it mediates ZIKV infection of glial cells. Axl-mediated ZIKV entry requires the Axl ligand Gas6, which bridges ZIKV particles to glial cells. Following binding, ZIKV is internalized through clathrin-mediated endocytosis and traffics to Rab5+ endosomes to establish productive infection. During entry, the ZIKV/Gas6 complex activates Axl kinase activity, which downmodulates interferon signaling and facilitates infection. ZIKV infection of human glial cells is inhibited by MYD1, an engineered Axl decoy receptor, and by the Axl kinase inhibitor R428. Our results highlight the dual role of Axl during ZIKV infection of glial cells: promoting viral entry and modulating innate immune responses. Therefore, inhibiting Axl function may represent a potential target for future antiviral therapies. : ZIKA virus (ZIKV) is responsible for congenital microcephaly. Meertens et al. show that the Axl receptor is expressed in microglia and astrocytes in the human developing brain. They also highlight the dual role of Axl during infection, which promotes viral entry and dampens innate immune responses in glial cells.