Host serum-circulating flavivirus NS1 co-opts mosquito miRNA processing to suppress early immune defense.

Flaviviruses pose growing global health threats and are transmitted by Aedes mosquitoes. Yet, how these viruses overcome early mosquito immunity remains unclear. Here, we reveal a cross-host immune evasion strategy in which the flavivirus NS1 protein, abundantly secreted into infected human serum, is taken up by mosquitoes during blood feeding and rapidly internalized into midgut epithelial cells-prior to viral replication. NS1 hijacks the mosquito spliceosome-associated factor Prp19 to promote miR-275-5p maturation, which suppresses the caspase gene CASPS19, blocking apoptosis and enabling early viral replication. Engineered mosquitoes expressing a miR-275 sponge show enhanced resistance to dengue and Zika viruses. These findings uncover a mechanism by which a viral protein presented in infected host blood reprograms vector gene regulation, establishing a paradigm of cross-species immune manipulation by flaviviruses.