Upd-like/JAK/STAT signaling promotes regeneration and tolerance to bacterial infection in the Aedes midgut

Aedes aegypti, a major vector of arboviruses, relies on its midgut as a key interface with microbial communities that influence vector competence. While ingestion of pathogenic bacteria is known to trigger both immune and regenerative responses in the mosquito gut, the signaling pathways that govern epithelial renewal remain poorly defined. Here, we address this gap by performing transcriptomic profiling of the Aedes aegypti midgut following oral infection with entomopathogenic bacteria. We uncover a broad transcriptional activation of immune pathways, including IMD, Toll, and notably, the JAK-STAT signaling cascade. Functional knockdown experiments reveal that JAK-STAT signaling is essential for infection-induced epithelial cell proliferation and survival, but dispensable for bacterial clearance, supporting a specialized role in tissue repair and infection tolerance. We further identify a previously uncharacterized cytokine-like gene, Upd-like, structurally related to Drosophila Unpaired proteins and mammalian cytokines, which is strongly induced upon bacterial challenge and activates JAK-STAT signaling in mosquito cells. Silencing Upd-like markedly impairs epithelial regeneration after infection, establishing it as a key regulator of gut homeostasis. Together, these findings demonstrate a conserved function for JAK-STAT signaling in midgut epithelial renewal and identify Upd-like as a novel cytokine mediating regenerative responses during bacterial infection.