Engineering Upd-like to broadly restrict arbovirus infection and vector competence in mosquitoes

Abstract

The global expansion of mosquito-borne viruses poses a growing threat to public health, yet the endogenous signals that activate antiviral immunity in mosquito vectors remain incompletely understood. Here, we identify Aedes aegypti Upd as an activator of JAK/STAT signaling that restricts arbovirus infection. Loss of Upd increased infection and dissemination of the flaviviruses ZIKV and DENV, as well as the alphavirus SINV, whereas blood meal inducible midgut overexpression reduced ZIKV and SINV infection. Mechanistically, Upd associated with the extracellular region of the Domeless (Dome) receptor, and Upd deficiency markedly reduced STAT phosphorylation and nuclear accumulation in the midgut. Upd expression was transiently induced in the midgut by an uninfected blood meal but remained elevated following ZIKV challenge, linking physiological responses to blood feeding with antiviral defense. In mammal mosquito transmission models, Upd overexpression reduced viral acquisition from infected hosts, whereas Upd deficiency enhanced viral dissemination and increased transmission following systemic infection. Together, these findings identify Upd as an endogenous regulator of mosquito JAK/STAT signaling and provide proof of principle that temporally targeted Upd expression can reduce arbovirus susceptibility and vector competence.