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Summary Wolbachia- infected mosquitoes are refractory to super-infection with arthropod-borne pathogens, but the role of host cell signaling proteins in pathogen-blocking mechanisms remains to be elucidated. Here, we use an antibody microarray approach to provide a comprehensive picture of the signaling response of Aedes aegypti -derived cells to Wolbachia. This approach identifies the host cell insulin receptor as being downregulated by the bacterium. Furthermore, siRNA-mediated knockdown and treatment with a small-molecule inhibitor of the insulin receptor kinase concur to assign a crucial role for this enzyme in the replication of dengue and Zika viruses in cultured mosquito cells. Finally, we show that the production of Zika virus in Wolbachia -free live mosquitoes is impaired by treatment with the selective inhibitor mimicking Wolbachia infection. This study identifies Wolbachia -mediated downregulation of insulin receptor kinase activity as a mechanism contributing to the blocking of super-infection by arboviruses. Graphical Abstract Highlights • Antibody microarray to investigate mosquito host cell signaling response to Wolbachia • Wolbachia- infected cells show downregulation of the host cell insulin receptor (IR) • Inhibition or silencing of IR impairs the replication of dengue and Zika viruses in vitro • Mosquitoes fed the IR inhibitor have impaired Zika virus replication Wolbachia -infected mosquitoes are deployed in tropical regions to combat arbovirus transmission. However, the mechanism of superinfection blocking is unknown. Haqshenas et al. show that Wolbachia downregulates the mosquito's insulin receptor. Knockdown or inhibition of the mosquito's insulin receptor recapitulates the block of viral infection caused by Wolbachia. [ABSTRACT FROM AUTHOR]