Graphical Abstract Highlights d The gut commensal Serratia marcescens promotes mosquito permissiveness to arboviruses d S. marcescens facilitates arboviral infection via a secreted protein named SmEnhancin d SmEnhancin digests gut membrane-bound mucins to enhance viral dissemination in mosquitoes d S. marcescens enhances the susceptibility of field mosquitoes to dengue virus In Brief Wu et al. identified Serratia marcescens as a mosquito gut commensal bacterium critical for efficient arboviral acquisition. S. marcescens facilitates arboviral infection through secretion of a protein named SmEnhancin. Colonization of S. marcescens in field-derived Aedes mosquitoes enhances vector competence. Gut residence of S. marcescens correlates with regionspecific dengue prevalence.

Transmission from an infected mosquito to a host is an essential process in the life cycle of mosquito-borne flaviviruses. Numerous studies have demonstrated that mosquito saliva facilitates viral transmission. Here we find that a saliva-specific protein, named Aedes aegypti venom allergen-1 (AaVA-1), promotes dengue and Zika virus transmission by activating autophagy in host immune cells of the monocyte lineage. The AG6 mice (ifnar1–/–ifngr1–/–) bitten by the virus-infected AaVA-1-deficient mosquitoes present a lower viremia and prolonged survival. AaVA-1 intracellularly interacts with a dominant negative binder of Beclin-1, known as leucine-rich pentatricopeptide repeat-containing protein (LRPPRC), and releases Beclin-1 from LRPPRC-mediated sequestration, thereby enabling the initialization of downstream autophagic signaling. A deficiency in Beclin-1 reduces viral infection in mice and abolishes AaVA-1-mediated enhancement of ZIKV transmission by mosquitoes. Our study provides a mechanistic insight into saliva-aided viral transmission and could offer a potential prophylactic target for reducing flavivirus transmission.