A gut commensal Serratia marcescens inhibits dengue virus infection via prodigiosin-induced autophagy in Aedes albopictus

Abstract

ABSTRACT The mosquito gut microbiota plays a pivotal role in regulating arbovirus transmission, yet the specific antiviral metabolites produced by native symbiotic bacteria and their underlying mechanisms remain poorly understood. In this study, we isolated a natural gut symbiotic bacterium, Serratia marcescens strain WZ1, from field-caught Aedes albopictus in Wenzhou, China, and demonstrated its potent ability to inhibit dengue virus (DENV) infection. Through integrated metabolomic analysis, we identified the red pigment prodigiosin (PG) as a functional antiviral metabolite secreted by this strain. PG treatment suppressed DENV infection in mosquito cells in a dose- and time-dependent manner and significantly reduced DENV2 RNA levels in adult Ae. albopictus midguts. Mechanistic investigations revealed that PG preferentially localizes to the endoplasmic reticulum (ER), where it induces ER stress and upregulates the chaperone protein GRP78. This process subsequently activates a complete autophagic flux, as evidenced by enhanced conversion of Atg8-I to Atg8-II, increased autophagosome formation, and elevated lysosomal activity. Crucially, we further demonstrated that PG facilitates the convergence of autophagosomes and lysosomes, culminating in the colocalization of DENV with lysosomal compartments and subsequent viral clearance. Both genetic knockdown of the autophagy gene Atg8 and pharmacological inhibition of ER stress substantially attenuated PG-mediated viral suppression, confirming the functional link between PG-induced ER stress, autophagy activation, and viral clearance. Our findings elucidate a novel mechanism by which a native mosquito gut symbiont metabolite restricts arboviral infection through activation of the host ER stress–autophagy pathway, providing a mechanistic basis and candidate leads for future transmission-blocking studies.