Transmission-Blocking Antibodies against Mosquito C-Type Lectins for Dengue Prevention

C-type lectins are a family of proteins with carbohydrate-binding activity. Several C-type lectins in mammals or arthropods are employed as receptors or attachment factors to facilitate flavivirus invasion. We previously identified a C-type lectin in Aedes aegypti, designated as mosquito galactose specific C-type lectin-1 (mosGCTL-1), facilitating the attachment of West Nile virus (WNV) on the cell membrane. Here, we first identified that 9 A. aegypti mosGCTL genes were key susceptibility factors facilitating DENV-2 infection, of which mosGCTL-3 exhibited the most significant effect. We found that mosGCTL-3 was induced in mosquito tissues with DENV-2 infection, and that the protein interacted with DENV-2 surface envelop (E) protein and virions in vitro and in vivo. In addition, the other identified mosGCTLs interacted with the DENV-2 E protein, indicating that DENV may employ multiple mosGCTLs as ligands to promote the infection of vectors. The vectorial susceptibility factors that facilitate pathogen invasion may potentially be explored as a target to disrupt the acquisition of microbes from the vertebrate host. Indeed, membrane blood feeding of antisera against mosGCTLs dramatically reduced mosquito infective ratio. Hence, the immunization against mosGCTLs is a feasible approach for preventing dengue infection. Our study provides a future avenue for developing a transmission-blocking vaccine that interrupts the life cycle of dengue virus and reduces disease burden. Author Summary Dengue virus (DENV), a mosquito-borne flavivirus, is currently the most significant arbovirus afflicting tropical and sub-tropical countries worldwide. No vaccine or therapeutics are available, and dengue has rapidly spread over the last decade. Therefore, additional strategies to combat dengue are urgently needed. In this study, we characterized multiple C-type lectins as susceptibility factors for dengue infection in A. aegypti. These mosGCTLs directly interacted with dengue virus in vitro and in vivo. The combination of antisera against multiple mosGCTLs efficiently reduced DENV-2 infection after a blood meal, suggesting that it is feasible to develop a mosGCTL-based transmission-blocking vaccine to interrupt the life cycle of dengue virus and control disease burden in nature. This study substantially extends our understanding of dengue replication in vectors and provides a research avenue by which the development of therapeutics for preventing the dissemination of mosquito-borne viral diseases can be pursued in the future.