A mosquito salivary protein-driven influx of myeloid cells facilitates flavivirus transmission

Mosquitoes transmit many disease-relevant flaviviruses. Efficient viral transmission to mammalian hosts requires mosquito salivary factors. However, the specific salivary components facilitating viral transmission and their mechanisms of action remain largely unknown. Here, we show that a female mosquito salivary gland-specific protein, here named A. aegypti Neutrophil Recruitment Protein ( Aa NRP), facilitates the transmission of Zika and dengue viruses. Aa NRP promotes a rapid influx of neutrophils, followed by virus-susceptible myeloid cells toward mosquito bite sites, which facilitates establishment of local infection and systemic dissemination. Mechanistically, Aa NRP engages TLR1 and TLR4 of skin-resident macrophages and activates MyD88-dependent NF-κB signaling to induce the expression of neutrophil chemoattractants. Inhibition of MyD88-NF-κB signaling with the dietary phytochemical resveratrol reduces Aa NRP-mediated enhancement of flavivirus transmission by mosquitoes. These findings exemplify how salivary components can aid viral transmission, and suggest a potential prophylactic target. Synopsis Mosquito saliva contains factors that promote flavivirus infection in the animal host. This study reveals that the mosquito salivary protein Aa NRP mediates cutaneous recruitment of flavivirus-susceptible myeloid cells to mosquito bite sites, thus aiding flavivirus transmission. Aa NRP is a female-mosquito-specific salivary protein. Aa NRP stimulates skin-resident macrophages via TLR1/4-MyD88-NF-κB signaling to release chemoattractants for neutrophils. The Aa NRP-induced influx of myeloid cells promotes flaviviral cutaneous infection. Dietary supplementation with resveratrol suppresses Aa NRP-promoted flavivirus transmission by mosquitoes. Aa NRP is a female-specific mosquito salivary protein that promotes Zika and dengue virus infection by stimulating skin macrophage-dependent neutrophil recruitment.