A female mosquito salivary protein-driven influx of myeloid cells facilitates flavivirus transmission
Mosquitoes transmit many flaviviruses of global public health significance. Efficient viral transmission to mammalian hosts requires mosquito salivary factors that modulate local host responses, such as recruitment of virus-permissive myeloid cells to the bite sites. However, the specific salivary components facilitating viral transmission and their mechanisms of action remain largely unknown. Here, we showed that a female mosquito salivary gland-specific protein, named Aedes aegypti Neutrophil Recruitment Protein (AaNRP), acts as a key salivary component to facilitate the transmission of Zika (ZIKV) and dengue (DENV) viruses. AaNRP promotes a rapid influx of neutrophils followed by virus-susceptible myeloid cells toward mosquito bite sites, which facilitate establishment of local infection and systemic dissemination. Mechanistically, AaNRP engages TLR1 and TLR4 of skin resident macrophages and activates MyD88-dependent NF-?B signaling to induce the expression of neutrophil chemoattractants. Inhibition of MyD88-NF-?B with dietary resveratrol, a phytochemical, neutralizes the AaNRP effects, thus reducing flavivirus transmission by mosquitoes. This study offers mechanistic insight into saliva-aided viral transmission and provides a potential prophylactic target. Overall design: We investigated the underlying mechanism of the mosquito bite-mediated promotion of neutrophil infiltration by a single-cell RNA sequencing (scRNA-Seq). The skin of mouse footpads at 4 hpb or without mosquito bites was isolated for enzymatic digestion. The total skin CD45+ immunocytes were flow-sorted and subjected to 10x genomics scRNA-Seq.