Selective TLR ligand stimulation enhances in vivo mosquito-borne flavivirus pathogenicity

Mosquito saliva facilitates pathogen transmission and enhances the severity of diseases caused by mosquito-borne viruses; however, the underlying mechanisms are unknown. Here, we demonstrate that mosquito salivary gland extracts (SGEs) enhance flaviviral pathogenicity in vivo by activating innate immune responses following the accumulation of immune cells at the infection site. Among the innate immune signaling pathways, the TLR2 pathway enhances flaviviral pathogenicity in a manner similar to that of SGEs. TLR2 ligands and SGEs induce neutrophils to secrete chemokines that recruit virus-permissive monocytes and macrophages to infection sites. SGEs activate TLR2, and inhibition of TLR2 signaling markedly reduces mosquito-saliva-enhanced viral pathogenicity. Overall, this study provides important insights into vector-host interactions and suggests that TLR2 is a potential target for preventing mosquito-borne flaviviral infection.