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Saliva from the mosquito vector of flaviviruses is capable of changing the local immune environment, leading to an increase of flavivirus-susceptible cells at the infected bite site. Additionally, an antibody response towards specific salivary gland (SG) components changes the pathogenesis of flavivirus in human populations. To investigate if antigenic SG proteins are capable of enhancing Zika virus (ZIKV) infection, a re-emerging flavivirus primarily transmitted by the Aedes aegypti mosquito, we screened for antigenic SG proteins using a yeast display library, and demonstrate a previously undescribed SG protein, we term neutrophil stimulating factor 1 (NeSt1), activates primary mouse neutrophils ex vivo. Passive immunization against NeSt1 decreases pro-IL-1β and CXCL2 expression, prevents macrophages from infiltrating into the bite site, protects susceptible IFNAR-/-IFNGR-/- (AG129) mice from early ZIKV replication, and ameliorates viral-induced pathogenesis. These findings indicate that NeSt1 stimulates neutrophils at the mosquito bite site to change the immune microenviroment, allowing higher early viral replication and enhancing ZIKV pathogenesis. (156 Words) [ABSTRACT FROM AUTHOR]