Human sand fly challenge elicits saliva-specific innate and TH1-polarized immunity that promotes Leishmania killing.

In Leishmania-endemic areas, humans are constantly exposed to sand fly bites. To explore the immune consequences of this chronic vector exposure, we performed a human challenge study with the sand fly Lutzomyia longipalpis. Peripheral blood mononuclear cells were collected from fifteen healthy volunteers who underwent multiple controlled exposures to sand fly bites. We identified two Lu. longipalpis salivary proteins, LJM19 and LJL143, which elicited T_H1-polarized cytokine responses in cells from exposed individuals and which correlated with enhanced killing of Leishmania parasites in co-cultured macrophages. Interestingly, LJM19 also exerted this parasite-killing effect in cells from unexposed individuals, consistent with innate immune activation. In support of this, both LJM19 and LJL143 stimulated the production of the innate cytokines IL-1β and IFN-α. Our results demonstrate that repeated exposure to sand fly bites induces innate and adaptive cytokine responses to vector salivary proteins that can be co-opted to protect humans against Leishmania infection.