Repeated Exposure to <i>Lutzomyia intermedia</i> Sand Fly Saliva Induces Local Expression of Interferon-Inducible Genes Both at the Site of Injection in Mice and in Human Blood

<div><p>During a blood meal, <i>Lutzomyia intermedia</i> sand flies transmit <i>Leishmania braziliensis</i>, a parasite causing tegumentary leishmaniasis. In experimental leishmaniasis, pre-exposure to saliva of most blood-feeding sand flies results in parasite establishment in absence of any skin damages in mice challenged with dermotropic <i>Leishmania</i> species together with saliva. In contrast, pre-immunization with <i>Lu. intermedia</i> salivary gland sonicate (SGS) results in enhanced skin inflammatory exacerbation upon co-inoculation of <i>Lu. intermedia</i> SGS and <i>L. braziliensis</i>. These data highlight potential unique features of both <i>L. braziliensis</i> and <i>Lu. intermedia</i>. In this study, we investigated the genes modulated by <i>Lu. intermedia</i> SGS immunization to understand their potential impact on the subsequent cutaneous immune response following inoculation of both SGS and <i>L. braziliensis</i>. The cellular recruitment and global gene expression profile was analyzed in mice repeatedly inoculated or not with <i>Lu. intermedia</i>. Microarray gene analysis revealed the upregulation of a distinct set of IFN-inducible genes, an immune signature not seen to the same extent in control animals. Of note this INF-inducible gene set was not induced in SGS pre-immunized mice subsequently co-inoculated with SGS and <i>L. braziliensis</i>. These data suggest the parasite prevented the upregulation of this <i>Lu. intermedia</i> saliva-related immune signature. The presence of these IFN-inducible genes was further analyzed in peripheral blood mononuclear cells (PBMCs) sampled from uninfected human individuals living in a <i>L. braziliensis</i>-endemic region of Brazil thus regularly exposed to <i>Lu. intermedia</i> bites. PBMCs were cultured in presence or absence of <i>Lu. intermedia</i> SGS. Using qRT-PCR we established that the IFN-inducible genes induced in the skin of SGS pre-immunized mice, were also upregulated by SGS in PBMCs from human individuals regularly exposed to <i>Lu. intermedia</i> bites, but not in PBMCs of control subjects. These data demonstrate that repeated exposure to <i>Lu. intermedia</i> SGS induces the expression of potentially host-protective IFN-inducible genes.</p>