AUTHOR=Luz Nivea F. , DeSouza-Vieira Thiago , De Castro Waldione , Vivarini Aislan Carvalho , Pereira Lais , França Riam Rocha , Silveira-Mattos Paulo S. , Costa Diego L. , Teixeira Clarissa , Meneses Claudio , Boaventura Viviane S. , de Oliveira Camila I. , Lopes Ulisses Gazos , Aronson Naomi , Andrade Bruno B. , Brodskyn Claudia I. , Valenzuela Jesus G. , Kamhawi Shaden , Borges Valeria M. TITLE=Lutzomyia longipalpis Saliva Induces Heme Oxygenase-1 Expression at Bite Sites JOURNAL=Frontiers in Immunology VOLUME=9 YEAR=2018 URL=https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2018.02779 DOI=10.3389/fimmu.2018.02779 ISSN=1664-3224 ABSTRACT=

Sand flies bite mammalian hosts to obtain a blood meal, driving changes in the host inflammatory response that support the establishment of Leishmania infection. This effect is partially attributed to components of sand fly saliva, which are able to recruit and activate leukocytes. Our group has shown that heme oxygenase-1 (HO-1) favors Leishmania survival in infected cells by reducing inflammatory responses. Here, we show that exposure to sand fly bites is associated with induction of HO-1 in vivo. Histopathological analyses of skin specimens from human volunteers experimentally exposed to sand fly bites revealed that HO-1 and Nrf2 are produced at bite sites in the skin. These results were recapitulated in mice ears injected with a salivary gland sonicate (SGS) or exposed to sand fly bites, indicating that vector saliva may be a key factor in triggering HO-1 expression. Resident skin macrophages were the main source HO-1 at 24–48 h after bites. Additionally, assays in vivo after bites and in vitro after stimulation with saliva both demonstrated that HO-1 production by macrophages was Nrf2-dependent. Collectively, our data demonstrates that vector saliva induces early HO-1 production at the bite sites, representing a major event associated with establishment of naturally-transmitted Leishmania infections.