Lutzomyia longipalpis Saliva Induces Heme Oxygenase-1 Expression at Bite Sites

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

Lutzomyia longipalpis Saliva Induces Heme Oxygenase-1 Expression at Bite Sites

Submitted by Ana Maria Fiscina Sampaio ([email protected]) on 2018-12-19T16:23:43Z No. of bitstreams: 1 Luz NF. Lutzomyia longipalpis saliva...2018.pdf: 1955626 bytes, checksum: f84660a8c004e77cec0bb334c37bb074 (MD5)Approved for entry into archive by Ana Maria Fiscina Sampaio ([email protected]) on 2018-12-19T16:46:42Z (GMT) No. of bitstreams: 1 Luz NF. Lutzomyia longipalpis saliva...2018.pdf: 1955626 bytes, checksum: f84660a8c004e77cec0bb334c37bb074 (MD5)Made available in DSpace on 2018-12-19T16:46:42Z (GMT). No. of bitstreams: 1 Luz NF. Lutzomyia longipalpis saliva...2018.pdf: 1955626 bytes, checksum: f84660a8c004e77cec0bb334c37bb074 (MD5) Previous issue date: 2018Fundação de Amparo a Pesquisa do Estado da Bahia (FAPESB) e Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq), and by the Intramural Research Program of the NIH, National Institute of Allergy and Infectious Diseases. This study was financed in part by the Coordenação de Aperfeiçoamento de Pessoal de Nível Superior - Brasil (CAPES) - Finance Code 001. NL is a fellowship recipient from CAPES Brazil; PM is a fellowship recipient from FAPESB; AV is a fellowship recipient from Programa Nacional de Pós-Doutorado/CAPES; CdO, UL, CB and VMB are senior investigators of CNPq.Fundação Oswaldo Cruz. Instituto Gonçalo Moniz. Salvador, BA, Brasil.National Institutes of Health. National Institute of Allergy and Infectious Diseases. Laboratory of Malaria and Vector Research. Vector Molecular Biology Section. Rockville, MD, United States.National Institutes of Health. National Institute of Allergy and Infectious Diseases. Laboratory of Malaria and Vector Research. Vector Molecular Biology Section. Rockville, MD, USA.Federal University of Rio de Janeiro. Carlos Chagas Filho Biophysics Institute. Laboratory of Molecular Parasitology, Center of Health Science. Rio de Janeiro, RJ, Brazil.National Institutes of Health. National Institute of Allergy and Infectious Diseases. Laboratory of Malaria and Vector Research. Vector Molecular Biology Section. Rockville, MD, USA.Fundação Oswaldo Cruz. Instituto Gonçalo Moniz. Salvador, BA, Brasil / Universidade Federal da Bahia. Faculdade de Medicina. Salvador, BA, Brasil.Fundação Oswaldo Cruz. Instituto Gonçalo Moniz. Salvador, BA, Brasil / Universidade Federal da Bahia. Faculdade de Medicina. Salvador, BA, Brasil.National Institutes of Health. National Institute of Allergy and Infectious Diseases. Laboratory of Parasitic Diseases, Immunobiology Section. Bethesda, MD, USA.Fundação Oswaldo Cruz. Teresina, PI, Brasil.National Institutes of Health. National Institute of Allergy and Infectious Diseases. Laboratory of Malaria and Vector Research. Vector Molecular Biology Section. Rockville, MD, USA.Fundação Oswaldo Cruz. Instituto Gonçalo Moniz. Salvador, BA, Brasil / Universidade Federal da Bahia. Faculdade de Medicina. Salvador, BA, Brasil.Fundação Oswaldo Cruz. Instituto Gonçalo Moniz. Salvador, BA, Brasil / Universidade Federal da Bahia. Faculdade de Medicina. Salvador, BA, Brasil.Federal University of Rio de Janeiro. Carlos Chagas Filho Biophysics Institute. Laboratory of Molecular Parasitology, Center of Health Science. Rio de Janeiro, RJ, Brazil.Uniformed Services University of the Health Sciences. Infectious Diseases Division. Bethesda, MD, USA.Fundação Oswaldo Cruz. Instituto Gonçalo Moniz. Salvador, BA, Brasil / Universidade Federal da Bahia. Faculdade de Medicina. Salvador, BA, Brasil / Fundação José Silveira, Bahia. Multinational Organization Network Sponsoring Translational and Epidemiological Research. Salvador, BA, Brasil.Fundação Oswaldo Cruz. Instituto Gonçalo Moniz. Salvador, BA, Brasil / Universidade Federal da Bahia. Faculdade de Medicina. Salvador, BA, Brasil.National Institutes of Health. National Institute of Allergy and Infectious Diseases. Laboratory of Malaria and Vector Research. Vector Molecular Biology Section. Rockville, MD, USA.National Institutes of Health. National Institute of Allergy and Infectious Diseases. Laboratory of Malaria and Vector Research. Vector Molecular Biology Section. Rockville, MD, United States.Fundação Oswaldo Cruz. Instituto Gonçalo Moniz. Salvador, BA, Brasil / Universidade Federal da Bahia. Faculdade de Medicina. Salvador, BA, Brasil.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