title: Lutzomyia longipalpis saliva drives apoptosis and enhances parasite burden in neutrophils.
abstract: Neutrophils are considered the host's first line of defense against infections and have been implicated in the immunopathogenesis of Leishmaniasis. Leishmania parasites are inoculated alongside vectors' saliva, which is a rich source of pharmacologically active substances that interfere with host immune response. In the present study, we tested the hypothesis that salivary components from Lutzomyia longipalpis, an important vector of visceral Leishmaniasis, enhance neutrophil apoptosis. Murine inflammatory peritoneal neutrophils cultured in the presence of SGS presented increased surface expression of FasL and underwent caspase-dependent and FasL-mediated apoptosis. This proapoptosis effect of SGS on neutrophils was abrogated by pretreatment with protease as well as preincubation with antisaliva antibodies. Furthermore, in the presence of Leishmania chagasi, SGS also increased apoptosis on neutrophils and increased PGE(2) release and decreased ROS production by neutrophils, while enhancing parasite viability inside these cells. The increased parasite burden was abrogated by treatment with z-VAD, a pan caspase inhibitor, and NS-398, a COX-2 inhibitor. In the presence of SGS, Leishmania-infected neutrophils produced higher levels of MCP-1 and attracted a high number of macrophages by chemotaxis in vitro assays. Both of these events were abrogated by pretreatment of neutrophils with bindarit, an inhibitor of CCL2/MCP-1 expression. Taken together, our data support the hypothesis that vector salivary proteins trigger caspase-dependent and FasL-mediated apoptosis, thereby favoring Leishmania survival inside neutrophils, which may represent an important mechanism for the establishment of Leishmania infection.
authors.affiliation: Centro de Pesquisa Goncalo Moniz -Fundacao Oswaldo Cruz, Salvador, Brazil.
authors.forename: Deboraci Brito
authors.initials: DB
authors.lastname: Prates
authors.forename: Théo
authors.initials: T
authors.lastname: Araújo-Santos
authors.forename: Nívea Farias
authors.initials: NF
authors.lastname: Luz
authors.forename: Bruno B
authors.initials: BB
authors.lastname: Andrade
authors.forename: Jaqueline
authors.initials: J
authors.lastname: França-Costa
authors.forename: Lilian
authors.initials: L
authors.lastname: Afonso
authors.forename: Jorge
authors.initials: J
authors.lastname: Clarêncio
authors.forename: José Carlos
authors.initials: JC
authors.lastname: Miranda
authors.forename: Patrícia T
authors.initials: PT
authors.lastname: Bozza
authors.forename: George A
authors.initials: GA
authors.lastname: Dosreis
authors.forename: Cláudia
authors.initials: C
authors.lastname: Brodskyn
authors.forename: Manoel
authors.initials: M
authors.lastname: Barral-Netto
authors.forename: Valéria Matos
authors.initials: VM
authors.lastname: Borges
authors.forename: Valéria de Matos
authors.initials: VM
authors.lastname: Borges
authors.forename: Aldina
authors.initials: A
authors.lastname: Barral
mesh_terms: D000818:Animals; D017209:Apoptosis; D020169:Caspases / Q000378:metabolism; D018932:Chemokine CCL2 / Q000378:metabolism; D002633:Chemotaxis; D053222:Fas Ligand Protein / Q000378:metabolism; D005260:Female; D006790:Host-Parasite Interactions; D015151:Immunoblotting; D007891:Leishmania; D007896:Leishmaniasis / Q000276:immunology* / Q000469:parasitology; D008264:Macrophages / Q000276:immunology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009504:Neutrophils / Q000276:immunology / Q000469:parasitology* / Q000473:pathology*; D011576:Psychodidae / Q000276:immunology* / Q000469:parasitology; D017382:Reactive Oxygen Species / Q000378:metabolism; D012463:Saliva / Q000737:chemistry / Q000276:immunology* / Q000469:parasitology; D012469:Salivary Glands / Q000166:cytology / Q000276:immunology / Q000469:parasitology
chemical_list: D018932:Chemokine CCL2; D053222:Fas Ligand Protein; C505658:Fasl protein, mouse; D017382:Reactive Oxygen Species; D020169:Caspases