title: Nucleosides present on phlebotomine saliva induce immunossuppression and promote the infection establishment.
abstract: BACKGROUND
  Sand fly saliva plays a crucial role in establishing Leishmania infection. We identified adenosine (ADO) and adenosine monophosphate (AMP) as active pharmacologic compounds present in Phlebotomus papatasi saliva that inhibit dendritic cell (DC) functions through a PGE2/IL 10-dependent mechanism.
  
  
  RESULTS
  Herein, we prepared a mixture of ADO and AMP in equimolar amounts similar to those present in the salivary-gland extract (SGE) form one pair of salivary glands of P. papatasi and co-injected it with Leishmania amazonensis or L. major into mouse ears. ADO+AMP mimicked exacerbative effects of P. papatasi saliva in leishmaniasis, increasing parasite burden and cutaneous lesions. Enzymatic catabolism of salivary nucleosides reversed the SGE-induced immunosuppressive effect associated with IL-10 enhancement. Immunosuppressive factors COX2 and IL-10 were upregulated and failed to enhance ear lesion and parasite burden in IL 10-/- infected mice. Furthermore, nucleosides increased regulatory T cell (Treg) marker expression on CD4+CD25- cells, suggesting induction of Tregs on effector T cells (T eff). Treg induction (iTreg) was associated with nucleoside-induced tolerogenic dendritic cells (tDCs) expressing higher levels of COX2 and IL-10. In vitro generation of Tregs was more efficient in DCs treated with nucleosides. Suppressive effects of nucleosides during cutaneous leishmaniasis were mediated through an A2AR-dependent mechanism. Using BALB/c mice deficient in A2A ADO receptor (A2AR-/-), we showed that co-inoculated mice controlled infection, displaying lower parasite numbers at infection sites and reduced iTreg generation.
  
  
  CONCLUSIONS
  We have demonstrated that ADO and AMP in P. papatasi saliva mediate exacerbative effects of Leishmania infection by acting preferentially on DCs promoting a tolerogenic profile in DCs and by generating iTregs in inflammatory foci through an A2AR mechanism.
authors: Department of Biochemistry and Immunology, School of Medicine of Ribeirão Preto, University of São Paulo, Ribeirão Preto, Brazil.
authors: Vanessa
authors: V
authors: Carregaro
authors: Section of Vector Biology, Laboratory of Malaria and Vector Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, United States of America; Vector Molecular Biology Unit, Laboratory of Malaria and Vector Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, United States of America.
authors: José M
authors: JM
authors: Ribeiro
authors: Section of Vector Biology, Laboratory of Malaria and Vector Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, United States of America; Vector Molecular Biology Unit, Laboratory of Malaria and Vector Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, United States of America.
authors: Jesus G
authors: JG
authors: Valenzuela
authors: Department of Biochemistry and Immunology, School of Medicine of Ribeirão Preto, University of São Paulo, Ribeirão Preto, Brazil.
authors: Djalma L
authors: DL
authors: Souza-Júnior
authors: Department of Biochemistry and Immunology, School of Medicine of Ribeirão Preto, University of São Paulo, Ribeirão Preto, Brazil.
authors: Diego L
authors: DL
authors: Costa
authors: Institute of Biological and Natural Sciences, Federal University of Triângulo Mineiro, Uberaba, Brazil.
authors: Carlo J F
authors: CJ
authors: Oliveira
authors: Department of Biochemistry and Immunology, School of Medicine of Ribeirão Preto, University of São Paulo, Ribeirão Preto, Brazil.
authors: Laís A
authors: LA
authors: Sacramento
authors: Department of Biochemistry and Immunology, School of Medicine of Ribeirão Preto, University of São Paulo, Ribeirão Preto, Brazil.
authors: Manuela S L
authors: MS
authors: Nascimento
authors: Department of Biochemistry and Immunology, School of Medicine of Ribeirão Preto, University of São Paulo, Ribeirão Preto, Brazil.
authors: Cristiane M
authors: CM
authors: Milanezi
authors: Department of Biochemistry and Immunology, School of Medicine of Ribeirão Preto, University of São Paulo, Ribeirão Preto, Brazil; Department of Pharmacology, School of Medicine of Ribeirão Preto, University of São Paulo, Ribeirão Preto, Brazil.
authors: Fernando Q
authors: FQ
authors: Cunha
authors: Department of Biochemistry and Immunology, School of Medicine of Ribeirão Preto, University of São Paulo, Ribeirão Preto, Brazil.
authors: João S
authors: JS
authors: Silva
mesh_terms: D000818:Animals; D003713:Dendritic Cells; D005260:Female; D007165:Immunosuppression Therapy; D016753:Interleukin-10 / Q000378:metabolism; D007896:Leishmaniasis / Q000276:immunology / Q000469:parasitology*; D051379:Mice; D008807:Mice, Inbred BALB C; D009705:Nucleosides / Q000494:pharmacology*; D011576:Psychodidae / Q000378:metabolism* / Q000469:parasitology; D012463:Saliva / Q000737:chemistry*
chemical_list: D009705:Nucleosides; D016753:Interleukin-10