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(Referência obtida automaticamente do Web of Science, por meio da informação sobre o financiamento pela FAPESP e o número do processo correspondente, incluída na publicação pelos autores.)

Nucleosides Present on Phlebotomine Saliva Induce Immunossuppression and Promote the Infection Establishment

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Autor(es):
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Carregaro, Vanessa [1] ; Ribeiro, Jose M. [2, 3] ; Valenzuela, Jesus G. [3, 2] ; Souza-Junior, Djalma L. [1] ; Costa, Diego L. [1] ; Oliveira, Carlo J. F. [4] ; Sacramento, Lais A. [1] ; Nascimento, Manuela S. L. [1] ; Milanezi, Cristiane M. [1] ; Cunha, Fernando Q. [1, 5] ; Silva, Joao S. [1]
Número total de Autores: 11
Afiliação do(s) autor(es):
[1] Univ Sao Paulo, Sch Med Ribeirao Preto, Dept Biochem & Immunol, BR-14049 Ribeirao Preto - Brazil
[2] NIAID, Sect Vector Biol, Lab Malaria & Vector Res, NIH, Bethesda, MD 20892 - USA
[3] NIAID, Vector Mol Biol Unit, Lab Malaria & Vector Res, NIH, Bethesda, MD 20892 - USA
[4] Univ Fed Triangulo Mineiro, Inst Biol & Nat Sci, Uberaba - Brazil
[5] Univ Sao Paulo, Sch Med Ribeirao Preto, Dept Pharmacol, BR-14049 Ribeirao Preto - Brazil
Número total de Afiliações: 5
Tipo de documento: Artigo Científico
Fonte: PLoS Neglected Tropical Diseases; v. 9, n. 4 APR 2015.
Citações Web of Science: 10
Resumo

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 PGE(2)/IL 10-dependent mechanism. Methodology/Principal Findings 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 A2(A)R-dependent mechanism. Using BALB/c mice deficient in A2A ADO receptor (A2(A)R(-/-)), we showed that co-inoculated mice controlled infection, displaying lower parasite numbers at infection sites and reduced iTreg generation. Conclusion/Significance 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 A2(A)R mechanism. (AU)

Processo FAPESP: 13/08216-2 - CPDI - Centro de Pesquisa em Doenças Inflamatórias
Beneficiário:Fernando de Queiroz Cunha
Linha de fomento: Auxílio à Pesquisa - Centros de Pesquisa, Inovação e Difusão - CEPIDs