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

Author(s):Show less -

Carregaro, Vanessa ^[1] ; Ribeiro, Jose M. ^{[2, 3]} ; Valenzuela, Jesus G. ^{[2, 3]} ; 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]

Affiliation

^[1] Univ Sao Paulo, Sch Med Ribeirao Preto, Dept Biochem & Immunol, BR-14049 Ribeirao Preto - Brazil

^[2] NIAID, Vector Mol Biol Unit, Lab Malaria & Vector Res, NIH, Bethesda, MD 20892 - USA

^[3] NIAID, Sect Vector Biol, 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

• Document type: Journal article
• Source: PLoS Neglected Tropical Diseases; v. 9, n. 4 APR 2015.
• Web of Science Citations: 10

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 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)

• FAPESP's process: 13/08216-2 - CRID - Center for Research in Inflammatory Diseases
• Grantee: Fernando de Queiroz Cunha
• Support Opportunities: Research Grants - Research, Innovation and Dissemination Centers - RIDC