Open AccessNucleosides Present on Phlebotomine Saliva Induce Immunossuppression and Promote the Infection Establishment
Author(s) -
Vanessa Carregaro,
José M. C. Ribeiro,
Jesús G. Valenzuela,
Djalma L. Souza-Júnior,
Diego L. Costa,
Carlo José Freire Oliveira,
Laís Amorim Sacramento,
Manuela Sales Lima Nascimento,
Cristiane M. Milanezi,
Fernando Cunha,
João Silva
Publication year - 2015
Publication title -
plos neglected tropical diseases
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.99
H-Index - 135
eISSN - 1935-2735
pISSN - 1935-2727
DOI - 10.1371/journal.pntd.0003600
Subject(s) - saliva , virology , neglected tropical diseases , biology , microbiology and biotechnology , immunology , medicine , pathology , public health , biochemistry
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 COX 2 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.