Dataset Information

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.

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 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.

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 A2AR mechanism.

SUBMITTER: Carregaro V

PROVIDER: S-EPMC4388340 | biostudies-literature | 2015 Apr

REPOSITORIES: biostudies-literature

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Publications

Nucleosides present on phlebotomine saliva induce immunossuppression and promote the infection establishment.

Carregaro Vanessa V Ribeiro José M JM Valenzuela Jesus G JG Souza-Júnior Djalma L DL Costa Diego L DL Oliveira Carlo J F CJ Sacramento Laís A LA Nascimento Manuela S L MS Milanezi Cristiane M CM Cunha Fernando Q FQ Silva João S JS

PLoS neglected tropical diseases 20150407 4

<h4>Background</h4>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.<h4>Methodology/principal findings</h4>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 sa ...[more]

PMID: 25849562

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Dataset Information

Nucleosides present on phlebotomine saliva induce immunossuppression and promote the infection establishment.

Background

Methodology/principal findings

Conclusion/significance

Publications

Nucleosides present on phlebotomine saliva induce immunossuppression and promote the infection establishment.

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