Nucleosides present on phlebotomine saliva induce immunossuppression and promote the infection establishment.
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.Here...
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ftdoajarticles:oai:doaj.org/article:a4565c52678c4e9c8704cc5e50e15385 2023-05-15T15:12:46+02:00 Nucleosides present on phlebotomine saliva induce immunossuppression and promote the infection establishment. Vanessa Carregaro José M Ribeiro Jesus G Valenzuela Djalma L Souza-Júnior Diego L Costa Carlo J F Oliveira Laís A Sacramento Manuela S L Nascimento Cristiane M Milanezi Fernando Q Cunha João S Silva 2015-04-01T00:00:00Z https://doi.org/10.1371/journal.pntd.0003600 https://doaj.org/article/a4565c52678c4e9c8704cc5e50e15385 EN eng Public Library of Science (PLoS) http://europepmc.org/articles/PMC4388340?pdf=render https://doaj.org/toc/1935-2727 https://doaj.org/toc/1935-2735 1935-2727 1935-2735 doi:10.1371/journal.pntd.0003600 https://doaj.org/article/a4565c52678c4e9c8704cc5e50e15385 PLoS Neglected Tropical Diseases, Vol 9, Iss 4, p e0003600 (2015) Arctic medicine. Tropical medicine RC955-962 Public aspects of medicine RA1-1270 article 2015 ftdoajarticles https://doi.org/10.1371/journal.pntd.0003600 2022-12-31T01:48:57Z 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.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.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. Article in Journal/Newspaper Arctic Directory of Open Access Journals: DOAJ Articles Arctic PLOS Neglected Tropical Diseases 9 4 e0003600 |
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Open Polar |
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Directory of Open Access Journals: DOAJ Articles |
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ftdoajarticles |
language |
English |
topic |
Arctic medicine. Tropical medicine RC955-962 Public aspects of medicine RA1-1270 |
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Arctic medicine. Tropical medicine RC955-962 Public aspects of medicine RA1-1270 Vanessa Carregaro José M Ribeiro Jesus G Valenzuela Djalma L Souza-Júnior Diego L Costa Carlo J F Oliveira Laís A Sacramento Manuela S L Nascimento Cristiane M Milanezi Fernando Q Cunha João S Silva Nucleosides present on phlebotomine saliva induce immunossuppression and promote the infection establishment. |
topic_facet |
Arctic medicine. Tropical medicine RC955-962 Public aspects of medicine RA1-1270 |
description |
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.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.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. |
format |
Article in Journal/Newspaper |
author |
Vanessa Carregaro José M Ribeiro Jesus G Valenzuela Djalma L Souza-Júnior Diego L Costa Carlo J F Oliveira Laís A Sacramento Manuela S L Nascimento Cristiane M Milanezi Fernando Q Cunha João S Silva |
author_facet |
Vanessa Carregaro José M Ribeiro Jesus G Valenzuela Djalma L Souza-Júnior Diego L Costa Carlo J F Oliveira Laís A Sacramento Manuela S L Nascimento Cristiane M Milanezi Fernando Q Cunha João S Silva |
author_sort |
Vanessa Carregaro |
title |
Nucleosides present on phlebotomine saliva induce immunossuppression and promote the infection establishment. |
title_short |
Nucleosides present on phlebotomine saliva induce immunossuppression and promote the infection establishment. |
title_full |
Nucleosides present on phlebotomine saliva induce immunossuppression and promote the infection establishment. |
title_fullStr |
Nucleosides present on phlebotomine saliva induce immunossuppression and promote the infection establishment. |
title_full_unstemmed |
Nucleosides present on phlebotomine saliva induce immunossuppression and promote the infection establishment. |
title_sort |
nucleosides present on phlebotomine saliva induce immunossuppression and promote the infection establishment. |
publisher |
Public Library of Science (PLoS) |
publishDate |
2015 |
url |
https://doi.org/10.1371/journal.pntd.0003600 https://doaj.org/article/a4565c52678c4e9c8704cc5e50e15385 |
geographic |
Arctic |
geographic_facet |
Arctic |
genre |
Arctic |
genre_facet |
Arctic |
op_source |
PLoS Neglected Tropical Diseases, Vol 9, Iss 4, p e0003600 (2015) |
op_relation |
http://europepmc.org/articles/PMC4388340?pdf=render https://doaj.org/toc/1935-2727 https://doaj.org/toc/1935-2735 1935-2727 1935-2735 doi:10.1371/journal.pntd.0003600 https://doaj.org/article/a4565c52678c4e9c8704cc5e50e15385 |
op_doi |
https://doi.org/10.1371/journal.pntd.0003600 |
container_title |
PLOS Neglected Tropical Diseases |
container_volume |
9 |
container_issue |
4 |
container_start_page |
e0003600 |
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1766343409144954880 |