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Leishmania infantum Parasites subvert the host inflammatory response through the adenosine A2(A) receptor to Promote the establishment of infection

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Lima, Mikhael H. F. ; Sacramento, Lais A. ; Quirino, Gustavo F. S. ; Ferreira, Marcela D. ; Benevides, Luciana ; Santana, Alynne K. M. ; Cunha, Fernando Q. ; Almeida, Roque P. ; Silva, Joao S. ; Carregaro, Vanessa
Número total de Autores: 10
Tipo de documento: Artigo Científico
Fonte: FRONTIERS IN IMMUNOLOGY; v. 8, JUL 20 2017.
Citações Web of Science: 6

Adenosine is an endogenously released purine nucleoside that signals through four widely expressed G protein-coupled receptors: A1, A2(A), A2(B), and A3. Of these, A(2A)R is recognized as mediating major adenosine anti-inflammatory activity. During cutaneous leishmaniasis, adenosine induces immunosuppression, which promotes the establishment of infection. Herein, we demonstrated that A(2A)R signaling is exploited by Leishmania infantum parasites, the etiologic agent that causes Visceral Leishmaniasis, to successfully colonize the vertebrate host. A(2A)R gene-deleted mice exhibited a well-developed cellular reaction with a strong Th1 immune response in the parasitized organs. An intense infiltration of activated neutrophils into the disease-target organs was observed in A(2A)R(-/-) mice. These cells were characterized by high expression of CXCR2 and CD69 on their cell surfaces and increased cxcl1 expression. Interestingly, this phenotype was mediated by IFN-gamma. on the basis that a neutralizing antibody specific to this cytokine prevented neutrophilic influx into parasitized organs. In evaluating the immunosuppressive effects, we identified a decreased number of CD4(+) FOXP3(+) T cells and reduced il10 expression in A2AR-/- infected mice. During ex vivo cell culture, A(2A)R(-/-) splenocytes produced smaller amounts of IL-10. In conclusion, we demonstrated that the A(2A)R signaling pathway is detrimental to development of Th1-type adaptive immunity and that this pathway could be associated with the regulatory process. In particular, it promotes parasite surveillance. (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
Processo FAPESP: 15/12526-2 - Mecanismos reguladores da resposta inflamatória na gravidade da Leishmaniose visceral
Beneficiário:Vanessa Carregaro Pereira
Linha de fomento: Auxílio à Pesquisa - Regular