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Doctoral Thesis
Full name
Manuela Sales Lima Nascimento
Knowledge Area
Date of Defense
Ribeirão Preto, 2016
Silva, João Santana da (President)
Santos, Isabel Kinney Ferreira de Miranda
Oliveira, Camila Indiani de
Roselino, Ana Maria Ferreira
Title in Portuguese
A sinalização via NOD2-RIP2 modula a imunidade adaptativa contra Leishmania infantum
Keywords in Portuguese
células dendríticas
imunidade adaptativa
Leishmania infantum
Abstract in Portuguese
Células produtoras de IFN-? e IL-17A são envolvidas na proteção contra infecção por Leishmania infantum (L. infantum). Ainda não está claro como o sistema imune coordena, ou o parasito manipula, o balanço entre Th1 e Th17 durante a leishmaniose visceral (LV). Utilizando RNAseq, PCR array e citometria de fluxo, nós demonstramos que, enquanto o padrão Th1 é altamente induzido, o perfil Th17 é inibido durante a infecção por L. infantum, e que as células B compõem uma fonte importante de IL-17A nesse modelo. Usando animais Nod2-/- e Rip2-/- nós caracterizamos essa via como um regulador negativo de células Th17 na LV. Por outro lado, a potente indução de Th1 foi dependente da sinalização via NOD2-RIP2 em células dendríticas CD8??+XCR1+, o que foi crucial para produção de IL-12 através da fosforilação de p38 e JNK. Como consequência, camundongos Nod2-/- e Rip2-/- tiveram defeito na resposta Th1, aumento de Th17, e maiores cargas parasitárias comparado com camundongos WT. Juntos, os dados mostram que a via de NOD2-RIP2 desempenha um papel importante na modulação da resposta imune adaptativa e promove proteção contra LV causada por L. infantum
Title in English
NOD2-RIP2-mediated signaling contributes to shape adaptive immunity in visceral leishmaniasis
Keywords in English
adaptive immunity
dendritic cells
Leishmania infatum
Abstract in English
IFN-? and IL-17A-producing cells are described to be related to protection against Leishmania infantum (L. infantum) infection. How the immune system coordinates, or the parasite manipulates, the balance between Th1 and Th17 during visceral leishmaniasis (VL) is still unknown. We showed here that Th17 is suppressed during L. infantum infection and B cells are an important source of IL-17A in this model. By using Nod2-/- and Rip2-/- mice we characterized this pathway as a negative regulator for Th17 cells in VL. On the other hand, the high level of Th1 induction was dependent on the NOD2-RIP2 signaling in CD8?+XCR1+ dendritic cells (DCs), which was crucial for IL-12 production through the phosphorylation of p38 and JNK. As a consequence, Nod2-/- and Rip2-/- mice showed a Th1 defective response, more Th17, and higher parasite loads compared to WT mice. Together, the data demonstrate that NOD2-RIP2 signaling pathway plays a role in shaping adaptive immunity and promotes protection against VL caused by L. infantum
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