Characterization of the mechanisms involved in the generation and modulation of protective immune response during Leishmania infantum infection

• Grant number: 13/01967-2
• Support Opportunities: Scholarships in Brazil - Doctorate
• Start date: April 01, 2013
• End date: February 29, 2016
• Field of knowledge: Biological Sciences - Immunology - Cellular Immunology
• Principal Investigator: João Santana da Silva
• Grantee: Manuela Sales Lima Nascimento
• Host Institution: Faculdade de Medicina de Ribeirão Preto (FMRP). Universidade de São Paulo (USP). Ribeirão Preto , SP, Brazil
• Associated scholarship(s): 14/10347-0 - Role of NLRP10 in the induction of Th1 and Th17 cells during Leishmania infantum infection, BE.EP.DR

Abstract

The leishmaniasis is a complex of diseases caused by protozoa of the Leishmania genus, which includes several species responsible for different disease clinical forms. The visceral leishmaniasis is a systemic, chronic and potentially fatal disease caused by Leishmania infantum, endemic in Brazil. The Th1 response is classically associated with protection, furthermore, recent data also suggest that there is a positive correlation between Th17-related cytokines and protection against this parasite. On the other hand, innate immunity pattern recognition receptors, as Nod-like receptors (NLR), are important for the induction of adaptative immune response, including activation and differentiation of Th1 and Th17 profiles. The activation of NLRs Nod1/Nod2 or Nlrp1-14 generates a Rip2 and Asc dependent cascade, respectively, and the second one activating caspase-1. Our preliminary data demonstrate that ASC, caspase-1, Rip2, Nod2, and Nod1/Nod2 (DKO) deficiency makes the animals more susceptible to infection and, curiously, Rip 2 down modulates IL-17 and up regulates IFN-³, whereas, caspase-1 up regulates IL-17 and do not have any effect on IFN-³ production. In addition, the absence of Nod1, Nod2, Rip2, Asc and Caspase-1 on the macrophage and dendritic cells-derived bone marrow reflects on inhibition of the total functional expression of MHC class II, CD40, CD86 and Th1 and Th17 polarizing cytokines. It is clear, therefore, that the parasite interferes on the innate immunity, and Nod1, Nod2, Rip2, Asc and Caspase-1 might have influence on the lymphocytes differentiation. Based on that, the aim of this project is to determine the mechanisms involved in the generation and/or modulation of the protective immune response, which produces IL-17 and IFN-³, induced by L. infantum infection. The research will involve deficient animals to the molecules Nod1, Nod2, Rip2, ASC, caspase-1 and C57BL/6 WT controls, focusing on immunological and pathological parameters induced by infection. We believe that this analysis will provide important information for understanding the mechanisms involved in the parasite/host interface in VL, and could help the therapeutic interventions development for leishmaniasis control.

Scientific publications

(References retrieved automatically from Web of Science and SciELO through information on FAPESP grants and their corresponding numbers as mentioned in the publications by the authors)

LIMA NASCIMENTO, MANUELA SALES; CARREGARO, VANESSA; LIMA-JUNIOR, DJALMA SOUZA; COSTA, DIEGO LUIS; RYFFEL, BERNHARD; DUTHIE, MALCOLM S.; DE JESUS, AMELIA; DE ALMEIDA, ROQUE PACHECO; DA SILVA, JOAO SANTANA. Interleukin 17A Acts Synergistically With Interferon gamma to Promote Protection Against Leishmania infantum Infection. Journal of Infectious Diseases, v. 211, n. 6, p. 1015-1026, MAR 15 2015. (13/01967-2, 12/14524-9)

Academic Publications

(References retrieved automatically from State of São Paulo Research Institutions)

NASCIMENTO, Manuela Sales Lima. NOD2-RIP2-mediated signaling contributes to shape adaptive immunity in visceral leishmaniasis. 2016. Doctoral Thesis - Universidade de São Paulo (USP). Faculdade de Medicina de Ribeirão Preto (PCARP/BC) Ribeirão Preto.