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IFN-gamma-induced priming during chronic experimental malaria: study of the molecular and effector mechanisms involved

Grant number: 14/00810-5
Support type:Scholarships in Brazil - Post-Doctorate
Effective date (Start): August 01, 2014
Effective date (End): July 31, 2015
Field of knowledge:Biological Sciences - Immunology
Cooperation agreement: Coordination of Improvement of Higher Education Personnel (CAPES)
Principal Investigator:Maria Regina D'Império Lima
Grantee:Henrique Borges da Silva
Home Institution: Instituto de Ciências Biomédicas (ICB). Universidade de São Paulo (USP). São Paulo , SP, Brazil

Abstract

Introduction: The mechanisms by which the protective immunity to Plasmodium is lost in the absence of continuous exposure to parasites are still not well understood. The IFN-³ produced during acute malaria (in both humans and mouse models) stimulates the immune responses to toll-like receptor (TLR) agonists by a mechanism called priming. Moreover, recently, our research group showed that this mechanism remains active during the chronic experimental malaria. Briefly, we verified that the maintenance of the IFN-³-induced priming is correlated with higher numbers of effector/effector memory CD4+ T cells. When the reminiscent parasitemia is completely eliminated, this effect is abolished, which is related to the loss of ability to respond to parasite challenge. When the cured animals were treated with suboptimal IFN-³ doses, these mice recover the ability to control reinfections, and the numbers of effector/effector memory CD4+ T cells are enhanced, as well as the ability to respond to TLR agonists. Thus, we showed that the IFN-³-induced priming seems to be important in the maintenance of the protective immunity to experimental malaria.Problem: On the other way, the molecular mechanisms behind the importance of the IFN-³-induced priming during the chronic phase, as well as the effector mechanisms affected by this effect, are not well understood.Main objectives: Considering these aspects, our objectives are to evaluate in experimental malaria: A) the molecular mechanisms behind the importance of the IFN-³-induced priming in the maintenance of effector memory CD4+ T cells, and B) the effector mechanisms that are supposedly modulated by priming.Experimental strategies: To elucidate these objectives, we will utilize four different experimental strategies, in chronically infected animals: 1) To evaluate the importance of the presence of IFN receptor (IFNR) in memory CD4+ T cells, by studies performed in CD4KO mice adoptively transferred with CD4+ T cells from C57BL/6 and IFNRKO mice; 2) To evaluate the genic expression of effector memory/central memory/effector CD4+ T cells, as well as of antigen presenting cells, in response to IFN-³-induced priming in vivo and in vitro, as well as to evaluate the genic expression of the CD4+ T cells obtained in the experiments performed in the objective (1); 3) To evaluate the protein expression (by flow cytometry) of IFN-³-induced proteins in CD4+ T cells and antigen presenting cells in response to IFN-³-induced priming; and 4) To quantify, by in vivo, ex vivo and in vitro approaches, the phagocytic ability of different splenic cells in the presence or not of IFN-³-induced priming. Expected results: We expect, based on the experimental strategies listed above: 1) To verify whether the IFN-³-induced priming during chronic experimental malaria acts only on innate immunity cells, or if there is a direct effect on memory/effector CD4+ T cells; and 2) To verify, in our experimental model, how the IFN-³-induced priming affects the ability of splenic cells to eliminate the Plasmodium parasites from circulation. Expected contributions to the field: We believe that the elucidation of these processes will be crucial for a better understanding of the immune responses to Plasmodium parasites, with possible implications in the development of vaccination strategies against malaria. Existing supports: This study is fully compatible with the works being developed by our research group, with the support of FAPESP (regular grant, and scolarships for masters and doctorate) and of CNPq (productivity fellowship). (AU)

Matéria(s) publicada(s) na Agência FAPESP sobre a bolsa:
Research elucidates mechanism of immune response against malaria 

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)
MOREIRA, VANESSA; TEIXEIRA, CATARINA; DA SILVA, HENRIQUE BORGES; D'IMPERIO LIMA, MARIA REGINA; DOS-SANTOS, MARIA CRISTINA. The role of TLR2 in the acute inflammatory response induced by Bothrops atrox snake venom. Toxicon, v. 118, p. 121-128, AUG 2016. Web of Science Citations: 6.
DA SILVA, HENRIQUE BORGES; FONSECA, RAISSA; PEREIRA, ROSANA MOREIRA; CASSADO, ALEXANDRA DOS ANJOS; ALVAREZ, JOSE MARIA; D'IMPERIO LIMA, MARIA REGINA. Splenic macrophage subsets and their function during blood-borne infections. FRONTIERS IN IMMUNOLOGY, v. 6, SEP 22 2015. Web of Science Citations: 39.
DA SILVA, HENRIQUE BORGES; FONSECA, RAISSA; ALVAREZ, JOSE M.; D'IMPERIO LIMA, MARIA REGINA. IFN-gamma Priming Effects on the Maintenance of Effector Memory CD4(+) T Cells and on Phagocyte Function: Evidences from Infectious Diseases. CLINICAL & DEVELOPMENTAL IMMUNOLOGY, 2015. Web of Science Citations: 5.

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