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Role of dendritic cells and neutrophils in modulating the adaptive immune response in response to Paracoccidioides brasiliensis: analysis of the transcriptional profile of the cells populations involved

Grant number: 13/26245-0
Support type:Regular Research Grants
Duration: November 01, 2014 - October 31, 2016
Field of knowledge:Biological Sciences - Immunology - Cellular Immunology
Principal Investigator:Angela Maria Victoriano de Campos Soares
Grantee:Angela Maria Victoriano de Campos Soares
Home Institution: Instituto de Biociências (IBB). Universidade Estadual Paulista (UNESP). Campus de Botucatu. Botucatu , SP, Brazil
Assoc. researchers:Graziela Gorete Romagnoli ; João Pessoa Araújo Junior ; Luciane Alarcão Dias-Melicio ; Ramon Kaneno

Abstract

The fungus Paracoccidioides brasiliensis is thermodimorphic and the etiological agent of paracoccidioidomycosis, a systemic mycosis endemic in Latin America. Studies aiming to characterize the immune response of the infected host have given attention to the role of subpopulations of CD4+ cells, focusing on mechanisms involved in induction of one or other subpopulation, associated in the majority of early interaction between the infectious agent and the cells of the innate immune response. Thus, the dendritic cells (DCs) play a crucial role, but other cells as neutrophils (PMNs) have attracted attention in the last years. In this direction, the present study will be aimed at assessing the role of DCs and PMNs in directing the type of adaptive immune response that develops in response to the fungus. With regard to DCs in previous studies to evaluate the role of eicosanoids in relation DCs/Pb detected, contrary to expectations, the fungus inhibits endogenous PGE2 production. Accordingly, to understand the mechanisms of this inhibition on the response of DCs, we hypothesized that inhibition of PGE2 production by DCs, when meeting with the fungus, could be linked to the immunopathogenesis PCM. This inhibition would result in decreased expression of the enzyme indoleamine 2, 3 dioxygenase (IDO) with consequent failure in the induction of regulatory T cells (TRegs) and preferential induction of Th17 that during fungal infections can be associated with the development of a protective immune response not. To test the main hypothesis, we consider the analysis of how certain targets are being regulated molecules that participate in the proposed mechanisms. On the other hand, the challenge of DCs with fungus and cultivation of these cells with CD4+ cells results in the induction of expression of various genes in both cells that include encoders, several other molecules not considered initially as targets but that may have regulated their expression and thus participate in the proposed mechanisms. Thus, we decided to choose an experimental approach to analysis of the global transcriptional profile of DCs in response to the fungus, as well as of CD4+ in response to DCs. The objectives of the SUBPROJECT 1: will be: 1 - Analyze the transcriptional profile of DCs in response to Pb, with special attention to genes involved in the control of IDO and metabolism of arachidonic acid; 2 - Analyze the transcriptional profile of CD4+ cells co-cultured with DCs sensitized with Pb, with special attention to the transcription factors and cytokines involved in the differentiation of different subpopulations of these lymphocytes. With regard to PMNs, we test whether these cells play an important role in modulating the adaptive response to fungus and similarly, we use as an experimental approach to analyze transcriptional profiles of cell populations involved. The objectives of the SUBPROJECT 2: will be: 1 - Analyze the transcriptional profile of PMNs in response to the fungus, with special attention to the molecules involved in the recruitment of different subpopulations of CD4 + cells, recruiting and modulating the activity of DCs as regards the antigen presentation process and in regulating the differentiation of subpopulations of CD4+; 2 - Lymphocytes analyze the transcriptional profile of DCs in response to PMNs infected with the fungus, with special attention to phenotypic molecules maturation and production of regulatory cytokines differentiation of subpopulations CD4+; 3 - Evaluate the transcriptional profile of CD4+ cells co-cultured with DCs who came in contact with PMNs primed with the fungus, focusing on transcription factors and regulatory cytokines differentiation of subpopulations of these cells. (AU)