Previous studies in paracoccidioidomycosis (PCM), the most prevalent systemic mycosis in Latin America, revealed that immunity of hosts is tightly regulated by several suppressive mechanisms mediated by tolerogenic plasmacytoid dendritic cells, the enzyme 2,3 indoleamine dioxygenase (IDO1) and regulatory T cells (Treg). IDO1 was also seen to orchestrate local and systemic immunosuppressive effects through the recruitment and activation of myeloid-derived suppressor cells (MDSCs), a heterogeneous population of myeloid cells with a potent ability to suppress T cell responses. These cells regulate immune responses and tissue repair in healthy individuals and rapidly expands during infection. The involvement of MDSC during PCM was never investigated, leading us to propose this study that aims to characterize the participation of MDSCs in the immunity against P. brasileinsis infection. The presence, phenotype and activity of MDSCs will be evaluated at several post infection periods. In addition, the disease severity and several features of the immune response will be assessed in MDSC-depleted and non-depleted C57BL/6 mice using a specific monoclonal antibody. Based on previous studies that established a positive correlation between IDO activity and MDCS infiltration we also intend to do a comparative study on MDSC function in pulmonary PCM using IDO-deficient and sufficient-mice. These studies will be complemented by the characterization of the transcriptional and proteomic responses of granulomatous lesions as well as P. brasiliensis yeasts obtained from these lesions at several post-infection periods. These data will be compared to those obtained from the original inoculum and non-infected lung tissue. This approach, never used in chronic PCM, will possibly reveal the main changes in gene expression and proteins production by P. brasiliensis cells under the stress conditions determined by the host immune system. A better understanding of immunoregulation in pulmonary PCM, mediated by MDSCs and adaptive behavior of yeasts cells in pulmonary granulomas will possibly advance the current knowledge of the host-pathogen responses that control the severity of PCM and will open new perspectives for more effective therapies. (AU)
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(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)
DE CASTRO, PATRICIA ALVES;
COLABARDINI, ANA CRISTINA;
SILVA, LILIAN PEREIRA;
ROCHA, MARINA CAMPOS;
SILVA, ROBERTO NASCIMENTO;
DYER, PAUL S.;
LOURES, FLAVIO VIEIRA;
WONG, KOON HO;
GOLDMAN, GUSTAVO H.
Novel Biological Functions of the NsdC Transcription Factor in Aspergillus fumigatus.
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