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Function, mechanisms of activation and regulation of PI3K delta and PI3K gamma signaling pathway in the control of Trypanosoma Cruzi infection

Grant number: 18/20130-0
Support type:Scholarships in Brazil - Post-Doctorate
Effective date (Start): January 01, 2019
Effective date (End): December 31, 2020
Field of knowledge:Biological Sciences - Immunology
Principal Investigator:João Santana da Silva
Grantee:Maria Cláudia da Silva
Home Institution: Faculdade de Medicina de Ribeirão Preto (FMRP). Universidade de São Paulo (USP). Ribeirão Preto , SP, Brazil
Associated research grant:13/08216-2 - CRID - Center for Research in Inflammatory Diseases, AP.CEPID


During the immune response against different classes of microoganisms several intracellular signaling pathways are activated, including phosphatidylinositol 3-kinases-dependent pathways. The PI3K-delta, a member of class IA PI3Ks and the PI3K-gamma, the unique member of class IB PI3Ks, are expressed mainly in hematopoietic cells and they are important for development of immune response in several inflammatory experimental models. Recently we showed that the PI3K-gamma is essential to confer resistance to Trypanosoma cruzi (T. cruzi) infected mice and it is involved in the tissue parasitism control during the experimental infection and during the human Chagas disease. Then, this pathway can modulate the immune response, the parasite growth and, consequently, the myocarditis in infected mice and in patients. In fact and according to previous results, a specific polymorphism in PI3K-gamma gene can interfere in the clinical form and severity of the disease. Moreover, searching new signaling pathways able to interfere in PI3K-gamma activation is important to understand the implications of this pathway during the experimental infection by T. cruzi and during the Chagas disease. Then, we intend to evaluate the role of PI3K-delta and the mechanisms of activation and regulation of PI3K-gamma pathway during the infection by T. cruzi. Moreover, we will evaluate the way by which PI3K-gamma is activated by infected macrophages and whether the activation of the enzyme in macrophages only, is enough to confer resistance to T. cruzi infection. Another objective is to investigate whether a specific polymorphism in PI3K-gamma gene, able to interfere in the clinical form and in the disease severity, can affect the enzyme expression and/or activation. Since PI3K-gamma can control the parasite growth and the host resistance to T. cruzi infection, understanding the mechanisms of activation and regulation of this pathway will contribute to the search of new therapeutic target to the control of this important neglected disease.