Mitochondrial plasticity in Chagas Disease

• Grant number: 18/00869-0
• Support Opportunities: Scholarships in Brazil - Doctorate
• Start date: July 01, 2018
• End date: March 31, 2022
• Field of knowledge: Biological Sciences - Physiology - Physiology of Organs and Systems
• Principal Investigator: Julio Cesar Batista Ferreira
• Grantee: Márcio Augusto Campos Ribeiro
• Host Institution: Instituto de Ciências Biomédicas (ICB). Universidade de São Paulo (USP). São Paulo , SP, Brazil

Abstract

Currently affecting 8 million people, mainly in Latin America (endemic area), Chagas Disease (CD) is caused by the protozoan Tryoanosoma cruzi (T. cruzi). The 2 medicines (Benznidazole and Nifurtimox) avaliable to treat CD focus on killing the parasite and are partially effective only in the acute phase of the disease. Based on this, new targets and therapies are needed. It was recently demonstrated that during T. cruzi infection there is an increase in mitochondrial density and size of the host cell. These alterations were followed by the parasite proliferation and by parasite co-localization with the host mitochondria. However the real contribution of the host cell mitochondria to the T. cruzi infection and tissue degeneration in CD remains unknown. It is well known that mitochondria are extremely dynamic and plastic organelles capable of changing their number, size and density, based on tissue metabolic demands. Here we hypothesized that the parasite infection and the tissue degeneration relies on mitochondrial plasticity and function of the host cell. Moreover, we believe that the modulation of these processes can control and/or prevent the parasite infection and progression of CD. In this context, the aim of this project is to investigate the role of mitochondrial plasticity of the host cell during T. cruzi infection and tissue degeneration. Therefore, we divided this project in five sub-aims: 1) characterize the mitochondrial dynamics (fusion and fission), mitophagy and bioenergetics in mouse embryonic fibroblasts (MEFs) infected with T. cruzi; 2) evaluate the individual contribution of mitochondrial dynamics (fusion and fission) and mitophagy to the infection and parasite proliferation using knockout MEFs (ATG7, Mfn1, Mfn2, Mfn1/2, Opa1, Drp1 and Parkin); 3) validate these findings using the siRNA technology in isolated adult cardiomyocytes; 4) proof of concept using transgenic mice displaying compromised mitochondrial fusion, fission and mitophagy; and 5) characterize the protein expression profile of mitochondrial fusion, fission and mitophagy in cardiac biopsies of patients with Chagas cardiomyopathy. For the in vivo study, animals will be infected and the cardiac phenotype and systemic inflammatory profile will be used to evaluate the efficiency of infection and the disease progression. It should also be pointed out that the transgenic mice are already available in the laboratory and they will be used according to the findings of the previous stages. Our preliminary results are promising and demonstrate that chagasic human hearts display a mitochondrial dysfunction and an accumulation of mitophagy markers. In summary, we expect that clarifying the involvement of the host cell mitochondrial plasticity in the parasite infection, as well as its role during tissue degeneration in CD, may contribute for future therapeutic strategies against CD. It is worth mentioning that Edecio Cunha-Neto (InCor-USP) and Ariel Mariano Silber (ICB-USP), both with expertise in CD, will be our collaborators in this project. (AU)

Academic Publications

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

RIBEIRO, Márcio Augusto Campos. Mitochondrial plasticity in Chagas disease.. 2022. Doctoral Thesis - Universidade de São Paulo (USP). Instituto de Ciências Biomédicas (ICB/SDI) São Paulo.