Our team investigates the mechanisms of cellular signal transduction (i.e. how cells communicate with each other) during host-pathogen relationship. Signal transduction is highly relevant for medicine in general, since a wide range of human diseases (cancer, immune diseases, neurodegenerative diseases, vascular diseases) are characterized by severe disturbances in this mechanism. We are particularly interested in protein kinases, a very large family of enzymes that regulate almost all aspects of cellular function.
Trypanosoma cruzi is the causative agent of one of most neglected parasitic diseases, called Chagas’ disease. Chagas’ disease is highly prevalent and urgent public health problem endemic to Latin America that afflicts between 15 and 18 million people worldwide. It has been recently estimated that less than 0.5% of worldwide research and development for neglected diseases was aimed at Chagas’ disease. Protein Kinases (PKs) are central components of multiple pathways involved in signal transduction and have been widely acknowledged as targets for proliferative diseases such as cancer. Therefore, several pharmaceutical companies regard signal transduction pathways as highly relevant targets for the development of new drugs against PKs to control cancer and other diseases. Given that parasitic diseases are also proliferative and that parasites display a complex life cycle, we assumed that the characterization of PKs and signal transduction pathways from both the point of view of the parasite and its host may be an important step in the designing of new inhibitors against Chagas’ disease.
The complex life cycle of T. cruzi includes an ignored but potentially infective form called extracellular amastigote, the object of our study. Extracellular amastigotes mobilize and are totally dependent on cell actin polymerization to invade host cells. Actin forms a cup-like structure surrounding the parasite at the sites of cell entry. (Figure). The actin cytoskeleton is a dynamic network composed of actin polymers and a large variety of associated proteins. The remodeling and functions of the actin cytoskeleton are highly regulated by signaling pathways. In this sense, we are exploring signaling molecules from the cell side, such as cortactin and protein kinase D and both are required by the parasite soon after actin recruitment in a concerted number of events culminating in parasite invasion and intracellular growth.
The parasite also contributes to its virulence fitness by secreting molecules such as the enzyme mevalonate kinase. Secreted components may affect parasite infectivity and modulate interaction with specific cellular receptors to trigger cell signaling and parasite entry. The discovery of new molecules that are able to inhibit parasite survival was one of the main goals after completed genome projects. The deep knowledge of signal transduction pathways from the both sides- parasite and host cell – may be carefully considered in designing drugs.
Sinalização Celular de Patógenos Eucariotas
dianabahia@hotmail.com
Universidade Federal de Minas Gerais - Instituto de Ciências Biológicas
Departamento de - Belo Horizonte, MG - Brazil
Phone: +55 31 MG