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Characterization of the interaction of Trypanosoma cruzi with the host cell nuclear machinery investigating repair pathways and measurement of DNA damage

Abstract

Trypanosoma cruzi is a protozoan that causes Chagas Disease (CD), which is capable of invading almost any type of cell. At the beginning of infection, T. cruzi interacts with molecules on the surface of the host cell to adhere and penetrate and several changes in cellular metabolism and morphological changes occur in both cells. However, little is known about host nuclear organization during T. cruzi infection. We demonstrate that during initial infection, T. cruzi deforms the host cell nucleus, modulating the activity of RNA polymerase II, transcription and splicing proteins. This parasite interaction causes a stop in the transcription and splicing machinery and reinforces the idea that the parasite can modulate several host nuclear responses. Recently, we demonstrated that T. cruzi induces DNA double-strand breaks and activates the DNA damage response (DDR) pathway in non-phagocytic cells. T. cruzi does not penetrate the host cell nucleus, so we wondered whether the parasite's extracellular vesicles (EVs) could contribute as activators of damage and/or repair in host cells. Therefore, this project focuses on 1) characterizing the proteins that participate in the DNA damage response pathway in cells infected by T. cruzi and, consequently, in the cellular repair machinery; and 2) the consequences that this involvement of DNA damage produces in infected cells through the study of the cell cycle; 3) we will also investigate the role of T. cruzi extracellular vesicles (EVs) and their interaction with the host cell nucleus. This study will provide new evidence for events not yet described in the literature, and will add more information about the interaction between T. cruzi and the host cell, in order to contribute to the search for possible therapeutic targets against Chagas Disease. (AU)

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