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Identification and characterization of novel actin cytoskeleton mediators during host cell invasion by the extracellular amastigote forms of Trypanosoma cruzi

Grant number: 16/17770-1
Support type:Scholarships in Brazil - Post-Doctorate
Effective date (Start): March 01, 2017
Effective date (End): February 28, 2019
Field of knowledge:Biological Sciences - Parasitology - Protozoology of Parasites
Principal researcher:Renato Arruda Mortara
Grantee:Alexis de Sá Ribeiro do Bonfim de Melo
Home Institution: Escola Paulista de Medicina (EPM). Universidade Federal de São Paulo (UNIFESP). Campus São Paulo. São Paulo , SP, Brazil
Associated research grant:16/15000-4 - Trypanosoma cruzi: intra and interspecific genomic variability and mechanisms of cell invasion/egress, AP.TEM

Abstract

The etiologic agent of Chagas Disease, Trypanosoma cruzi is able to infect professional and non-professional phagocytic cells by mechanisms that depend, among other factors, on the parasite form. While bloodstream trypomastigotes rely on host cell lysosome exocytosis, extracellular amastigotes (AEs), object of our study, mainly depend on the actin cytoskeleton to invade mammalian host cells. HeLa cells treated with cytochalasin D, an actin depolymerizing drug, present dramatically inhibition invasion by EAs; additionally, actin is recruited to and colocalizes with actin binding/regulating proteins to the EAs invasion sites. However, the mechanisms regulating these processes are still poorly characterized. Using techniques such confocal microscopy and gene editing by lentiviral transduction in recent years our laboratory has described the role of key regulators of actin polymerization, the Cdc42 and Rac1 GTPases, and two of its ligand/effector proteins (N-WASP and WAVE2, respectively). Our results showed that Cdc42/N-WASP and Rac1/WAVE2 host signaling pathways play a role in actin polymerization during AE internalization; additionally our results also suggested a possible co-regulation/co-participation between these two pathways perhaps simultaneously to other host pathways or proteins still not identified within this process. Based on these observations the aim of this project is to identify new actin dynamics mediators during host cell invasion by AEs using techniques to isolate, identify and characterize biological ligands of filamentous actin (polymerized) and Cdc42 and Rac1 GTPases. Finally, with this approach we aim to describe new host signaling pathways regulating actin dynamics during EA internalization. (AU)

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