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The Cdc42/N-WASP and Rac1/WAVE2 pathways regulation of actin dynamics during cellular invasion by extracellular amastigotes of Trypanosoma cruzi

Grant number: 12/21335-8
Support type:Scholarships in Brazil - Doctorate
Effective date (Start): March 01, 2013
Effective date (End): October 31, 2016
Field of knowledge:Biological Sciences - Parasitology - Protozoology of Parasites
Principal Investigator: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:11/51475-3 - Molecular and cellular biology of the parasitism by Trypanosoma cruzi, AP.TEM

Abstract

Chagas' disease is caused by the flagellated protozoan Trypanosoma cruzi. The extracellular amastigotes (EA) cellular invasion is highly dependent on the actin cytoskeleton of the host cell whose regulation during this specific interaction remains poorly characterized. The Cdc42 and Rac1 GTPases are involved in a variety of in various cellular processes, but mainly in the regulation of the actin cytoskeleton where its main effector molecules, N-WASP and Wave2 respectively, crucially act as nucleators of actin polymerization during the formation of filopodia and lamelipodia. Several studies have shown the involvement of both pathways - Cdc42/N-WASP and Rac1/WAVE2 - in the regulation of actin cytoskeleton during cellular invasion by parasites and bacteria but there is no information regarding mammalian cell invasion by T. cruzi. Thus, the present project aims to evaluate the role of these two signaling pathways in actin dynamics during cell invasion by EAs. To assess so the (i) recruitment and (ii) invasion by EAs and the (iii) interaction of these proteins will be evaluated in cells stably overexpressing their native and mutant constructs fused to fluorescent proteins and also expressing interference RNA sequences. These three aspects which properly characterize the role of both pathways in actin polymerization during cell invasion by AEs will be evaluated in living and fixed cells; the latter by means of confocal microscopy. Finally, this strategy will also be used in coinfections studies with cells colonized by the bacteria Coxiella burnetii, whose infection alters the organization of the host cell cytoskeleton and probably the signaling underlying its regulation.

Scientific publications
(References retrieved automatically from Web of Science and SciELO through information on FAPESP grants and their corresponding numbers as mentioned in the publications by the authors)
BONFIM-MELO, ALEXIS; FERREIRA, EDEN R.; FLORENTINO, PILAR T. V.; MORTARA, RENATO A. Amastigote Synapse: The Tricks of Trypanosoma cruzi Extracellular Amastigotes. FRONTIERS IN MICROBIOLOGY, v. 9, JUN 27 2018. Web of Science Citations: 3.
BONFIM-MELO, ALEXIS; FERREIRA, EDEN R.; MORTARA, RENATO A. Rac1/WAVE2 and Cdc42/N-WASP Participation in Actin-Dependent Host Cell Invasion by Extracellular Amastigotes of Trypanosoma cruzi. FRONTIERS IN MICROBIOLOGY, v. 9, FEB 28 2018. Web of Science Citations: 7.

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