Recent contributions for a better understanding of the Trypanosoma cruzi - muscle cell interaction

Submitted by Sandra Infurna ([email protected]) on 2019-10-01T17:30:53Z No. of bitstreams: 1 MariaNazareMeirelles_HeleneSBarbosa_etal_IOC_1984.pdf: 343927 bytes, checksum: 989cebcbdaa66a7e9bf83f084eed3b11 (MD5)Approved for entry into archive by Sandra Infurna ([email protected]) on 2019-10-01T17:39:28Z (GMT) No. of bitstreams: 1 MariaNazareMeirelles_HeleneSBarbosa_etal_IOC_1984.pdf: 343927 bytes, checksum: 989cebcbdaa66a7e9bf83f084eed3b11 (MD5)Made available in DSpace on 2019-10-01T17:39:28Z (GMT). No. of bitstreams: 1 MariaNazareMeirelles_HeleneSBarbosa_etal_IOC_1984.pdf: 343927 bytes, checksum: 989cebcbdaa66a7e9bf83f084eed3b11 (MD5) Previous issue date: 1984Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Centro de Microscopia Eletrônica. Rio de Janeiro, RJ, Brasil.Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Centro de Microscopia Eletrônica. Rio de Janeiro, RJ, Brasil.Universidade Federal do Rio de Janeiro. Instituto de Biofísica, Rio de Janeiro, RJ, Brasil.Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Centro de Microscopia Eletrônica. Rio de Janeiro, RJ, Brasil

Mechanism of action of a nitroimidazole-thiadiazole derivate upon Trypanosoma cruzi tissue culture amastigotes

Megazol (CL 64,855) a very effective drug in experimental infections by Trypanosoma cruzi, and also in in vitro assays with vertebrate forms of the parasite, had its parasite, had its activity upon macromolecule biosynthesis tested using tissue culture-derived amastigote forms. Megazol presented a drastic inhibition of [3H]-uridine incorporation, suggesting a selective activity upon protein synthesis. Comparing the three drugs, megazol was more potent than nifurtimox and benznidazole in inhibiting protein an DNA synthesis. Megazol showed a 91% of inhibition of [3H]-leucine incorporation whereas nifurtimox and benznidazole, 0% and 2%, respectively. These latter two drugs inhibited the incorporation of all the precursors tested at similar levels, but the concentration of benznidazole was always three times higher, suggesting different mechanisms of action or, more probably, a greater efficiency of the 5-nitrofuran derivate in relation to the 2-nitroimidazole. So, wes conclude that the mode of action of megazol is different from the ones of nifurtimox and benznidazole and that its primary effect is associated with an impairment of protein synthesis

Amiodarone inhibits Trypanosoma cruzi infection and promotes cardiac cell recovery with gap junction and cytoskeleton reassembly in vitro

Submitted by Sandra Infurna ([email protected]) on 2018-08-08T11:25:02Z No. of bitstreams: 1 daniel _adesse_etal_IOC_2010.pdf: 6190363 bytes, checksum: 186c26faeff51157c4b30590631545db (MD5)Approved for entry into archive by Sandra Infurna ([email protected]) on 2018-08-08T11:36:02Z (GMT) No. of bitstreams: 1 daniel _adesse_etal_IOC_2010.pdf: 6190363 bytes, checksum: 186c26faeff51157c4b30590631545db (MD5)Made available in DSpace on 2018-08-08T11:36:02Z (GMT). No. of bitstreams: 1 daniel _adesse_etal_IOC_2010.pdf: 6190363 bytes, checksum: 186c26faeff51157c4b30590631545db (MD5) Previous issue date: 2011Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Laboratório de Ultraestrutura Celular. Rio de Janeiro, RJ, Brasil.Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Laboratório de Ultraestrutura Celular. Rio de Janeiro, RJ, Brasil.Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Laboratório de Ultraestrutura Celular. Rio de Janeiro, RJ, Brasil.Instituto Venezolano de Investigaciones Cientificas. Centro de Biofísica y Bioquímica. Laboratório de Química Biológica. Caracas, Venezuela.Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Laboratório de Ultraestrutura Celular. Rio de Janeiro, RJ, Brasil.We present the results of the first detailed study of the antiproliferative and ultrastructural effects of amiodarone on Trypanosoma cruzi, the causative agent of Chagas' disease. Moreover, we report the effects of this compound on the recovery of F-actin fibrils, connexin43, and contractility in T. cruzi-infected cardiac myocytes. Amiodarone is the most prescribed class III antiarrhythmic agent and is frequently used for the symptomatic treatment of Chagas' disease patients with cardiac compromise. In addition, recent studies identified its antifungal and antiprotozoal activities, which take place through Ca(2+) homeostasis disruption and ergosterol biosynthesis blockade. We tested different concentrations of amiodarone (2.5 to 10 μM) on infected primary cultures of heart muscle cells and observed a dose- and time-dependent effect on growth of the clinically relevant intracellular amastigote form of T. cruzi. Ultrastructural analyses revealed that amiodarone had a profound effect on intracellular amastigotes, including mitochondrial swelling and disorganization of reservosomes and the kinetoplast and a blockade of amastigote-trypomastigote differentiation. Amiodarone showed no toxic effects on host cells, which recovered their F-actin fibrillar organization, connexin43 distribution, and spontaneous contractility concomitant with the drug-induced eradication of the intracellular parasites. Amiodarone is, therefore, a promising compound for the development of new drugs against T. cruzi

Trypanosoma cruzi recognition by macrophages and muscle cells: perspectives after a 15-year study

Macrophages and muscle cells are the main targets for invasion of Trypanosoma cruzi. Ultrastructural studies of this phenomenon in vitro showed that invasion occurs by endocytosis, with attachment and internalization being mediated by different components capable of recognizing epi-or trypomastigotes (TRY). A parasitophorus vacuole was formed in both cell types, thereafter fusing with lysosomes. Then, the mechanism of T. cruzi invasion of host cells (HC) is essentially similar (during a primary infection in the abscence of a specific immune response), regardless of wether the target cell is a professional or a non-professional phagocytic cell. Using sugars, lectins, glycosidases, proteinases and proteinase inhibitors, we observed that the relative balance between exposed sialic acid and galactose/N-acetyl galactosamine (GAL) residues on the TRY surface, determines the parasite's capacity to invade HC, and that lectin-mediated phagocytosis with GAL specificity is important for internalization of T. cruzi into macrophages. On the other hand, GAL on the surface to heart muscle cells participate on TRY adhesion. TRY need to process proteolytically both the HC and their own surface, to expose the necessary ligands and receptors that allow binding to, and internalization in the host cell. The diverse range of molecular mechanisms which the parasite could use to invade the host cell may correspond to differences in the available "receptors"on the surface of each specific cell type. Acute phase components, with lectin or proteinase inhibitory activities (a-macroglobulins), may also be involved in T. cruzi-host cell interaction