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Antimicrobial Agents and Chemotherapy, November 2009, p. 4694-4701, Vol. 53, No. 11
0066-4804/09/$08.00+0     doi:10.1128/AAC.00580-09
Copyright © 2009, American Society for Microbiology. All Rights Reserved.

Pharmacological Inhibition of Transforming Growth Factor β Signaling Decreases Infection and Prevents Heart Damage in Acute Chagas' Disease{triangledown}

Mariana C. Waghabi,1,3 Elen M. de Souza,2 Gabriel M. de Oliveira,2 Michelle Keramidas,4,5,6 Jean-Jacques Feige,4,5,6 Tania C. Araújo-Jorge,1,{dagger} and Sabine Bailly4,5,6,{dagger}*

Laboratório de Inovações em Terapias, Ensino e Bioprodutos,1 Laboratório de Biologia Celular,2 Laboratório de Genômica Funcional e Bioinformática, Instituto Oswaldo Cruz, Av. Brasil 4365, Rio de Janeiro, RJ 20045-900, Brazil,3 Institut National de la Santé et de la Recherche Médicale, U878, 17 rue des Martyrs, 38054 Grenoble,4 Commissariat à l'Energie Atomique, Institut de Recherches en Technologies et Sciences pour le Vivant/Laboratoire Angiogenèse et Physiopathologie Vasculaire,5 Université Joseph Fourier, Grenoble, France6

Received 30 April 2009/ Returned for modification 27 July 2009/ Accepted 25 August 2009

Chagas' disease induced by Trypanosoma cruzi infection is an important cause of mortality and morbidity affecting the cardiovascular system for which presently available therapies are largely inadequate. We previously reported that transforming growth factor β (TGF-β) is implicated in several regulatory aspects of T. cruzi invasion and growth and in host tissue fibrosis. This prompted us to evaluate the therapeutic action of an inhibitor of TGF-β signaling (SB-431542) administered during the acute phase of experimental Chagas' disease. Male Swiss mice were infected intraperitoneally with 104 trypomastigotes of T. cruzi (Y strain) and evaluated clinically for the following 30 days. SB-431542 treatment significantly reduced mortality and decreased parasitemia. Electrocardiography showed that SB-431542 treatment was effective in protecting the cardiac conduction system. By 14 day postinfection, enzymatic biomarkers of tissue damage indicated that muscle injury was decreased by SB-431542 treatment, with significantly lower blood levels of aspartate aminotransferase and creatine kinase. In conclusion, inhibition of TGF-β signaling in vivo appears to potently decrease T. cruzi infection and to prevent heart damage in a preclinical mouse model. This suggests that this class of molecules may represent a new therapeutic agent for acute and chronic Chagas' disease that warrants further clinical exploration.

* Corresponding author. Mailing address: INSERM, U878, 17 rue des Martyrs, 38054 Grenoble Cedex 9, France. Phone: (33) 438 789 214. Fax: (33) 438 785 058. E-mail: sbailly{at}cea.fr

{triangledown} Published ahead of print on 8 September 2009.

{dagger} Tania C. Araújo-Jorge and Sabine Bailly made equal contributions to this work.

Antimicrobial Agents and Chemotherapy, November 2009, p. 4694-4701, Vol. 53, No. 11
0066-4804/09/$08.00+0     doi:10.1128/AAC.00580-09
Copyright © 2009, American Society for Microbiology. All Rights Reserved.





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