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

Abstract

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.

The TGF-β Pathway as an Emerging Target for Chagas Disease Therapy

“…44 The infection of mice expressing a T-cell-specific dominant-negative TGF-β receptor type II allowed the conclusion that TGF-β regulates T. cruzi infection. 46 Our studies using the ALK5 inhibitor SB-431542, 31 as well as similar molecules, 48 have consistently shown that inhibition of the TGF-β signaling pathway decreased heart inflammation (the number of inflammatory infiltrates), possibly as a consequence of lower tissue parasite load. Different approaches aiming at therapeutically modulating inflammation, such as L-685-818 (tacrolimus analog) and CD40 ligand, 49 antagonists of CCR1/CCR5 (Met-RANTES), 50 or anti-TNF-α (infliximab), 51 partially succeeded in reducing some parameters of infection, but all of them targeted TGF-β-independent mechanisms.…”

TGF-β and VEGF cooperatively control the immunotolerant tumor environment and the efficacy of cancer immunotherapies

“…We selected sunitinib, targeting the VEGF pathway (26,27), and SB431542, an inhibitor of TGF-β signaling (45,46). While SB431542 and sunitinib alone induce moderate effects on B16 growth (a respective increase of 1 and 5.5 days of median survival), their combination appears synergistic ( Figure 7, E and F) and leads to a significant 10.5 days increase in the median survival ( Figure 7F).…”

Chagas disease: Present status of pathogenic mechanisms and chemotherapy

“…In one of them, the parasites secrete proteases responsible of TGF-β activation (Araujo-Jorge et al, 2008;Waghabi et al, 2009;Waghabi et al, 2005). In addition, phagocytosis of apoptotic bodies originated from T-cells or neutrophils and generated by the action of TNF-β, induces a prostaglandin-dependent production of TGF-β in macrophages.…”