Impact of renin-angiotensin system modulators on Trypanosoma cruzi infection in vitro and in vivo

Abstract

American trypanosomiasis or Chagas disease is caused by the protozoan Trypanosoma cruzi. This disease is endemic in Latin America and about 8 million people are infected worldwide. Acute infections are often asymptomatic and deaths are uncommon. Conversely, chronic cardiomyopathy is the most severe clinical manifestation of Chagas disease, which if related to heart failure and death. Currently, the etiological treatment is limited to benznidazole and nifurtmox, which present high toxicity and low cure rates in chronic infections (10-20%). In patients with chronic cardiomyopathy, renin-angiotensin system (RAS) modulating drugs, such as angiotensin-converting enzyme (ACE) inhibitors, are used to improve cardiovascular function. Interestingly, these drugs have also been associated with better parasitological control and attenuation of myocarditis in T. cruzi-infected hosts. Although these drugs are immunomodulatory, it is still poorly understood whether antitrypanosomal effects are due to an enhanced immune response or direct antiparasitic effects. Thus, we used a systematic review framework and an in vitro and in vivo experimental approach to evaluate the impact of RAS modulating drugs on T. cruzi infection. According to our systematic review, captopril, losartan and enalapril increase parasite uptake by host cells, upregulate IL-12 and IFN-γ expression and downregulate IL-10 and IL-17 production by leukocytes in vitro. In infected animals, the studies reviewed indicated a marked reduction of parasitemia, tissue parasitism, inflammation and mortality. In our experimental models, our in vitro findings indicated that ramipril and losartan increased cardiomyocytes infection rate. Surprisingly, the angiotensin-(1-7) antagonist A-779 was able to reduce trypomastigotes viability, cardiomyocytes infection and the endocytic index. The angiotensin’s II and 1-7 had no effect on T. cruzi infection, while the ECA activator diminazene aceturate (DMZ) had a toxic dose-dependent effect on trypomastigotes. Our in vivo findings indicated that ramipril and DMZ did not prevented myocarditis or interfere with parasitemia peak, IgG plasma levels, and animal weight loss. However, both drugs reduced hepatomegaly, cardiomegaly and mortality in infected mice; while ramipril also attenuated skeletal myositis compared to infected untreated animals. Taken together, our findings supports the evidence that RAS modulating drugs, but not angiotensin’s II and 1-7, exerts antiparasitic effects in vitro potentially mediated by indirect immunomediated processes, as well as by direct toxic effects on infective forms of T. cruzi. However, the antiparasitic effect of ramipril and DMZ observed in vitro did not manifest in our murine model of T. cruzi infection, indicating limited relevance of these drugs to the treatment of experimental Chagas disease.