fThe intracellular protozoan parasite Trypanosoma cruzi is the etiologic agent of Chagas disease, a serious disorder that affects millions of people in Latin America. Cell invasion by T. cruzi and its intracellular replication are essential to the parasite's life cycle and for the development of Chagas disease. Here, we present evidence suggesting the involvement of the host's cyclooxygenase (COX) enzymes during T. cruzi invasion. Pharmacological antagonists for COX-1 (aspirin) and COX-2 (celecoxib) caused marked inhibition of T. cruzi infection when rat cardiac cells were pretreated with these nonsteroidal anti-inflammatory drugs (NSAIDs) for 60 min at 37°C before inoculation. This inhibition was associated with an increase in the production of NO and interleukin-1␤ and decreased production of transforming growth factor ␤ (TGF-␤) by cells. Taken together, these results indicate that COX-1 more than COX-2 is involved in the regulation of anti-T. cruzi activity in cardiac cells, and they provide a better understanding of the influence of TGF-␤-interfering therapies on the innate inflammatory response to T. cruzi infection and may represent a very pertinent target for new therapeutic treatments of Chagas disease.

There is evidence suggesting that exercise training (ET) acts as a factor toward resistance to Trypanosoma cruzi infection. However, the effects of mean arterial pressure (MAP), heart rate (HR), and nitric oxide (NO) during the acute phase of infection has not been elucidated yet. Swiss mice were randomly assigned into four groups: sedentary control (SC, n = 30), trained control (TC, n = 30), sedentary infected (SI, n = 30), and trained infected (TI, n = 30). ET was performed on the treadmill for 9 weeks. After training, the mice were infected with 5 × 103 trypomastigotes of T. cruzi (Y strain) or PBS. We observed resting bradycardia and improved performance in trained animals compared with sedentary ones. On the 20th day post-infection (DPI), we found a decrease in HR in SI animals compared to TI animals (699.73 ± 42.37 vs. 742.11 ± 25.35 bpm, respectively, P < 0.05). We also observed increased production of NO in cardiac tissue on the 20th DPI in the SI group, normalized in TI group (20.73 ± 2.74 vs. 6.51 ± 1.19 μM, respectively). Plasma pro-inflammatory cytokines (IL-12, TNF-α, IFN-γ,) and MCP-1 were increased in SI animals, but decreased in TI animals. The increase in parasitemia on the 15th and 17th DPI in the SI group was attenuated in the TI group. Our results suggest that previous ET plays a preventive role in resistance to T. cruzi infection, modulating cardiovascular aspects, inflammatory reaction, and NO levels of infected mice.

Long-chain omega-3 polyunsaturated fatty acids (LC n-3 PUFA) are known to modulate a variety of immune cell functions. On occasion, this has led to diminished host resistance to certain viral and bacterial infections. Little is known about the impact of n-3 PUFA on host resistance to parasitic infection, however, based on results from a small study conducted more than two decades ago, we hypothesized that providing mice LC n-3 PUFA will diminish host resistance to Trypanosoma cruzi, the parasitic pathogen responsible for Chagas disease. To investigate this, C57BL/6 mice were supplemented by gavage (0.6% v/w) with phosphate-buffered saline, corn oil (CO), or menhaden fish oil (FO, a fat source rich in LC n-3 PUFA) for 15 days prior to T cruzi (Y strain) challenge and throughout the acute phase of infection. FO supplementation was associated with a transient 2-fold greater peak of blood parasitemia at 7 days postinfection (dpi), whereas subsequent cardiac parasitemia was ~60% lower at 12 dpi. FO treatment also ameliorated the leukopenia and thrombocytopenia observed in the early stages of a T cruzi infection. FO supplementation reduced circulating and cardiac nitric oxide at 7 and 12 dpi, respectively. FO supplementation altered ex vivo prostaglandin E and cytokine and chemokine production by splenocytes isolated from uninfected and infected mice. Overall, our results suggest that oral administration of LC n-3 PUFA from FO can have beneficial effects on the host in the early course of a T cruzi infection.

Chagas disease, caused by protozoan Trypanosoma cruzi, is one of the main causes of death due to cardiomyopathy and consequent heart failure in Latin American countries. The goal of treatment is to eliminate the parasite and decrease the probability of cardiomyopathy and interrupt the cycle of disease transmission. Benznidazole (BZ) and nifurtimox (NFX) are recognized by the World Health Organization as effective drugs for treatment of disease, but both are very toxic with limited efficacy, especially in the chronic phase. Studies have shown that low doses of aspirin (ASA) were protective in experimental T. cruzi Infection. We evaluated the efficacy of BZ in combination with ASA in low doses using a chronic infection model with T. cruzi Y strain. Our results show that ASA treatment prevented the typical cardiovascular dysfunction (hypertension and tachycardia) and cardiac lesions on chronic phase of disease. Moreover, mice treated with BZ+ASA had a smaller cardiac fibrotic area than those of BZ‐treated mice. These results were associated with an increase of eosinophils and reticulocytes and high levels of nitric oxide in plasma and cardiac tissue of animals treated with ASA compared to the controls. The protective effects of ASA or BZ+ASA on chronically infected mice disappeared when we used Boc‐2 (LXA4 receptor antagonist), indicating that the protector effect of ASA was mediated by aspirin‐triggered lipoxin. These results emphasize the importance of exploring new drug combinations in treatments that can be used in the acute phase of Chagas disease that are beneficial to chronic patients. Support or Funding Information The present study was supported by grants from Fundação Araucária ‐ chamada de projeto 09/2016 Programa Institucional de Pesquisa Básica e Aplicada ‐ Conv. 001/2017 ‐ protocolo 47.396 ‐ SIT. 31675, Conselho Nacional Desenvolvimento Científico e Tecnológico (CNPq), CAPES. PPF, MCMP, MILM, WAVJ, LMYL, SFYO are research fellows of CNPq. BFCL and ERT are research fellows of CAPES. RPS was supported by Ministério da Ciência e Tecnologia, Ensino Superior e Técnico Profissional de Mocambique. Graphical abstract

Trypanosoma cruzi infection causes heart inflammation and fibrosis with changes in the architecture and functionality of the heart. The literature shows that physical activity (PA) of chronic moderate‐intensity acts as a factor of resistance against T. cruzi infection in animals. The parameters of mean arterial pressure, heart rate (HR) and nitric oxide (NO) accompanying the acute phase of infection in animals trained have not been clarified. We aimed to evaluate the cardiovascular parameters, production of NO in the heart and plasma, parasitaemia and mortality in trained mice infected with T. cruzi. This study was approved by our institutional ethic committee (process number: 28105.2014.72). The AF was performed on treadmill for nine weeks. Then, the mice were infected with 5×103 trypomastigotes of T. cruzi (Y strain) or PBS (control). On days 7, 14 and 20 after inoculation (dpi) cardiovascular parameters were evaluated by CODA platform. The parasitemia was performed using the method of Brenner and dosage of NO by the Griess method. Data were analyzed using analysis of variance two‐way ANOVA. We observed resting bradycardia (758bpm vs 703bpm) and a better performance in the performance test (2.2 vs 1.5 km / h) in trained animals (n = 27) compared with sedentary (n = 14). With 20 dpi we found a decrease in HR in infected sedentary animals (SI) (n = 10) compared to the infected trained (TI) (n = 10) (669 vs 765bpm, p<0.05). We observed a decreased production of NO in cardiac tissue in IT compared with IS (6,51 vs 20.73 NO2μM). We observed a decrease in parasitemia in IT compared to IS in the 15 dpi (2,03×106 vs 1,17×106 parasites / ml) and 17 dpi (3,37×106 vs 1,02×106 parasites / ml). IT animals showed increased survival compared to SI. Exercise training improves cardiovascular parameters during infection by T. cruzi, contributing to the increased survival of infected animals, and NO may participate in this process.Support or Funding InformationCAPES (Coordenação de Aperfeiçoamento de Pessoal de Nível Superior)