Experimental acute infection with Trypanosoma cruzi in mice promotes an intense myocarditis and other systemic changes. However, the network of pathophysiological disorders and renal injury caused by the infection has not been elucidated. Our previous results with a murine model observed a discrete acute myocarditis and high mortality with significant inflammatory kidney injury with T. cruzi infection. The aim of this study was to investigate the mechanisms of kidney injury caused by the parasite in mice during the experimental acute phase. Results employing BALB/c mice infected with T. cruzi of Y strain showed renal injury on the 6th day postinfection (dpi) caused by a transitory decrease of renal blood flow. Acute kidney injury (AKI) was also observed similar to the model of ischemia/reperfusion lesion in these infected mice. The injury was not related to the presence (or multiplication) of parasites. Only rare nests were microscopically detected, and the presence of scattered parasites in renal parenchyma was seen on the 15th dpi. Thus, it was observed that during the acute phase of the disease, AKI in infected mice is linked to early cardiovascular effects, including heart failure, caused by striking inflammatory lesions in the myocardium, which lead to the high mortality rate of animals.

Fas/Fas ligand (Fas-L) engagement, a potent inducer of apoptosis, is also important for cellular activation, regulation of effector and chemotactic activity, and secretion of chemokines and cytokines. We evaluated the relevance of Fas/Fas-L in the regulation of myocarditis induced by Trypanosoma cruzi infection and observed that in Fas-L(-/-) mice (gld/gld), cardiac infiltration was significantly reduced, accordingly showing less cardiomyocyte destruction. Fluorescence-activated cell sorting analysis of cardiac inflammatory cells showed higher numbers of CD8(+) T cells in BALB/c compared with gld/gld mice but similar levels of lymphocyte function-associated antigen-1, intercellular adhesion molecule, CD2, and CD69 expression; MAC-1(+) myeloid cells and mast cells were increased in BALB/c mice, whereas gld/gld mice exhibited an enrichment of CD4(+/low) T cells. Intracellular labeling of cytokines revealed no clear cardiac skewing of Th1 or Th2 responses, but we found a higher number of interleukin-10(+) cells in gld/gld mice and a deficient expression of vascular cell adhesion molecule-1 on cardiac endothelial cells in gld/gld mice. Finally, we found a population of CD3(+) but CD4/CD8 double negative cardiac T cells in both groups of infected mice, but down-regulation of some adhesion molecules and surface receptors was only observed in gld/gld mice, indicating a targeted T-cell population mostly affected by the lack of Fas-L engagement. These results point to a role for myocarditis regulation by Fas/Fas-L beyond its possible direct relevance in cellular death.

Chagas disease, caused by the protozoan Trypanosoma cruzi, remains a serious public health problem in Latin America. In relation to digestive problems, 4.5% of patients show mega syndromes (megacolon) in the chronic phase. In this article, we evaluated intestinal motility at the acute phase of T. cruzi infection through charcoal ingestion in adult mice. After infection, Swiss mice were administered an aqueous suspension of charcoal in water by gavage. Decrease in intestinal motility was determined by increased time of appearance of charcoal in the feces. The uninfected group showed a mean time of charcoal elimination of 109.0 +/- 14.6 min throughout the assay. On the other hand, infected mice presented a significant increase in charcoal defecation time during infection. At 15 days postinfection, infected mice showed a significant increase in charcoal defecation time, 310.2 +/- 67.4 min when compared to the uninfected group, which presented 97.8 +/- 31.8 min, indicating that the T. cruzi infection interferes with intestinal motility. Our results demonstrate that the use of charcoal is an ethical and efficient procedure to evaluate the intestinal motility in the murine model of T. cruzi infection.

Chagas disease (CD), caused by Trypanosoma cruzi, affects approximately eight million individuals in Latin America and is emerging in nonendemic areas due to the globalisation of immigration and nonvectorial transmission routes. Although CD represents an important public health problem, resulting in high morbidity and considerable mortality rates, few investments have been allocated towards developing novel anti-T. cruzi agents. The available therapy for CD is based on two nitro derivatives (benznidazole (Bz) and nifurtimox (Nf)) developed more than four decades ago. Both are far from ideal due to substantial secondary side effects, limited efficacy against different parasite isolates, long-term therapy, and their well-known poor activity in the late chronic phase. These drawbacks justify the urgent need to identify better drugs to treat chagasic patients. Although several classes of natural and synthetic compounds have been reported to act in vitro and in vivo on T. cruzi, since the introduction of Bz and Nf, only a few drugs, such as allopurinol and a few sterol inhibitors, have moved to clinical trials. This reflects, at least in part, the absence of well-established universal protocols to screen and compare drug activity. In addition, a large number of in vitro studies have been conducted using only epimastigotes and trypomastigotes instead of evaluating compounds' activities against intracellular amastigotes, which are the reproductive forms in the vertebrate host and are thus an important determinant in the selection and identification of effective compounds for further in vivo analysis. In addition, due to pharmacokinetics and absorption, distribution, metabolism, and excretion characteristics, several compounds that were promising in vitro have not been as effective as Nf or Bz in animal models of T. cruzi infection. In the last two decades, our team has collaborated with different medicinal chemistry groups to develop preclinical studies for CD and investigate the in vitro and in vivo efficacy, toxicity, selectivity, and parasite targets of different classes of natural and synthetic compounds. Some of these results will be briefly presented, focusing primarily on diamidines and related compounds and naphthoquinone derivatives that showed the most promising efficacy against T. cruzi.

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Introduction: Trypanosoma cruzi infection is a serious public health problem in Latin America. Despite positive results from programs directed to the interruption of vectorial transmission, there are still millions of people infected, and a large number, at the risk of infection. Chagas disease is typically associated with cardiac complications, and chronic symptoms include heart failure and megaesophagus development. Objective: In this study, we aimed to evaluate the importance of the cardiorenal axis and renin-angiotensin-aldosterone system (RAAS) activation in experimental T.cruzi infection. We also evaluated the influence of aldosterone and the angiotensin II receptor type 1 (AT1R) on the mortality of infected mice. Methods: BALB/c mice infected with the Y strain of T.cruzi were treated with spironolactone or losartan. We assessed parasitemia, mortality, and renal and cardiac function by using non-invasive methods. Results: Our data show that AT1R promotes an important (and necessary) inotropic positive effect in the heart and minimizes acute kidney injury. Conversely, aldosterone increases the release of K + and aggravates heart failure. It also has associated effects on the renal, cardiovascular, and cardiac electrical conduction systems. Consequently, the aldosterone antagonist reduced the mortality rate by 50%, whereas the AT1R antagonist increased it by 20%. Conclusions: The RAAS connects the cardiorenal systems, and its components differentially affect the mortality of animals experimentally infected by T.cruzi.

Chagas disease, caused by Trypanosoma cruzi, is an important public health problem in Latin America. Disturbances in gastrointestinal motility are observed in 15-20% of patients at the chronic phase. We previously observed a decrease in intestinal motility in mice infected with Y strain from T. cruzi. Thus, we decided to test if infection with other T. cruzi strains also caused the intestinal disturbance. Male adult Swiss mice were infected intraperitoneally with CL-Brener clone (CL-B), Brazil strain (Br), or Dm28 clone (Dm) of T. cruzi. All infected mice presented a low cumulative mortality (CL-B, 17%; Br, 8%; Dm, 25%) at 35 days post infection (dpi) and their typical parasitemia curves. Br and Dm groups exhibited a maximal reduction of intestinal motility at 35 dpi (176.8 +/- 51.3 and 198.3 +/- 52.6 min, respectively), when compared with non-infected mice (90.2 +/- 19.5 min). However, CL mice presented the peak of delayed intestinal transit at 12 dpi (191.0 +/- 33.3 min), when compared with non-infected mice (105.6 +/- 26.4 min), very close to the 15 dpi for the intense alteration (310.2 +/- 67.4 min) observed with the Y strain. We clearly demonstrate a reduction in intestinal motility in mice infected with different groups of T. cruzi during the acute phase of the infection. Since Br, Dm, and CL strains presented low mortality rates in adult Swiss mice, a prospective study concerning the chronic intestinal alteration is encouraged, particularly for studies of alternative therapies.

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