Schistosoma mansoni co-infection modulates Chagas disease development but does not impair the effect of benznidazole-based chemotherapy.

The adequate management of parasite co-infections represents a challenge that has not yet been overcome, especially considering that the pathological outcomes and responses to treatment are poorly understood. Thus, this study aimed to evaluate the impact of Schistosoma mansoni infection on the efficacy of benznidazole (BZN)-based chemotherapy in Trypanosoma cruzi co-infected mice. BALB/c mice were maintained uninfected or co-infected with S. mansoni and T. cruzi, and were untreated or treated with BZN. Body weight, mortality, parasitemia, cardiac parasitism, circulating cytokines (Th1/Th2/Th17); as well as heart, liver and intestine microstructure were analyzed. The parasitemia peak was five times higher and myocarditis was more severe in co-infected than T. cruzi-infected mice. After reaching peak, parasitemia was effectively controlled in co-infected animals. BZN successfully controlled parasitemia in both co-infected and T. cruzi-infected mice and improved body mass, cardiac parasitism, myocarditis and survival in co-infected mice. Co-infection dampened the typical cytokine response to either parasite, and BZN reduced anti-inflammatory cytokines in co-infected mice. Despite BZN normalizing splenomegaly and liver cellular infiltration, it exacerbated hepatomegaly in co-infected mice. Co-infection or BZN exerted no effect on hepatic granulomas, but increased pulmonary and intestinal granulomas. Marked granulomatous inflammation was identified in the small intestine of all schistosomiasis groups. Taken together, our findings indicate that BZN retains its therapeutic efficacy against T. cruzi infection even in the presence of S. mansoni co-infection, but with organ-specific repercussions, especially in the liver.

4-nitrobenzoylcoumarin potentiates the antiparasitic, anti-inflammatory and cardioprotective effects of benznidazole in a murine model of acute Trypanosoma cruzi infection.

The anti-inflammatory and cardioprotective potential of coumarin metabolites in infectious myocarditis remains overlooked. Thus, the impact of the synthetic 4-nitrobenzoylcoumarin (4NB) alone and combined with benznidazole (Bz) in a murine model of Trypanosoma cruzi-induced acute myocarditis was investigated. Swiss mice infected with T. cruzi were randomized in 8 groups: uninfected, infected untreated or treated with 50 and 100 mg/kg 4NB or Bz alone and combined. Treatments were administered by gavage for 20 days. Cytokines (IL-2, IL-6, IL-10, IL-17, TNFα, and IFN-γ), immunoglobulin reactivity index (total IgG, IgG1, IgG2a and IgG2b), atrial natriuretic peptide (ANP), parasitemia, serum transaminases, heart and liver cellularity were analyzed. T. cruzi infection induced blood parasitism, heart and liver inflammation, upregulated all cytokines, IgG reactivity index, ANP and transaminase levels, determining 43% mortality in untreated mice. Transaminase levels, mean parasitemia, heart inflammation and ANP were reduced in 4NB-treated mice, reaching a 100% survival rate. Total survival (100%) was also obtained in all combinations of Bz and 4NB, which were effective in reducing blood parasitism, transaminases, cytokines and ANP levels, IgG reactivity index, liver and heart interstitial cellularity compared to 50 mg/kg Bz. Our findings indicated that 4NB alone and combined with Bz was well tolerated, showing no evidence of hepatotoxicity. Mainly in combination, these drugs exerted protective effects against T. cruzi-induced acute myocarditis by attenuating blood parasitism, systemic and heart inflammation. Thus, combinations based on 4NB and Bz are potentially relevant to develop new and more effective drug regimens for the treatment of T. cruzi-induced myocarditis.