Treatment with low-dose bicistronic immunotherapy mitigates parasite persistence and improves serological and cardiac outcomes in adult mice infected with Trypanosoma cruzi: comparative analysis with benznidazole

Chagas disease (CD), caused by Trypanosoma cruzi (Tc), remains difficult to treat in adults, as benznidazole (BZN) has limited curative efficacy and notable adverse effects. This study evaluated a newly-designed immunotherapy without (BCV) and with RIG-I adjuvant (BCVR). Adult C57BL/6 mice were infected and treated with BCV/BCVR (0.5 mg/kg, two doses, 21-day interval) or BZN (50 mg/kg for 6-weeks). Outcomes included parasite burden, biomarkers of inflammation, fibrosis, and heart disease, and left ventricular (LV) function. Infected/untreated mice developed high acute parasite burden, and persistence of proinflammatory, tissue damage, and clinical disease-related biomarkers in circulation and cardiac tissue. Treatment with BCV, BCVR or BZN achieved >95% control of parasite burden. Tissue inflammatory infiltrate and peripheral biomarkers of inflammation, necrosis, and heart involvement were significantly reduced throughout the infection and disease by BCV, while BCVR- and BZN-mediated protection was pronounced in the chronic phase. Pro-fibrotic gene expression and cardiac hypertrophy were blocked in CD mice post-treatment (BCV > BCVR = BZN). Morphological changes in the LV walls’ thickness associated with compromised systolic and diastolic performance of the heart were abated by BCV/BCVR, while BZN moderately controlled the LV dysfunction in CD mice. We surmise that BCV/BCVR immunotherapies outperformed BZN in controlling the parasite persistence and ameliorating cardiac pathology and LV dysfunction that contribute to heart failure and death in CD. Overall, BCV and BCVR are promising alternatives to prevent and control CD morbidities that have not been uniformly feasible because of the adverse effects of BZN in adults.