Brincidofovir

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.

Cardiomyopathy and stroke are major complications of Chagas disease (CD). We investigated if hypercoagulability, endothelial cell (EC) dysfunction, and blood stasis cause cardiac-cerebral fibrinogenesis in CD. C57BL/6 mice infected with Trypanosoma cruzi (Tc) were evaluated at acute (AT), indeterminate (IT), and chronic (CT) stages of CD. Mice were given anti-parasite, bicistronic immunogens (BCV or BCVR) to determine the role of Tc in fibrinogenesis. We monitored (1) platelet and coagulation cascade activation; (2) cardiac-cerebral blood vessels injury; (3) proinflammatory/prothrombotic phenotypes of microglia, macrophages, and vascular cells; and (4) fibrinogenesis. After a quiescent acute phase, plasma levels of coagulation and other factors of platelet activation/aggregation, hypercoagulability, and clotting capacity were increased in IT-CT mice. Proinflammatory and prothrombotic cytokines/chemokines in cardiac-cerebral blood vessels were also significantly increased in IT-CT mice. Loss of cardiac EC and a marked increase in their proinflammatory/cell-adhesion response were not compensated for by a pro-angiogenic/wound-healing response in cardiac-cerebral tissues of infected mice. Microglial proinflammatory activation preceded the vascular inflammation suggesting a feedback cycle of EC activation in brain of infected mice. Treatment with BCV/BCVR controlled the parasite persistence and hypercoagulability/vascular inflammation in infected mice. Importantly, BCV/BCVR treatment abolished the fibrin clots that otherwise were pronounced in heart and brain of IT-CD mice. We conclude that acute Tc infection triggered a subdued hemodynamic disorder, and the persistence of low-grade parasites contributed to a cardiovascular/cerebrovascular proinflammatory and prothrombotic response and fibrin deposition in mice. BCV/BCVR offer potential immunotherapies for reducing the recurrent clot formation and risk of stroke in CD.