Treatment with low-dose bicistronic immunotherapy mitigates parasite persistence and improves serological and cardiac outcomes in adult mice infected with <i>Trypanosoma cruzi</i>: comparative analysis with benznidazole.
Bicistronic immunotherapy showed over 95% control of parasite burden in mice infected with Trypanosoma cruzi, outperforming benznidazole in reducing inflammation and cardiac pathology.
Where it sits
this study against the rest of the lypressin corpusSummary and findings
This study evaluated the effects of bicistronic immunotherapy (BCV and BCVR) compared to benznidazole (BZN) in adult mice infected with Trypanosoma cruzi. The treatments were administered at doses of 0.5 mg/kg for BCV and BCVR, and 50 mg/kg for BZN over 6 weeks. Results indicated that all treatments achieved over 95% control of parasite burden.
Abstract
Chagas disease (CD), caused by <i>Trypanosoma cruzi</i> (<i>Tc</i>), 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.
Background
Chagas disease, caused by Trypanosoma cruzi, is challenging to treat in adults due to the limited efficacy and adverse effects of benznidazole. Previous studies have indicated that alternative therapies may be necessary to improve treatment outcomes. This study investigates the efficacy of a newly-designed immunotherapy, both with and without an adjuvant, to address the limitations of existing treatments.
Methods
The study utilized adult C57BL/6 mice infected with Trypanosoma cruzi. Mice were treated with bicistronic immunotherapy (BCV and BCVR) at a dose of 0.5 mg/kg in two doses with a 21-day interval, or benznidazole at 50 mg/kg for 6 weeks. Primary outcomes included parasite burden, biomarkers of inflammation, fibrosis, and cardiac function.
Results
All treatments (BCV, BCVR, and BZN) achieved >95% control of parasite burden. BCV significantly reduced tissue inflammatory infiltrate and peripheral biomarkers of inflammation, necrosis, and heart involvement. Pro-fibrotic gene expression and cardiac hypertrophy were blocked in CD mice post-treatment (BCV > BCVR = BZN). Morphological changes in the LV walls' thickness were abated by BCV/BCVR, while BZN moderately controlled LV dysfunction.
Interpretation
While the study presents promising results for bicistronic immunotherapy, the effect sizes, particularly for BZN, were noted to be moderate. The findings suggest that BCV and BCVR may offer advantages over BZN, but the reliance on animal models limits the direct applicability to human conditions. The study's design and outcomes warrant cautious interpretation regarding clinical relevance.
Key findings
- Treatment with BCV, BCVR or BZN achieved >95% control of parasite burden.
- BCV significantly reduced tissue inflammatory infiltrate and peripheral biomarkers of inflammation, necrosis, and heart involvement.
- 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.
- BZN moderately controlled the LV dysfunction in CD mice.
Limitations
- Conducted in adult mice, limiting human applicability.
- Short follow-up duration may not assess long-term effects.
- Single-site study, potential for site-specific biases.
- Small sample size not reported in abstract.