Multi-therapeutic strategy targeting parasite and inflammation-related alterations to improve prognosis of chronic Chagas cardiomyopathy: a hypothesis-based approach

Abstract

Chagas disease (CD), caused by infection by the protozoan parasite Trypanosoma cruzi, presents as main clinical manifestation the chronic chagasic cardiomyopathy (CCC). CCC afflicts millions of people, mostly in Latin America, and vaccine and effective therapy are still lacking. Comprehension of the host/parasite interplay in the chronic phase of T. cruzi infection may unveil targets for rational trait-based therapies to improve CCC prognosis. In the present viewpoint, I critically summarise a collection of data, obtained by our network of collaborators and other groups on CCC and preclinical studies on pathogenesis, targeting identification for intervention and the use of drugs with immunomodulatory properties to improve CCC. In the last two decades, models combining mouse lineages and T. cruzi strains allowed replication of crucial clinical, histopathological, and immunological traits of CCC. This condition includes conduction changes (heart rate changes, arrhythmias, atrioventricular blocks, prolongation of the QRS complex and PR and corrected QT intervals), ventricular dysfunction and heart failure, CD8-enriched myocarditis, tissue remodeling and progressive fibrosis, and systemic inflammatory profile, resembling "cytokine storm". Studies on Chagas' heart disease pathogenesis begins to unveil the molecular mechanisms underpinning the inflammation-related cardiac tissue damage, placing IFNγ, TNF and NFκB signaling as upstream regulators of miRNAs and mRNAs associated with critical biological pathways as cell migration, inflammation, tissue remodeling and fibrosis, and mitochondrial dysfunction. Further, data on preclinical trials using hypothesis-based tools, targeting parasite and inflammation-related alterations, opened paths for multi-therapeutic approaches in CCC. Despite the long path taken using experimental CD models replicating relevant aspects of CCC and testing new therapies and therapeutic schemes, these findings may get lost in translation, as conceptual and economical challenges, underpinning the valley of death across preclinical and clinical trials. It is hoped that such difficulties will be overcome in the near future.

Fig. 1:. cytokines and inflammatory mediators may take part in parasite control but may also play a role in the pathogenesis of Chagas’ heart disease, fueling inflammation-related tissue damage. In the acute phase of the infection, antibodies (Ab) and low levels of cytokines (as TNF, IFNγ) and inflammatory mediator (as NO) are crucial for parasite control. As infection progresses to chronic phase, TNF, sTNFR1 and NO serum levels are associated with chronic chagasic cardiomyopathy (CCC) severity. Parasite persistence and this long-lasting systemic inflammatory profile scenario may contribute to inflammation-related heart tissue damage with increased expression of CC-chemokines / inflammation, TNF-and IFNγ-enriched milieu, miRNA/mRNA dysregulation, changes of ion channels expression, reactive oxygen species (ROS) increase, oxidative stress, mitochondrial dysfunction, increased MMP9 activity, hypertrophy, tissue remodeling and fibrosis, thus contributing to conduction and functional changes.

Fig. 2:. multi-therapeutic strategy targeting parasite and inflammation-related tissue changes impacted experimental chronic chagasic cardiomyopathy (CCC). Colombian-infected C57BL/6 mice showing clinical signs of CCC received vehicle (Veh), suboptimal dose of the trypanocidal drug benznidazole (Bz) or Bz plus the immunomodulator pentoxifylline (Bz+PTX). (A) The prolonged QTc, seen in vehicle-treated (Veh) infected mice was not impacted by Bz therapy, but restored, alike uninfected controls, after Bz+PTX therapy. (B) Data on gene expression in the heart tissue were reanalysed, focusing on the expression of molecules associated with cell migration (CCL3, CCL5, CXCL10, CXCL11, CXCR3), myocarditis (CD3ε, CD8a, CD4, CD19), inflammation (IFNγ, IL-10, IL-12a, IL-15, IL2R, IL-1Ra, IL-6, IL-7), and cytotoxic activity of T-cells (CTL; granzyme, perforin1). Compared with uninfected controls, in Veh-treated infected mice most of these genes were upregulated. Therapy with Bz and, crucially, Bz+PTX, mitigated the expression of these genes.

Fig. 3:. pharmacological and non-pharmacological potential candidates to compose multi-therapeutic strategies to confront the complexity of Chagas’ heart disease. Three major factors may sustain chronic chagasic cardiomyopathy (CCC): (i) parasite persistence (target by Low doses of Bz; New drugs), (ii) intrinsic cardiac alterations (target by the antiarrhythmic agent amiodarone; inhibitors of angiotensin converting enzyme - ACEi - and angiotensin receptor blockers - ARB; antioxidant agents or nutritional approaches using resveratrol and selenium), and (iii) immunological unbalance in heart and systemic inflammatory profile (target by immunoregulators as PTX and TGF signaling blocker, therapeutic vaccines, immunomodulatory properties of Low dose of Bz). Non-pharmacological strategies as physical exercises may also contribute to improve CCC prognosis.