Alterations to the cardiac metabolome induced by chronicT. cruziinfection relate to the degree of cardiac pathology

Abstract

Chronic Chagasic cardiomyopathy (CCC) is a Neglected Tropical Disease caused by the parasite Trypanosoma cruzi. The pathognomonic findings in symptomatic CCC patients and animal models includes diffuse cardiac fibrosis and persistent inflammation with persistent parasite presence in the heart. This study investigated chemical alterations in different regions of the heart in relation to cardiac pathology indicators to better understand the long-term pathogenesis of this neglected disease. We used data from echocardiography, fibrosis biomarkers, and histopathological analysis to fully evaluate cardiac pathology. Metabolites isolated from the pericardial and endocardial sides of the right ventricular myocardium were analyzed by liquid chromatography tandem mass spectrometry. The endocardial sections contained significantly less cardiac inflammation and fibrosis than the pericardial sections. Cardiac levels of acylcarnitines, phosphocholines, and other metabolites were significantly disrupted in accordance with cardiac fibrosis, inflammation, and serum fibrosis biomarker levels. These findings have potential implications in treatment and monitoring for CCC patients.

Localized cardiac metabolic trajectories and post-infectious metabolic sequelae in experimental Chagas disease

“…Based on our findings of tissue location-specific adverse metabolic trajectories during infection (Fig. 1C) and our prior observations of relation between experimental CD severity and magnitude of metabolic perturbation [31][32][33] , we hypothesized that the lack of clinical efficacy of BNZ in late-stage CD may be due to an inability to restore infection-induced metabolic alterations at specific cardiac locations. To test this hypothesis, mice were treated with BNZ standard-of-care (100 mg/kg BNZ for 18 days, beginning 69 days post-infection) (Fig.…”

“…We addressed these questions in the context of T. cruzi infection over time and following treatment with either the standard-of-care antiparasitic BNZ 56 , or an experimental combination of BNZ and Tc24-C4/E6020-SE therapeutic vaccine, with a focus on infection-induced metabolic alterations. We elected to focus on metabolism given its extensive association with cardiac function 57 -59 , our findings of correlations between disease severity and degree of metabolic perturbation in chronic CD 32 , and our prior report of improved infection outcome via metabolic modulation in acute CD, independent of parasite burden 33 .…”

“…In CD, gradients of parasite burden, metabolic alterations and immune responses were observed in the heart 30,31 . Cardiac metabolic alterations were correlated to the degree of cardiac inflammation, and to serum profibrotic cytokine levels 32 . These metabolic alterations were causally linked to T. cruzi infection outcomes, and metabolism-targeting strategies prevented acute CD mortality in mouse models 33 .…”

Dysregulation of Glycerophosphocholines in the Cutaneous Lesion Caused by Leishmania major in Experimental Murine Models

“…Elevation of PCs is also a marker of the switch from monocyte to macrophage [ 33 ]. Increased PCs may also reflect phagolysosome membranes given the intracellular lifestyle of L. major [ 30 ], though PC elevation was also observed during infection with T. cruzi, which resides in the cytosol [ 34 , 35 ]. Lastly, PCs may also be derived from other immune cells attracted to the site of infection, such as T cells and dendritic cells.…”

Quo vadis? Central Rules of Pathogen and Disease Tropism

“…Although cecal and cervical azithromycin levels were comparable, C. trachomatis were less readily cleared from the cecum ( Yeruva et al., 2013 ). Importantly, although PK/PD studies are usually performed in healthy animals, there is a need to expand these studies to the context of infection, where select disease tropism may alter drug distribution and clearance ( Hoffman et al., 2020 ). Tropism considerations may thus be a major reason for the failure in vivo of new chemical entities that were promising in vitro.…”