Fat tissue regulates the pathogenesis and severity of cardiomyopathy in murine chagas disease

Abstract

Chronic Chagas cardiomyopathy (CCC) caused by a parasite Trypanosoma cruzi is a life-threatening disease in Latin America, for which there is no effective drug or vaccine. The pathogenesis of CCC is complex and multifactorial. Previously, we demonstrated T. cruzi infected mice lose a significant amount of fat tissue which correlates with progression of CCC. Based on this an investigation was undertaken during both acute and chronic T. cruzi infection utilizing the FAT-ATTAC murine model (that allows modulation of fat mass) to understand the consequences of the loss of adipocytes in the regulation of cardiac parasite load, parasite persistence, inflammation, mitochondrial stress, ER stress, survival, CCC progression and CCC severity. Mice were infected intraperitoneally with 5x104 and 103 trypomastigotes to generate acute and chronic Chagas models, respectively. Ablation of adipocytes was carried out in uninfected and infected mice by treatment with AP21087 for 10 days starting at 15DPI (acute infection) and at 65DPI (indeterminate infection). During acute infection, cardiac ultrasound imaging, histological, and biochemical analyses demonstrated that fat ablation increased cardiac parasite load, cardiac pathology and right ventricular dilation and decreased survival. During chronic indeterminate infection ablation of fat cells increased cardiac pathology and caused bi-ventricular dilation. These data demonstrate that dysfunctional adipose tissue not only affects cardiac metabolism but also the inflammatory status, morphology and physiology of the myocardium and increases the risk of progression and severity of CCC in murine Chagas disease.

Sex differences in cardio-pulmonary pathology of SARS-CoV2 infected and Trypanosoma cruzi co-infected mice

“…Indeed, previously we 5 demonstrated that pathogens like T. cruzi and Mycobacterium tuberculosis persists in WAT and that loss 5 of fat cells increases the risk of disease manifestation. For example, we showed that loss of body fat 5 correlated to increased cardiomyopathy in chronic Chagas disease murine model and increased pulmonary 5 pathology in aerosol infected TB murine model [20,22]. Our current study suggests that WAT may serve 5 as a reservoir for CoV2, sparing the lungs from the viral burden and infection severity.…”

“…Tissue lysates were prepared as previously described [20]. Each sample containing 30 μ g of protein were 1 resolved on SDS-PAGE and separately on native gel electrophoresis and the proteins were transferred to 1 nitrocellulose membrane for immunoblot analysis.…”

“…The copyright holder for this preprint this version posted September 18, 2021. ; https://doi.org/10.1101/2021.09.18.460895 doi: bioRxiv preprint housed in groups of 3-5 per cage with unlimited access to water and chow. Once they reached indeterminate stage [20] (65 DPI; no circulating parasitemia and pro-inflammatory markers), one set of mice was coinfected intra-nasally with 1x10 4 pfu SARS-CoV2 (NR-52281, Isolate USA-WA1/2020 COV-2 virus, NIH-BEI resources). After 10 DPI CoV2 (i.e.…”

“…ApN levels and progression of cardiomyopathy during CD, wherein elevated levels of C-ApN were 3 associated with mortality due to cardiac dilation [20]. Here, we used native gel electrophoresis to 3 quantitate HMW-ApN and SDS-PAGE to quantitate the levels of globular ApN (gAd) to determine 3 whether the distribution pattern of ApN in the hearts differed between the sexes and infections (Fig.…”

Molecular and Clinical Aspects of Chronic Manifestations in Chagas Disease: A State-of-the-Art Review

“…Using a FAT-ATTAC murine model, in which mice were inoculated intra-peritoneally with trypomastigotes to cause acute and chronic disease, Lizardo et al [60] demonstrated the correlation of Chronic Ch-CMP progression to lose adipose tissue. During the acute phase, increased lipid accumulation in myocardial cells, infiltration of immune cells and elevated number of parasites was reported.…”