Cardiac Abnormalities in a Predictive Mouse Model of Chagas Disease

Francisco, Amanda Fortes; Sousa, Giovane R.; Vaughan, Mhairi; Langston, Harry; Khan, Archie; Jayawardhana, Shiromani; Taylor, Martin C.; Lewis, Michael D.; Kelly, John M.

doi:10.3390/pathogens12111364

Cited by 3 publications

(1 citation statement)

References 50 publications

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“…In this model, infected mice exhibited tissue damage, evidenced by the enhanced activity of serum levels of tissue-damage enzymes (LDH and GOT), and the increase in circulating pro-inflammatory monocytes (CD11b + Ly6C high ). Additionally, our model presents evidence of left ventricular dysfunction, which is consistent with various cardiac disorders observed in acute experimental models of Chagas disease. ,, These findings confirm the suitability of our model for analyzing and studying the robust early inflammatory response and the ventricular dysfunction triggered by the infection as well as for evaluating the restorative effects of fenofibrate.…”

Section: Discussionsupporting

confidence: 93%

Fenofibrate Induces a Resolving Profile in Heart Macrophage Subsets and Attenuates Acute Chagas Myocarditis

Ruiz Luque,

Cevey,

Pieralisi

et al. 2024

ACS Infect. Dis.

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Chagas disease, caused by Trypanosoma cruzi, stands as the primary cause of dilated cardiomyopathy in the Americas. Macrophages play a crucial role in the heart's response to infection. Given their functional and phenotypic adaptability, manipulating specific macrophage subsets could be vital in aiding essential cardiovascular functions including tissue repair and defense against infection. PPARα are ligand-dependent transcription factors involved in lipid metabolism and inflammation regulation. However, the role of fenofibrate, a PPARα ligand, in the activation profile of cardiac macrophages as well as its effect on the early inflammatory and fibrotic response in the heart remains unexplored. The present study demonstrates that fenofibrate significantly reduces not only the serum activity of tissue damage biomarker enzymes (LDH and GOT) but also the circulating proportions of pro-inflammatory monocytes (CD11b + LY6C high ). Furthermore, both CD11b + Ly6C low F4/80 high macrophages (MΦ) and recently differentiated CD11b + Ly6C high F4/80 high monocyte-derived macrophages (MdMΦ) shift toward a resolving phenotype (CD206 high ) in the hearts of fenofibrate-treated mice. This shift correlates with a reduction in fibrosis, inflammation, and restoration of ventricular function in the early stages of Chagas disease. These findings encourage the repositioning of fenofibrate as a potential ancillary immunotherapy adjunct to antiparasitic drugs, addressing inflammation to mitigate Chagas disease symptoms.

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Section: Discussionsupporting

confidence: 93%

Fenofibrate Induces a Resolving Profile in Heart Macrophage Subsets and Attenuates Acute Chagas Myocarditis

Ruiz Luque,

Cevey,

Pieralisi

et al. 2024

ACS Infect. Dis.

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The mitochondrial uncoupler 2,4-dinitrophenol modulates inflammatory and oxidative responses in Trypanosoma cruzi-induced acute myocarditis in mice

Caetano-da-Silva,

Gonçalves-Santos,

Domingues

et al. 2024

Cardiovascular Pathology

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Intermittent suppressive posaconazole therapy is ineffective at mitigating cardiac and digestive tract pathologies in an experimental model of chronic Chagas disease

Jayawardhana,

Olmo,

Fortes Francisco

et al. 2024

Preprint

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Infections withTrypanosoma cruzicause Chagas disease, a chronic condition that can give rise to debilitating cardiac and/or gastrointestinal damage. However, it is unclear why only ~30% of individuals progress to symptomatic pathology, why this can take decades to become apparent, and why there is such a wide range of disease outcomes. Disease pathology is a long-term cumulative process resulting from collateral damage caused by inflammatory immune responses that continually eliminate transient parasite infections in the heart and/or gastrointestinal tract. The guiding principle behind anti-parasitic drug development is that sterile cure is required to prevent progression to symptomatic pathology. Evidence suggests that the cumulative damage required to reach the symptomatic threshold is determined by a number of factors, including host and parasite genetics, which govern the intensity and location(s) of infection. Therefore, an alternative therapeutic strategy could involve long-term intermittent treatment, which may not confer sterile cure, but is able to suppress the parasite burden to a level where the disease does not become symptomatic within the life-time of the infected individual. To test this hypothesis, we used an experimental murine model that displays both cardiac and digestive tract pathology. Mice were given intermittent treatment with posaconazole, under conditions that reduced the parasite burden by >99%, but did not confer sterile clearance. Our results show that this did not provide long-term protection against the key cardiac or gastrointestinal manifestations of Chagas disease, and that sterile cure should remain the single goal of the drug development community.

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Cardiac Abnormalities in a Predictive Mouse Model of Chagas Disease

Cited by 3 publications

References 50 publications

Fenofibrate Induces a Resolving Profile in Heart Macrophage Subsets and Attenuates Acute Chagas Myocarditis

Fenofibrate Induces a Resolving Profile in Heart Macrophage Subsets and Attenuates Acute Chagas Myocarditis

The mitochondrial uncoupler 2,4-dinitrophenol modulates inflammatory and oxidative responses in Trypanosoma cruzi-induced acute myocarditis in mice

Intermittent suppressive posaconazole therapy is ineffective at mitigating cardiac and digestive tract pathologies in an experimental model of chronic Chagas disease

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