Deciphering the mechanism of action of carnitine, a novel treatment for chronic Chagas disease

点击翻译按钮获取中文摘要

Project summary/abstract Chagas disease is a leading but poorly-understood infectious cause of heart failure, resulting from infection with Trypanosoma cruzi parasites. T. cruzi has a worldwide prevalence of 7 million, with over 300,000 infected individuals in the United States. Chagas disease causes a significant burden on health care and the economy of over $7 billion annually in total costs. No vaccines are available, and current treatment options are limited by significant adverse effects, long treatment duration, and poor efficacy in late-stage disease. New treatment options for Chagas disease have therefore been identified as a research priority by the World Health Organization, the World Heart Federation, and the Inter-American Society of Cardiology. Our work has identified L-carnitine as a novel treatment regimen for acute and chronic T. cruzi infection, able to improve readouts of cardiac damage and disease severity, and with a good safety profile alone and in combination with the antiparasitic standard-of-care benznidazole. L-carnitine has high potential for clinical translatability, being affordable, readily available, and already FDA-approved to treat inborn metabolic disorders. However, the mechanism of action of L-carnitine in chronic T. cruzi infection is currently unknown. The overall objective of this proposal is to elucidate this mechanism of action, enabling in the long-term continued development of L- carnitine into clinical implementation, and the identification of new alternative treatment regimens for Chagas disease. L-carnitine differs from classic antiparasitic agents in that it improves T. cruzi infection outcomes without reducing parasite load. Thus, results will also expand our understanding of Chagas disease pathogenesis. The central hypothesis of this proposal is that L-carnitine’s mechanism of action is mediated by lessening cardiac fatty acid oxidation, increasing cardiac glucose metabolism, and lowering infection-induced cardiac contractile impairment. This central hypothesis will be tested in experimental models of chronic T. cruzi infection, using three complementary yet independent aims. We will combine metabolomic and pharmacological analyses of the impact of L-carnitine on fatty acid oxidation (aim 1) and on glucose oxidation (aim 2) with echocardiographic analyses of the impact of L-carnitine treatment on cardiac contractility (aim 3). The proposed research is innovative because it centers around a new candidate treatment regimen for Chagas disease with novel mechanism of action, and it will lead to the identification of additional avenues for Chagas disease treatment. The proposed research is significant because it will lead to a rigorous understanding of L- carnitine’s mechanism of action, facilitating its progression to the clinic, and will identify novel candidates for further Chagas disease drug development. Overall, this work will provide valuable new translational avenues for Chagas disease treatment, as well as significant fundamental insight into cardiac Chagas disease pathogenesis.