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Abstract：
Chagas disease causes a cardiac illness characterized by immunoinflammatory reactions leading to myocardial fibrosis and remodeling. The development of Chronic Chagas Cardiomyopathy (CCC) in some patients while others remain asymptomatic is not fully understood, but dysregulated inflammatory responses are implicated. The Aryl hydrocarbon receptor (AhR) plays a crucial role in regulating inflammation. Certain tryptophan (Trp) metabolites have been identified as AhR ligands with regulatory functions.
We investigated AhR expression, agonist response, ligand production, and AhR-dependent responses, such as IDO activation and regulatory T (Treg) cells induction, in two T. cruzi-infected mouse strains (B6 and Balb/c) showing different polymorphisms in AhR. Furthermore, we assessed the metabolic profile of Trp catabolites and AhR agonistic activity levels in plasma samples from patients with chronic Chagas disease (CCD) and healthy donors (HD) using a luciferase reporter assay and liquid chromatography-mass spectrophotometry (LC-MS) analysis. T. cruzi-infected B6 mice showed impaired AhR-dependent responses compared to Balb/c mice, including reduced IDO activity, kynurenine levels, Treg cell induction, CYP1A1 up-regulation, and AhR expression following agonist activation. Additionally, B6 mice exhibited no detectable AhR agonist activity in plasma and displayed lower CYP1A1 up-regulation and AhR expression upon agonist activation. Similarly, CCC patients had decreased AhR agonistic activity in plasma compared to HD patients and exhibited dysregulation in Trp metabolic pathways, resulting in altered plasma metabolite profiles. Notably, patients with severe CCC specifically showed increased N-acetylserotonin levels in their plasma. The methods and findings presented here contribute to a better understanding of CCC development mechanisms and may identify potential specific biomarkers for T. cruzi infection and the severity of associated heart disease. These insights could be valuable in designing new therapeutic strategies. Ultimately, this research aims to establish the AhR agonistic activity and Trp metabolic profile in plasma as an innovative, non-invasive predictor of prognosis for chronic Chagas disease.
We investigated AhR expression, agonist response, ligand production, and AhR-dependent responses, such as IDO activation and regulatory T (Treg) cells induction, in two T. cruzi-infected mouse strains (B6 and Balb/c) showing different polymorphisms in AhR. Furthermore, we assessed the metabolic profile of Trp catabolites and AhR agonistic activity levels in plasma samples from patients with chronic Chagas disease (CCD) and healthy donors (HD) using a luciferase reporter assay and liquid chromatography-mass spectrophotometry (LC-MS) analysis. T. cruzi-infected B6 mice showed impaired AhR-dependent responses compared to Balb/c mice, including reduced IDO activity, kynurenine levels, Treg cell induction, CYP1A1 up-regulation, and AhR expression following agonist activation. Additionally, B6 mice exhibited no detectable AhR agonist activity in plasma and displayed lower CYP1A1 up-regulation and AhR expression upon agonist activation. Similarly, CCC patients had decreased AhR agonistic activity in plasma compared to HD patients and exhibited dysregulation in Trp metabolic pathways, resulting in altered plasma metabolite profiles. Notably, patients with severe CCC specifically showed increased N-acetylserotonin levels in their plasma. The methods and findings presented here contribute to a better understanding of CCC development mechanisms and may identify potential specific biomarkers for T. cruzi infection and the severity of associated heart disease. These insights could be valuable in designing new therapeutic strategies. Ultimately, this research aims to establish the AhR agonistic activity and Trp metabolic profile in plasma as an innovative, non-invasive predictor of prognosis for chronic Chagas disease.
摘要：
■恰加斯病引起心脏疾病，其特征是导致心肌纤维化和重塑的免疫炎症反应。一些患者的慢性Chagas心肌病（CCC）的发展，而另一些患者仍然无症状，尚不完全了解。但与炎症反应失调有关.芳香烃受体（AhR）在调节炎症中起着至关重要的作用。某些色氨酸(Trp)代谢物已被鉴定为具有调节功能的AhR配体。
■我们研究了AhR表达，激动剂反应，配体生产，和AhR依赖的反应，如IDO激活和调节性T（Treg）细胞诱导，在AhR中显示不同多态性的两个克氏杆菌感染的小鼠品系（B6和Balb/c）中。此外，我们使用荧光素酶报告基因测定和液相色谱-质谱(LC-MS)分析评估了慢性查加斯病(CCD)患者和健康供体(HD)血浆样本中Trp分解代谢产物的代谢谱和AhR激动活性水平.与Balb/c小鼠相比，T.cruzi感染的B6小鼠显示出AhR依赖性反应受损，包括减少IDO活动，犬尿氨酸水平,Treg细胞诱导,CYP1A1上调，和激动剂激活后的AhR表达。此外,B6小鼠在血浆中没有表现出可检测的AhR激动剂活性,并且在激动剂激活时表现出更低的CYP1A1上调和AhR表达。同样，与HD患者相比，CCC患者血浆中的AhR激动活性降低，并且在Trp代谢途径中表现出失调，导致血浆代谢物谱改变。值得注意的是,重度CCC患者血浆中N-乙酰5-羟色胺水平升高.本文提出的方法和发现有助于更好地理解CCC的发展机制，并可能确定克氏锥虫感染的潜在特异性生物标志物和相关心脏病的严重程度。这些见解在设计新的治疗策略时可能是有价值的。最终,本研究旨在建立血浆中AhR激动活性和Trp代谢谱，慢性查加斯病预后的非侵入性预测指标。
■我们研究了AhR表达，激动剂反应，配体生产，和AhR依赖的反应，如IDO激活和调节性T（Treg）细胞诱导，在AhR中显示不同多态性的两个克氏杆菌感染的小鼠品系（B6和Balb/c）中。此外，我们使用荧光素酶报告基因测定和液相色谱-质谱(LC-MS)分析评估了慢性查加斯病(CCD)患者和健康供体(HD)血浆样本中Trp分解代谢产物的代谢谱和AhR激动活性水平.与Balb/c小鼠相比，T.cruzi感染的B6小鼠显示出AhR依赖性反应受损，包括减少IDO活动，犬尿氨酸水平,Treg细胞诱导,CYP1A1上调，和激动剂激活后的AhR表达。此外,B6小鼠在血浆中没有表现出可检测的AhR激动剂活性,并且在激动剂激活时表现出更低的CYP1A1上调和AhR表达。同样，与HD患者相比，CCC患者血浆中的AhR激动活性降低，并且在Trp代谢途径中表现出失调，导致血浆代谢物谱改变。值得注意的是,重度CCC患者血浆中N-乙酰5-羟色胺水平升高.本文提出的方法和发现有助于更好地理解CCC的发展机制，并可能确定克氏锥虫感染的潜在特异性生物标志物和相关心脏病的严重程度。这些见解在设计新的治疗策略时可能是有价值的。最终,本研究旨在建立血浆中AhR激动活性和Trp代谢谱，慢性查加斯病预后的非侵入性预测指标。
