Crilly Nathan P, Zita Marcelle Dina, Beaver Alexander K, Sysa-Shah Polina, Bhalodia Aashik, Gabrielson Kathy, Adamo Luigi, Mugnier Monica R
Department of Molecular and Comparative Pathobiology, Johns Hopkins University, School of Medicine, Baltimore, Maryland, USA.
Department of Molecular Microbiology and Immunology, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland, USA.
Microbiol Spectr. 2025 Feb 4;13(2):e0162324. doi: 10.1128/spectrum.01623-24. Epub 2025 Jan 10.
is a protozoan parasite that causes human and animal African trypanosomiases (HAT and AAT). Cardiac symptoms are commonly reported in HAT patients, and intracardiac parasites with accompanying myocarditis have been observed in both natural hosts and animal models of infection. Despite the importance of as a cause of cardiac dysfunction and the dramatic socioeconomic impact of African trypanosomiases in sub-Saharan Africa, there are currently no reproducible murine models of associated cardiomyopathy. We present the first clinically relevant, reproducible murine model of cardiac dysfunction in chronic infection. Similar to humans, mice showed histological evidence of myocarditis and elevation of serum NT-proBNP with electrocardiographic abnormalities. Serum NT-proBNP levels were elevated prior to the development of severe ventricular dysfunction. On flow cytometry, myocarditis was associated with an increase of most myocardial immune cell populations, including multiple T cell and macrophage subsets, corroborating the notion that associated cardiac damage is an immune-mediated event. This novel mouse model represents a powerful and practical tool to investigate the pathogenesis of -mediated heart damage and supports the development of therapeutic options for -associated cardiac disease. In characterizing this model, we provide evidence that causes cardiac disease, and we suggest that immunopathology is an important contributor to cardiac pathology. Along with other recent studies, our work demonstrates the importance of extravascular spaces, including the heart, for pathogenesis.
African trypanosomiasis is a neglected tropical disease affecting both people and cattle, which represents a major public health problem in sub-Saharan Africa with an enormous socioeconomic impact. Cardiac disease represents an underappreciated clinical manifestation of African trypanosomiasis that may lead to lifelong illness despite successful treatment of infection. However, this aspect of African trypanosomiasis remains poorly understood, partially due to a lack of well-characterized and practical animal models. In this study, we present the development and characterization of a novel, reproducible, and cost-effective mouse model of cardiac dysfunction in African trypanosomiasis. We demonstrate that this model recapitulates major features of cardiac dysfunction in natural infection, including the presence of parasites in the cardiac interstitial spaces, alterations of cardiac biomarkers, and functional changes. This model represents a resource to support the understanding of cardiac complications of trypanosomiasis and the development of new therapies to prevent and treat cardiac involvement in African trypanosomiasis.
是一种原生动物寄生虫，可导致人类和动物的非洲锥虫病（人类非洲锥虫病和动物非洲锥虫病）。人类非洲锥虫病患者通常会出现心脏症状，在自然宿主和感染动物模型中均观察到心脏内有寄生虫并伴有心肌炎。尽管作为心脏功能障碍的病因很重要，且非洲锥虫病在撒哈拉以南非洲地区具有巨大的社会经济影响，但目前尚无与相关心肌病可重复的小鼠模型。我们提出了首个慢性感染中与心脏功能障碍相关的、具有临床相关性且可重复的小鼠模型。与人类相似，小鼠表现出心肌炎的组织学证据以及血清N末端脑钠肽前体（NT-proBNP）升高并伴有心电图异常。在严重心室功能障碍出现之前，血清NT-proBNP水平就已升高。通过流式细胞术检测发现，心肌炎与大多数心肌免疫细胞群体增加有关，包括多个T细胞和巨噬细胞亚群，这证实了相关心脏损伤是免疫介导事件的观点。这个新的小鼠模型是研究介导的心脏损伤发病机制的有力且实用的工具，并支持开发针对相关心脏病的治疗方案。在对该模型进行表征时，我们提供了导致心脏病的证据，并表明免疫病理学是心脏病理学的重要促成因素。与其他近期研究一起，我们的工作证明了包括心脏在内的血管外间隙在发病机制中的重要性。
非洲锥虫病是一种被忽视的热带病，影响人类和牛群，是撒哈拉以南非洲地区的一个主要公共卫生问题，具有巨大的社会经济影响。心脏病是非洲锥虫病一种未得到充分认识的临床表现，尽管感染已成功治愈，但仍可能导致终身疾病。然而，非洲锥虫病的这一方面仍知之甚少，部分原因是缺乏特征明确且实用的动物模型。在本研究中，我们展示了一种新型、可重复且具有成本效益的非洲锥虫病心脏功能障碍小鼠模型的开发和表征。我们证明该模型概括了自然感染中心脏功能障碍的主要特征，包括心脏间质空间中存在寄生虫、心脏生物标志物的改变以及功能变化。这个模型是一种资源，有助于理解锥虫病的心脏并发症，并支持开发预防和治疗非洲锥虫病心脏受累的新疗法。
