Intra-host Trypanosoma cruzi parasite dynamics in naturally-infected macaques and Chagas disease progression

项目摘要 自然感染猕猴体内克氏锥虫寄生动态 和南美锥虫病进展 恰加斯病是一种主要的媒介传播寄生虫病， 原生动物寄生虫克氏锥虫，在美洲有600多万病例。 慢性肥厚性心肌病（chronic chagglycemia，CCC）是最常见的心肌病， 恰加斯病的表现，它在最初感染后多年发展， 20 - 40%的患者。然而，疾病进展仍然知之甚少，因为 需要长期随访，缺乏精确的生物标志物，广泛的寄生虫遗传学， 和生物多样性等等。一个主要的差距是， 发展中的严重疾病不能与那些可能留在 无症状慢性期，使任何预后不确定，并使患者并发症 护理和治疗。重要的是，越来越多的证据表明， 感染是由多种寄生虫株引起的。这种多重的影响 感染对疾病进展和临床表现的影响尚不清楚，但 菌株之间的相互作用可能会发生，这可能会影响疾病的进展。 因此，我们的总体目标是确定T.克氏寄生虫多样性 在慢性期的疾病进展，通过监测一个队列的自然- 感染的恒河猴。我们将跟踪自然感染的恰古猿， 已感染1 - 6年的动物的良好建立的队列。顺序 血液样本将用于通过qPCR和寄生虫 通过NGS进行基因分型，以评估24个月随访期间的寄生虫菌株动态- 起来这些将与ECG记录相关，以评估心脏功能。我们将 还对PBMC进行批量和单细胞RNA测序，以评估 根据寄生虫多样性的转录谱。这种系统免疫学方法 将告知疾病进展的免疫相关性。最后，我们将测量 血浆纤连蛋白降解和其他候选生物标志物， 通过寄生虫负荷和ECG改变测量的疾病进展。这些 研究将是更好地了解自然感染的恰加斯病进展的关键 宿主，并测试寄生虫遗传多样性在形成疾病进展中的作用。 连同潜在生物标志物的验证，这项工作预计将有一个 通过导致更好的治疗和预后， 霍乱患者

PROJECT SUMMARY Intra-host Trypanosoma cruzi parasite dynamics in naturally-infected macaques and Chagas disease progression Chagas disease is a major vector borne parasitic disease cause by the protozoan parasite Trypanosoma cruzi, with over 6 million cases in the Americas. Chronic chagasic cardiomyopathy (CCC) is the most common and life-threathening manifestation of Chagas disease, which develops many years after the initial infection in 20-40% of patients. However, disease progression is still poorly understood, due to the need for prolonged follow-up, the lack of precise biomarkers, extensive parasite genetic and biological diversity, among others. A major gap is that patients at increased risk of developing severe disease cannot be distinguished from those who may remain in the asymptomatic chronic stage, making any prognosis uncertain and complicating patient care and treatment. Importantly, there is growing evidence that a large proportion of infections are caused by multiple parasite strains. The implications of such multiple infections on disease progression and clinical manifestations are unclear, but interactions among strains are likely to occur, that may shape disease progression. Therefore, our general objective is to determine the effects of T. cruzi parasite diversity on disease progression during the chronic phase by monitoring a cohort of naturally- infected rhesus macaques. We will follow naturally-infected Chagasic macaques from a well established cohort of animals that have been infected for 1-6 years. Sequential blood samples will be used to measure parasite burden by qPCR and parasite genotyping through NGS to assess parasite strain dynamics over 24 months of follow- up. These will be associated with ECG recordings to assess cardiac function. We will also perform bulk and single cell RNA-sequencing of PBMCs to assess differences in transcriptional profiles according to parasite diversity. This system immunology approach will inform on immune correlates for disease progression. Finally, we will measure plasma fibronectin degradation and other candidate biomarkers, to correlate with disease progression as measured by parasite burden and ECG alterations. These studies will be key to better understand Chagas disease progression in naturally-infected hosts, and test for the role of parasite genetic diversity in shaping disease progression. Together with the validation of potential biomarkers, this work is expected to have an important translational impact by leading to better treatments and prognosis for Chagasic patients.