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

自然感染的猕猴体内克氏锥虫寄生虫动态和恰加斯病进展

• 批准号: 10645822
• 负责人: ERIC DUMONTEIL
• 金额: $ 19.06万
• 依托单位: TULANE UNIVERSITY OF LOUISIANA
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-02-06 至 2025-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10645822
• 关键词: Americas; Animal Model; Animals; Biodiversity; Biological Markers; Blood; Blood specimen; Cessation of life; Chagas Disease; Chronic; Chronic Phase; Clinical; Data; Disease; Disease Progression; Early identification; Economics; Electrocardiogram; Fibronectins; Gene Expression Profile; Genetic Variation; Genotype; Human; Immune; Immune response; Immunology; In Vitro; Infection; Lead; Life; Macaca; Macaca mulatta; Measures; Megacolon; Methods; Monitor; Names; Parasites; Parasitic Diseases; Pathogenesis; Patient Care; Patients; Peripheral Blood Mononuclear Cell; Pharmaceutical Preparations; Plasma; Play; Predisposition; Prognosis; Risk; Role; Shapes; System; Testing; Time; Trypanosoma cruzi; Validation; Virulence; Work; burden of illness; candidate marker; chagasic cardiomyopathy; chronic infection; cohort; disability-adjusted life years; early detection biomarkers; follow-up; heart function; improved; in vivo; neglected tropical diseases; potential biomarker; response; single-cell RNA sequencing; transcriptomics; translational impact; vector; vector-borne; years of life lost

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.

项目摘要 主持锥体内锥虫在天然感染猕猴中的寄生虫动力学 和查加斯病进展 查加斯病是主要的载体寄生疾病。 原生动物寄生虫锥虫克鲁齐（Cruzi），美洲有超过600万例病例。 慢性chagasic心肌病（CCC）是最常见和生命的最常见的 最初感染后多年发展的Chagas疾病的表现 20-40％的患者。但是，由于 需要长时间的随访，缺乏精确的生物标志物，广泛的寄生虫遗传 和生物多样性等。一个主要差距是，患者的风险增加 发展严重疾病不能与可能留在的人区分开 无症状的慢性阶段，使任何预后不确定且复杂的患者 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菌株引起的。这种倍数的含义 疾病进展和临床表现的感染尚不清楚，但 可能会发生菌株之间的相互作用，这可能会影响疾病进展。 因此，我们的总体目标是确定克鲁兹寄生虫多样性的影响 通过监测自然的队列，关于慢性期的疾病进展 感染的恒河猕猴。我们将遵循自然感染的chagasic猕猴 已经感染了1 - 6年的动物队列良好。顺序 血液样本将用于测量QPCR和寄生虫的寄生虫负担 通过NGS进行基因分型，以评估24个月后续24个月的寄生虫菌株动力学 向上。这些将与心电图记录有关，以评估心脏功能。我们将 还执行PBMC的批量和单细胞RNA测序以评估 根据寄生虫多样性的转录曲线。这种系统免疫学方法 将告知疾病进展的免疫相关。最后，我们将衡量 血浆纤连蛋白降解和其他候选生物标志物与 通过寄生虫负担和心电图改变，疾病进展。这些 研究将是更好地了解自然感染的Chagas疾病进展的关键 宿主，并测试寄生虫遗传多样性在塑造疾病进展中的作用。 再加上潜在生物标志物的验证，这项工作有望具有 重要的翻译影响通过导致更好的治疗和预后 chagasic患者。