An integrated approach to understand and diagnose congenital Chagas disease

了解和诊断先天性恰加斯病的综合方法

• 批准号: 10522685
• 负责人: Natalie McCarter Bowman
• 金额: $ 73.98万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-06-15 至 2027-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10522685
• 关键词: Adult; Affect; Age; Algorithms; Americas; Area; Biological Assay; Birth; Blood; Bolivia; Brain; Cardiac; Cardiomyopathies; Chagas Disease; Characteristics; Child; Chronic; Clinical; Clinical Research; Cohort Studies; Conflict (Psychology); DNA; Diagnosis; Diagnostic; Diagnostic tests; Disease; Early Diagnosis; Early identification; Early treatment; Enrollment; Environmental Risk Factor; Epidemiology; Equipment; Family; Gene Expression; Gene Expression Profile; Gene Expression Regulation; Genetic; Genomics; Genotype; Goals; Heart; High Prevalence; Hospitals; Immune Evasion; Infant; Infection; Invaded; Lateral; Latin America; Lead; Life; Liver; Medical History; Molecular; Morbidity - disease rate; Newborn Infant; Outcome; Parasites; Parasitic infection; Pathogenesis; Performance; Perinatal mortality demographics; Persons; Pharmaceutical Preparations; Placenta; Polymerase; Polymerase Chain Reaction; Pregnancy; Pregnant Women; Premature Birth; Prospective cohort; Resource-limited setting; Resources; Risk; Risk Factors; Serology; Serology test; South America; Symptoms; Systemic disease; Techniques; Testing; Time; Tissues; Travel; Trypanosoma cruzi; Up-Regulation; Vertical Disease Transmission; Woman; accurate diagnosis; cohort; congenital infection; curative treatments; deep sequencing; detection method; diagnostic algorithm; diagnostic assay; diagnostic tool; disease transmission; epidemiology study; experience; gastrointestinal; high risk; high risk infant; improved; infancy; infant infection; infection risk; innovation; laboratory equipment; multidisciplinary; neonatal death; neonatal infection; neonate; novel; novel diagnostics; pathogen; performance tests; perinatal period; point of care; point-of-care diagnostics; recombinase; risk stratification; rural area; screening; seropositive; tool; transcriptomics; transmission process; vector-borne; young woman

PROJECT SUMMARY/ABSTRACT Nearly 6 million people worldwide are infected with the parasite Trypanosoma cruzi, the agent of Chagas disease, and vertical transmission accounts for 22% of all new infections. Between 5-10% of T. cruzi-infected women will transmit the infection to their children, leading to a spectrum of disease in the infant: the majority of infected infants are asymptomatic but up to 40% have systemic disease involving the heart, brain, or liver. Congenital infection can also result in premature birth, or, in rare cases, neonatal death. Nearly a third of infants, even those with no symptoms, will develop chronic cardiac and gastrointestinal problems later in life. Unfortunately, up to 75% of affected infants do not receive timely diagnosis or treatment. Most T. cruzi infections occur in resource-limited rural areas of Latin America where advanced diagnostic tools are unavailable. Because treatment is safer and more effective during infancy than in older children and adults, early diagnosis is critical. Infected infants will continue to miss their opportunity for lifesaving treatment until we develop better algorithms to identify high-risk infants and accurately diagnose congenital Chagas disease in the perinatal period. Our long-term goal is to accelerate the elimination of congenital Chagas disease by developing tools to predict and diagnose T. cruzi infections in infants. In this project, we propose to (1) identify maternal clinical and epidemiological risk factors for vertical transmission; (2) investigate the parasite’s mechanisms of invading through the placenta using parasite genotyping and identifying gene expression signatures associated with transmission; and (3) optimize and validate a new test for congenital T. cruzi infection using recombinase polymerase amplification (RPA), a DNA detection method that can be performed without advanced laboratory equipment or expertise and is adaptable to point-of-care platforms. To accomplish these goals, we propose a cohort study of pregnant women and their infants in Santa Cruz, Bolivia, a highly endemic area for T. cruzi. We hypothesize that by combining traditional epidemiological analyses with cutting- edge genomic techniques, we can better predict which infants born to women infected with T. cruzi are at highest risk of congenital infection. We also hypothesize that a new RPA assay will allow us to diagnose these infants more frequently and earlier than current standard diagnostics, which perform poorly to detect congenital infection in neonates. In Aim 1, we will identify risk factors for vertical transmission in a cohort of T. cruzi- infected women to better identify high-risk infants. In Aim 2, we will characterize parasite genetic factors associated with vertical transmission of T. cruzi using genotyping and transcriptomics. Finally, in Aim 3, we will optimize our RPA assay and test it in the clinical setting to evaluate its ability to diagnose neonates with congenital Chagas disease. Our innovative approach will integrate field epidemiology, cutting-edge sequencing techniques, and new diagnostics to identify infected infants in the first weeks of life. These advances have the potential to lead to a paradigm shift to accelerate cure of Chagas disease’s youngest victims.

项目摘要/摘要 全世界有近600万人感染了查加斯的代理人克氏锥虫寄生虫 疾病，垂直传播占所有新感染病例的22%。感染克鲁兹毛滴虫的人中有5%-10% 妇女会将感染传染给她们的孩子，导致婴儿患上一系列疾病：大多数 受感染的婴儿没有症状，但多达40%的婴儿有涉及心脏、大脑或肝脏的系统性疾病。 先天性感染也可能导致早产，在极少数情况下，还会导致新生儿死亡。近三分之一的人 婴儿，即使是那些没有症状的婴儿，在以后的生活中也会出现慢性心脏和胃肠道问题。 不幸的是，高达75%的受影响婴儿没有得到及时的诊断或治疗。大多数克氏锥虫 感染发生在拉丁美洲资源有限的农村地区，那里有先进的诊断工具 不可用。因为婴儿期的治疗比年龄较大的儿童和成年人更安全和有效， 早期诊断至关重要。受感染的婴儿将继续错过救命治疗的机会，直到我们 开发更好的算法来识别高危婴儿并准确诊断先天性恰加斯病 围产期围产期。我们的长期目标是通过以下方式加快消除先天性恰加斯病 开发预测和诊断婴儿毛滴虫感染的工具。在这个项目中，我们建议(1)确定 孕产妇垂直传播的临床和流行病学危险因素；(2)调查寄生虫的 利用寄生虫基因分型和基因表达鉴定胎盘侵袭机制 与传播相关的特征；以及(3)优化和验证先天性毛滴虫的新测试 使用重组酶聚合酶扩增(RPA)的感染，这是一种可以执行的DNA检测方法 没有先进的实验室设备或专业知识，并适用于护理点平台。要完成 为了实现这些目标，我们建议对玻利维亚圣克鲁斯的孕妇和她们的婴儿进行一项队列研究，这是一个高度 克鲁兹毛滴虫的流行区。我们假设通过将传统的流行病学分析与切割相结合- 边缘基因组技术，我们可以更好地预测感染了克鲁兹旋毛虫的妇女所生的婴儿 先天感染的风险最高。我们还假设，一种新的RPA检测将使我们能够诊断这些 比目前的标准诊断更频繁和更早的婴儿，这些诊断在检测先天性心脏病方面表现不佳 新生儿感染。在目标1中，我们将确定克鲁兹毛滴虫垂直传播的风险因素。 受感染的妇女更好地识别高危婴儿。在目标2中，我们将描述寄生虫的遗传因素 利用基因分型和转录组学与克鲁兹毛滴虫垂直传播相关。最后，在目标3中，我们将 优化我们的RPA检测方法，并在临床环境中进行测试，以评估其诊断新生儿肺炎的能力 先天性恰加斯病。我们的创新方法将把现场流行病学、尖端测序 技术和新的诊断方法，以在婴儿出生后的头几周识别受感染的婴儿。这些进步具有 有可能导致范式转变，加速恰加斯病最年轻患者的治愈。