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: 10645221
• 负责人: Natalie McCarter Bowman
• 金额: $ 69.02万
• 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/10645221
• 关键词: Acceleration; Adult; Affect; Age; Algorithms; Americas; Area; Biological Assay; Birth; Blood; Bolivia; Brain; Cardiac; Cardiomyopathies; Chagas Disease; Characteristics; Child; Chronic; Clinical; Clinical Research; Cohort Studies; DNA; Diagnosis; Diagnostic; Diagnostic tests; Disease; Early Diagnosis; Early identification; Early treatment; Enrollment; Environmental Risk Factor; Epidemiology; Equipment; Family; Friends; Gene Expression; Gene Expression Profile; Gene Expression Regulation; Genetic; Genomics; Genotype; Goals; Heart; High Prevalence; Hospitals; Immune Evasion; Infant; Infection; Invaded; Lateral; Latin America; Life; Liver; Medical History; Methods; Molecular; Morbidity - disease rate; Newborn Infant; Outcome; Parasites; Parasitic infection; Parasitology; Pathogenesis; Performance; Perinatal mortality demographics; Persons; Pharmaceutical Preparations; Placenta; Polymerase; Polymerase Chain Reaction; Pregnancy; Pregnancy Complications; Pregnant Women; Premature Birth; Prospective cohort; Resource-limited setting; Resources; Risk; Risk Factors; Serology; Serology test; South America; Symptoms; Systemic disease; Techniques; Testing; Tissues; Travel; Trypanosoma cruzi; Up-Regulation; Vertical Disease Transmission; Vertical 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.

项目总结/摘要 全世界有近600万人感染了寄生虫克氏锥虫，这是查加斯病的媒介 艾滋病毒/艾滋病是一种常见的疾病，垂直传播占所有新感染病例的22%。T.的5-10%之间。克氏病感染者 妇女会将感染传染给她们的孩子，导致婴儿的一系列疾病：大多数 受感染的婴儿没有症状，但多达40%的婴儿患有涉及心脏、大脑或肝脏的全身性疾病。 先天性感染也可能导致早产，或在极少数情况下导致新生儿死亡。近三分之一的 婴儿，即使没有任何病征，日后亦会患上慢性心脏病及肠胃病。 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T。cruzi 感染发生在拉丁美洲资源有限的农村地区，那里先进的诊断工具 不可用.由于婴儿期的治疗比年龄较大的儿童和成人更安全有效， 早期诊断至关重要。受感染的婴儿将继续错过挽救生命的治疗机会，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， 围产期我们的长期目标是加速消除先天性恰加斯病， 开发预测和诊断T.婴儿的Cruzi感染。在本项目中，我们建议（1）确定 母婴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鉴定基因表达研究侵入胎盘的机制 与传播相关的特征;（3）优化和验证先天性T. cruzi 使用重组酶聚合酶扩增（RPA）的感染，这是一种可以进行 没有先进的实验室设备或专业知识，并适用于护理点平台。完成 为了实现这些目标，我们建议对玻利维亚的圣克鲁斯的孕妇及其婴儿进行队列研究， T.克鲁兹我们假设通过结合传统的流行病学分析和切割- 边缘基因组技术，我们可以更好地预测哪些婴儿出生的妇女感染T。克鲁兹在 先天性感染的风险最高我们还假设一种新的RPA检测方法将使我们能够诊断这些疾病。 婴儿更频繁和更早地比目前的标准诊断，表现不佳，以检测先天性 新生儿感染。在目标1中，我们将确定T细胞垂直传播的危险因素。cruzi- 以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 与T. cruzi使用基因分型和转录组学。在目标3中，我们将 优化我们的RPA检测，并在临床环境中进行测试，以评估其诊断新生儿 先天性恰加斯病我们的创新方法将整合现场流行病学，尖端测序 技术和新的诊断方法，以确定感染的婴儿在生命的第一周。这些进步使 有可能导致范式转变，以加速治疗恰加斯病最年轻的受害者。