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.

项目摘要/摘要 全球近600万人感染了帕拉斯锥虫克鲁兹（Cruzi） 疾病，垂直传播占所有新感染的22％。介于5-10％的克鲁齐感染的T. 妇女会将感染传递给孩子，导致婴儿的各种疾病：大多数 受感染的婴儿不对称，但多达40％的患有全身性疾病涉及心脏，大脑或肝脏。 先天性感染也可能导致早产，或者在极少数情况下是新生儿死亡。近三分之一 婴儿，甚至没有症状的婴儿，都将在以后的生活中出现慢性心脏和胃肠道问题。 不幸的是，多达75％的受影响婴儿没有及时诊断或治疗。大多数T. Cruzi 感染发生在拉丁美洲的资源有限的农村地区，那里是高级诊断工具 不可用。因为治疗在婴儿期安全性和有效性比在大龄儿童和成人中更有效，所以 早期诊断至关重要。感染的婴儿将继续错过他们的救生治疗机会，直到我们 开发更好的算法来鉴定高危婴儿并准确诊断先天性chagas病中的疾病 围产期。我们的长期目标是通过通过 开发工具来预测和诊断婴儿中的T. Cruzi感染。在这个项目中，我们建议（1）确定 母体临床和流行病学风险因素的垂直传播因素； （2）调查寄生虫 使用寄生虫基因分型和鉴定基因表达的侵袭的机制 与传输相关的签名； （3）优化和验证先天性T. Cruzi的新测试 使用重组酶聚合酶扩增（RPA）感染，这是一种可以进行的DNA检测方法 没有高级实验室设备或专业知识，并且可以适应护理点平台。完成 这些目标，我们提出了对玻利维亚圣克鲁斯的孕妇及其婴儿的队列研究，这是一个高度的 T. Cruzi的内在区域。我们假设通过将传统流行病学分析与剪裁相结合 - 边缘基因组技术，我们可以更好地预测感染T. Cruzi的妇女出生的基础设施 先天性感染的最高风险。我们还假设一种新的RPA测定将使我们能够诊断这些方法 婴儿比目前的标准诊断更频繁，更早，这些诊断效果不佳，无法检测到先天性 在AIM 1中，我们将确定在T. cruzi的队列中垂直传播的风险因素 感染的妇女更好地识别高风险婴儿。在AIM 2中，我们将表征寄生虫遗传因素 使用基因分型和转录组学与Cruzi的垂直传播相关。最后，在AIM 3中，我们将 优化我们的RPA分析并在临床环境中对其进行测试，以评估其诊断新生儿的能力 先天性查加斯病。我们的创新方法将整合现场流行病学，尖端测序 在生命的头几周，技术和新诊断以识别受感染的婴儿。这些进步具有 可能导致范式转变以加速查加斯病最年轻的惊喜。