An integrated approach to understand and diagnose congenital Chagas disease

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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.