Vitamin A Status and its Relationship to S. mansoni Infection Intensity and Environmental Enteric Dysfunction in Preschool-Aged Children Receiving Treatment for Schistosomiasis in Uganda - PROJECT SUMMARY/ABSTRACT The overall goals of this proposal are to advance our understanding of the role of vitamin A deficiency in the pathogenesis of schistosomiasis and environmental enteric dysfunction (EED) and to advance the career development of the candidate. Understanding the mechanistic role of vitamin A deficiency in the pathogenesis of intestinal schistosomiasis will offer opportunities for nutrition-based interventions to reduce infection-related morbidity. In low- and middle-income countries (LMICs), the overlapping burdens of undernutrition and infection have significant health consequences for infants and children, including impaired linear growth and stunting. Stunting affects a third of children living in LMICs and can lead to life-long impact on educational outcomes, economic productivity, and birth outcomes for women. Vitamin A deficiency, intestinal schistosomiasis, and EED all contribute to childhood undernutrition and stunting and likely share common mechanisms through intestinal barrier dysfunction with concomitant activation of systemic immune responses. Studies from both animal models and humans provide scientific premise for the role of these insults in impaired linear growth. A recently developed inflammation-adjustment strategy allows for the determination of vitamin A status among individuals with infection or inflammation, but no studies have examined adjusted vitamin A status in the context of human schistosomiasis or EED. The proposed research will leverage the well- characterized samples and clinical data from an ongoing NIH-funded randomized, controlled phase II trial (R01 HD095562) of praziquantel (PZQ) treatment in N = 300 children under age four with Schistosoma mansoni infection in the Lake Albert region of Uganda. The parent trial hypothesizes that key morbidities related to schistosomiasis (undernutrition, anemia of inflammation, and linear growth stunting) are in part driven by EED with consequent malabsorption and systemic immune activation. The proposed research will add measurements of vitamin A in samples collected from the parent trial to examine mechanisms through which inflammation-adjusted vitamin A deficiency contributes to EED and schistosomiasis-related morbidity. The proposed research will 1) examine the relationships between adjusted vitamin A status and S. mansoni infection intensity and immunologic response markers collected at the baseline visit and 2) assess the relationships between vitamin A status and EED biomarkers both at baseline and longitudinally in response to PZQ treatment. This work will address innovative hypotheses regarding the role of vitamin A status in the pathophysiology of EED in the context of S. mansoni infection and its impact on treatment efficacy. Further, the proposed training plan will advance the career development of the candidate with respect to a) building subject matter expertise in the immunopathogenesis of schistosomiasis and EED, b) gaining research experience in the implementation of randomized controlled trials in vulnerable populations under a sponsor’s supervision, and c) expanding methodological capabilities to include longitudinal data analysis.
