Diarrhea-attributable mortality ranks as the second leading cause of death globally in children under five years, with a disproportionate 90% of deaths in South Asia and Sub-Saharan Africa. The conventional assumption that improved water, sanitation and hygiene (WASH) in low- and middle-income countries (LMICs) will eliminate pathogen reservoirs and resolve childhood diarrhea has been tested in recent large-scale interventional trials: household-level WASH interventions had no effect on the prevalence of diarrhea. Fundamentally new approaches to understanding and addressing the continued problem of childhood diarrhea must be considered. Campylobacter is an exceptional model organism for interrogating new hypotheses regarding diarrheal disease. Campylobacter species have emerged among the top diarrheal pathogens affecting infants in LMICs, with 85% of infants testing positive in the first year. This heavy burden suggests unknown reservoirs of Campylobacter. Through controlled human infection studies in healthy US adults, we observed Campylobacter strain persistence, an ?internal reservoir?, following appropriate antibiotic therapy among 15% of volunteers. Campylobacter strain persistence as an internal reservoir in young children in LMICs is unknown. Additionally, co-infection of Campylobacter with as many as 12 enteropathogens is common among infants in LMICs; however the contribution of enteric co-infection to Campylobacter persistence has not been examined. We hypothesize that strain persistence in infants is a major source of Campylobacter infection, and that enteric co-infection contributes to the risk of Campylobacter persistence. We will perform advanced metagenomics on repeat Campylobacter infections in longitudinal stool specimens previously collected from infants in Bangladesh to determine strain persistence by phylogenetic analysis. We will also apply machine learning approaches to evaluate the contribution of enteric co-infection to the risk of Campylobacter infection and persistence. Demonstration of Campylobacter persistence as a significant contributor to the infection burden in infants would require fundamentally different approaches to risk mitigation, moving beyond WASH interventions with new mechanistic questions and revised public health strategies. Furthermore, the mono-pathogen model of enteric infection must be re-evaluated if we find an independent contribution of enteric co-infection to Campylobacter persistence; shifting current approaches to ameliorating childhood diarrhea.
