Source Attribution and Transmission Dynamics of Campylobacter and Shigella Using Culture-Independent Molecular Methods in an Urban Slum in Dhaka, Bangladesh

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While the broad routes of exposure to enteric pathogens through fecal-oral contact are well-known, there are critical limitations to our understanding of pathogen-specific transmission, especially in young children in low-resource settings. A key reason for this evidence gap is the difficulty in detecting these pathogens due to the poor sensitivity of bacterial culture, which is particularly a problem for Shigella and Campylobacter. The development and application of quantitative, culture-independent molecular diagnostics for these pathogens has substantially revised our understanding of the human burden of disease and is poised to do the same for our understanding of the broader ecology of these pathogens. Shigella and Campylobacter are model organisms to interrogate transmission ecology because they lie on opposite ends of the continuum of person-to-person (Shigella) versus environmental (Campylobacter) transmission. The inclusion of both in this project provides a range of likely transmission pathways from which we can advance our understanding of enteric pathogen transmission. The objective of this proposal is therefore to understand the sources and routes of transmission of enteric pathogens in an urban low-resource setting in Dhaka, Bangladesh using culture-independent methods for detection. We will accomplish this by using a systems-dynamic modeling approach to analyze pathogen detection data generated in a household-level longitudinal study. The transmission cohort will include structured observations to quantify human contacts with the environment and broad sampling of household contacts, animal reservoirs, and the environment to identify and attribute sources for index infections. Viability PCR will be used to differentiate nucleic acid from viable organisms, which will allow us to directly measure the duration of shedding of transmissible pathogen after illness and establish quantitative thresholds for inferring viable pathogen from a wide range of samples. These data will then be used to parameterize two complementary mathematical models, a household dynamics and endemic incidence model, to interrogate the interdependence and relative importance of person-to-person and environmental transmission pathways. Pathogens will be characterized to the genome level using hybrid assembly from short- and long-read metagenomic sequencing of a subset of stool and environmental samples. This project will transform our understanding of enteric pathogen transmission by moving from a broad understanding of fecal-oral transmission routes to pathogen-specific household and environmental pathways of highest relevance. In endemic and urban settings, the relative importance of direct household contact versus environmental contamination for transmission of both Shigella and Campylobacter is unknown, and our modeling approach will contextualize where these model pathogens lie on this continuum.