Pathogen Transmission Dynamics among Wildlife and Human Settlements in Rural Western Uganda - Emerging infectious diseases are a growing threat to American and global health, with most originating from wildlife. Increasing interactions among humans, wildlife, and domestic animals are creating greater opportunities for zoonotic spillover, particularly in regions where humans and nonhuman primates (NHPs) live in close proximity. Despite their importance for outbreak prevention, critical knowledge gaps remain regarding pathogen transmission dynamics in complex natural environments. We will use adenovirus (AdV), a common virus shared by humans, NHPs, and other hosts, as a model system to identify and predict transmission pathways within a biodiversity-rich spillover hotspot in western Uganda. Using longitudinal surveillance data, next-generation sequencing, demographic information, and advanced phylogenetic analyses, we will: (1) characterize AdV prevalence and diversity across wildlife, domestic animals, insects, environmental reservoirs, and humans; (2) identify transmission pathways within and among hosts and environments; (3) determine ecological, demographic, and evolutionary factors associated with transmission; and (4) develop predictive models of spillover risk. This research must be conducted in Uganda because the study area represents a unique wildlife-human interface characterized by exceptional biodiversity, frequent human- animal contact, and active spillover risk that cannot be replicated in the United States. Genomic sequencing and strain-level characterization will be conducted at the Centre for Epidemic Response and Innovation (CERI), which possesses internationally recognized expertise, validated analytical pipelines, and specialized infrastructure for pathogen genomic surveillance and high-resolution transmission analyses that augment existing U.S. capabilities. By identifying transmission routes and factors driving pathogen emergence, this project will generate knowledge directly relevant to protecting American health and interests. The resulting surveillance tools, predictive models, and genomic insights will improve early detection of emerging zoonotic pathogens, strengthen outbreak preparedness, enhance risk assessment and point-of-entry screening efforts, and inform strategies to prevent future epidemics at the source and pandemics that threaten the United States and the global community. Modified Specific Aims Section Specific Aims Section Our central hypothesis is that variation in AdV strains and distribution provides an effective means of identifying, tracking, predicting, and ultimately limiting pathways for disease transmission. These invaluable insights, integrative analyses and predictive potential can be extrapolated to model transmission of other, less common, but potentially more dangerous viruses to mitigate disease transmission. The proposed research addresses a critical NIH priority by generating knowledge that is directly applicable to protecting American health from emerging infectious diseases. Western Uganda provides a unique wildlife-human interface with ecological conditions, biodiversity, and transmission opportunities that are not available in the United States, enabling investigation of pathogen emergence at its source. Genomic sequencing and strain-level characterization will be conducted at CERI, which provides specialized African pathogen genomic surveillance expertise and analytical pipelines necessary for high-resolution transmission analyses. Understanding the mechanisms that drive pathogen emergence and transmission in this biodiverse setting will improve predictive models, surveillance strategies, and outbreak prevention efforts that can be applied to emerging zoonotic threats worldwide, including those that pose risks to the United States and globally. Specifically, we hypothesize that: 1) Phylogenetic analyses of viral variation can be used to identify host origins and routes of transmission, generally and under changing natural and anthropogenic conditions; 2) The p
