ABSTRACT

Understanding and controlling emerging infectious diseases before they reach epidemic proportions is important for preventing devastating effects on human health, for promoting animal welfare, and for improving species conservation. Buruli ulcer disease is a chronic, debilitating infection that destroys skin, soft tissues, and bone, and has been reported from over 30 countries worldwide. Disease is caused by Mycobacterium ulcerans, a pathogen closely related to those that cause tuberculosis and leprosy. It is not clear how humans get M. ulcerans because there is uncertainty in identifying ecological reservoirs from which people can become infected, and mechanisms that allow the pathogen to live in and move around in the environment. This project tests how M. ulcerans has evolved to produce a novel molecular weapon that it uses to successfully live in environments where risk of humans contacting it is highest. This molecular weapon is the toxin responsible for Buruli ulcer. Furthermore, because pathogens like the one that causes Buruli ulcer constantly interact with communities of other microbes (microbiomes), this project examines how it persists and replicates in environmental and host microbiomes. Discovering new interactions between disease-causing organisms, where they live, and the other microbes living with them provides insight into the basic understanding of how diseases emerge and spread. This interdisciplinary project will train undergraduates, graduate students, and research professionals with focused inclusion of diverse individuals from underrepresented groups, military veterans, and indigenous cultures. In addition, this work will contribute publicly available data that can be used by other researchers and public health professionals to deliver educational tools necessary to improve broader health outcomes.

The research will test the Novel Weapons Hypothesis, which posits that some taxa can become dominant due to toxin production that is then subject to selection for this role in the invader's success. This will be achieved using a mycobacterial clade that demonstrates diversity of genes that produce mycolactone, the toxin responsible for Buruli ulcer. Mycolactone is hypothesized to have initially evolved to facilitate mycobacterial colonization and persistence in complex microbial consortia of environmental hosts and reservoirs, but also has a functional role in vertebrate pathogenesis: an attribute that aligns with the Coincidence of Virulence Hypothesis. This project will identify the ecological and evolutionary roles of mycolactone in watershed ecosystems of French Guiana, a French territory northeast of Brazil, where disease is endemic. Previous assessments of global M. ulcerans genetic diversity reveal the Guiana Shield to be a hotspot of molecular evolution. The research will be accomplished through expeditions to collect aquatic communities for quantifying the diversity of mycolactone producing mycobacteria along three watersheds. The team will conduct comparative genomic research on environmental mycobacteria, including a co-phylogenetic analysis involving a candidate fish host reservoir (guppies), which is now globally distributed due to anthropogenic dispersal. Several integrated mathematical modeling approaches will be used to synthesize project results to determine how molecular evolution of a pathogen toxin leads to human disease through complex ecological interactions across scales. The results will contribute insights into the mechanisms behind establishment, persistence and spread of disease-causing agents in naive host and environmental communities.

This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.

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