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Background: An understanding of the factors driving the distribution of pathogens is useful in preventing disease. Often we achieve this understanding at a local microhabitat scale; however the larger scale processes are often neglected. This can result in misleading inferences about the distribution of the pathogen, inhibiting our ability to manage the disease. One such disease is Buruli ulcer, an emerging neglected tropical disease afflicting many thousands in Africa, caused by the environmental pathogen Mycobacterium ulcerans. Herein, we aim to describe the larger scale landscape process describing the distribution of M. ulcerans. Methodology: Following extensive sampling of the community of aquatic macroinvertebrates in Cameroon, we select the 5 dominant insect Orders, and conduct an ecological niche model to describe how the distribution of M. ulcerans positive insects changes according to land cover and topography. We then explore the generalizability of the results by testing them against an independent dataset collected in a second endemic region, French Guiana. Principal Findings: We find that the distribution of the bacterium in Cameroon is accurately described by the land cover and topography of the watershed, that there are notable seasonal differences in distribution, and that the Cameroon model does not predict the distribution of M. ulcerans in French Guiana. Conclusions/Significance: Future studies of M. ulcerans would benefit from consideration of local structure of the local stream network in future sampling, and further work is needed on the reasons for notable differences in the distribution of this species from one region to another. This work represents a first step in the identification of large-scale environmental drivers of this species, for the purposes of disease risk mapping. Author Summary: Many pathogens persist in the environment, and an understanding of where they are can assist in disease control, allowing us to identify areas of risk to local human populations. Herein, we use general linear models to describe the distribution of a particular environmental pathogen, Mycobacterium ulcerans, describing the landscape conditions correlated with the presence of this pathogen in local biota, and mapping the distribution of these habitats in a region of Cameroon, Africa. Our findings identify the importance of the watershed as a factor determining the distribution of the bacterium, where landscape conditions upstream of the sample site can influence the abundance of the bacterium in downstream sites. We find that the bacterium has notable seasonal changes in its distribution, between the wet and dry seasons, which may have implications for human health. We also discuss sensitivity of these models to extrapolation, finding that they work well in the African region and underperforming when extrapolated to another region in South America. [ABSTRACT FROM AUTHOR]