Comparative genomics showsmigration and expansion has preceded the rise of Buruli ulcer in south-eastern Australia

Since 2012, cases of the neglected tropical disease Buruli ulcer, caused by infection withMycobacterium ulcerans,have increased 100-fold since 2000 around Melbourne, (population 4.4 million) the capital of Victoria in temperate south-eastern Australia. The reasons for this increase are unclear. Here, we have used whole genome sequence comparisons of 178M. ulceransisolates obtained primarily from human clinical specimens, spanning 70 years, to model the population dynamics of this pathogen from this region. Using phylogeographic and advanced Bayesian phylogenetic approaches, we found that there has been a migration of the pathogen from the east of the state, beginning in the 1980s, 300km west to the major human population centre around Melbourne. This move has then been followed by a significant increase inM. ulceranspopulation size. These analyses inform our thinking around Buruli ulcer transmission and control, indicating thatM. ulceransis introduced to a new environment and then expands, rather than the awakening of a quiescent pathogen reservoir.Importance:Buruli ulcer is a destructive skin and soft tissue infection caused byMycobacterium ulceransand characterized by progressive skin ulceration, which can lead to permanent disfigurement and long-term disability. Despite the majority of disease burden occurring in regions of west and central Africa, Buruli ulcer is also becoming increasingly common in south-eastern Australia. Major impediments to controlling disease spread are incomplete understanding of environmental reservoirs and modes of transmission ofM. ulceransThe significance of our research here is that we have used genomics to assess the population structure of this pathogen at the Australian continental scale. We have then reconstructed historical bacterial spread and modeled demographic dynamics to reveal bacterial population expansion across south-eastern Australia. These findings provide explanations for observed epidemiological trends with Buruli ulcer and suggest possible management directions to control disease spread.