Buruli Ulcer is a neglected tropical disease caused by the flesh-eating Mycobacterium ulcerans which results in a subcutaneous necrotic skin infection. If untreated at its early stage, the disease could result in prolonged morbidity. The transmission of the disease is currently unknown, but it is assumed that micropunctures in the skin, as well as insect vectors such as mosquitoes, could contribute to its transmission. The exponential growth of Buruli ulcer cases in Victoria has called for an urgent scientific response. The reasons for the Victorian epidemic are unclear but may relate to genotypic changes in the organism that have made it more transmissible or pathogenic, and/or genetic variation in the human host. However, there is no information available on the relationship between the genotype of an isolate or that of the patient (or both) and the clinical severity of the disease. Such knowledge may provide useful information improve understanding of interactions between M. ulcerans and pathogenesis in its human host. Using samples collected from a Barwon Health cohort (n=120), the overall aim of this project is to perform metagenomic sequencing to identify host and microbial factors contributing to the disease. Next-generation sequencing and bioinformatics approaches are being developed to extract host, pathogen and ulcer microbiome genomes. Using these data, host genetic variations associated with disease severity, pathogen strains, microbiome and their contribution to disease severity will be explored. Analysis pipelines have been developed, and genomic sequence analysis is currently underway. Results of the preliminary analysis of 120 samples will be discussed in context with disease severity.