Leprosy is one of humanity's oldest infectious diseases and has historically been attributed to Mycobacterium leprae, the canonical agent described in medical texts and still responsible for most diagnosed cases worldwide. However, just over a decade ago, a second leprosy‐causing species, Mycobacterium lepromatosis, was discovered, challenging the long‐standing assumption that a single bacterial species underpinned the full clinical spectrum of Hansen disease. Early reports suggested that M. lepromatosis was rare and geographically restricted, and its role or relevance in human disease was initially met with scepticism. Yet, it has since been reported in more than one hundred human cases, predominantly in the Americas. Paradoxically, despite this growing clinical footprint, genomic data have remained extremely limited, consisting until recently of only three strains from Mexican patients and seven genomes from infected red squirrels in Ireland and Great Britain, leaving major questions about its current and past diversity, and the origins of the species. By contrast, ancient and modern DNA work on M. leprae has demonstrated how integrating extant and time‐calibrated genomes can reconstruct pathogen origins, diversification, and historical spread, all aspects still unresolved for M. lepromatosis.
To address this gap, the geographic extent and evolutionary diversity of M. lepromatosis were investigated using a strategy built around the region where most cases have been reported: the Americas. We assembled and analysed a continent‐wide collection of contemporary biopsies and tissues from humans suspected of leprosy, aiming to obtain genome‐wide data that could resolve population structure and diversity, divergence times, and lineage turnover. However, modern sampling alone could not determine when or where the species became established. We therefore screened archaeological human remains predating European contact, reasoning that ancient infections would provide definitive evidence of long‐standing endemicity and directly inform competing hypotheses about the emergence of leprosy, as a disease, in the Americas. This combined approach yielded the detection of M. lepromatosis in 34 contemporary samples by species‐specific quantitative polymerase chain reaction (qPCR) and in three ancient individuals, with genome‐wide data recovered from 23 modern genomes and three ancient genomes through a combination of high‐throughput sequencing and targeted in‐solution enrichment. To strengthen downstream genotyping and phylogenetic inference, we also generated an improved reference genome (NHDP‐LPM‐385) using long‐ and short‐read sequencing, enabling higher‐confidence reconstruction of fine‐scale relationships among closely related strains. Strikingly, the recovered ancient genomes spanned from North and South America, demonstrating that M. lepromatosis infected human populations at a continent‐wide scale in the Americas long before European contact. These data establish that leprosy in the continent cannot be understood solely thro
a2001-1326