May 13, 2005
The Origins of Leprosy Using Genomics to Outline the History of an Age-Old Disease
Researchers at Institut Pasteur recently published the results of a study in the journal Science tracing the dissemination of leprosy throughout the world over the centuries. Because the bacillus responsible for the disease, Mycobacterium leprae cannot, for various reasons, be cultivated in the laboratory, this research team has used comparative genomics techniques to prove that a single clone of the bacillus is actually responsible for the pandemic. It appears that leprosy originated in East Africa or the Near East, and that it was propagated through the flow of successive human migrations occurring throughout history. Europeans or North Africans introduced the disease to West Africa and the Americas over the last 500 years.
The history of all living organisms is written in their genome. Comparative genomics techniques currently available to researchers make it possible to accurately determine the genealogical relationships between genomes and to use those relationships to piece together the origin of various life forms. Using these state-of-the-art methods, the Bacterial Molecular Genetics Unit at Institut Pasteur, under the direction of Professor Stewart Cole, was able to track the geographical origins of leprosy. This team had already gained extensive knowledge of the Mycobacterium leprae bacillus genome, as it had determined its complete sequence in 2001. In order to study the biodiversity of leprosy, it analyzed 175 strains from 21 countries on every continent.
What was known until now about the evolutionary origins of leprosy? Ancient texts describe the presence of leprosy in China, India and Egypt around 600 B.C. and skeletons bearing traces of the disease have been discovered in Egypt. It was thought that leprosy had originated on the Indian sub-continent and that it had been brought to Europe by Greek soldiers returning from campaigns led by Alexander the Great in India. From India, the disease also migrated toward China, then Japan, to more recently afflict certain Pacific islands such as New Caledonia in the 19th century. Until recently, very little was known about the situation in Sub-Saharan Africa, except that leprosy was already present before the colonial era.
The results obtained by researchers at Institut Pasteur have brought to light two plausible theories about the geographic origins of leprosy in the world. It may, in fact, have originated in Asia, but it seems more likely that its point of origin was in East Africa. "In any case, it has now been clearly determined that the pandemic is the result of the dissemination of a single strain that has hardly changed at all over the centuries," Prof. Cole tells us.
Regardless, this study has produced the first proof of a general evolutionary process of M. leprae and leads to two plausible conclusions concerning the global dissemination of leprosy that differ from historical reports and supplement them.
First of all, and quite unexpectedly, the disease was more likely introduced to West Africa by infected explorers, merchants or colonists from North Africa or Europe, rather than by migrants from East Africa. Early humans probably left East Africa to settle in Western and Southern Africa 50,000 years ago, before humans arrived in the Eurasian regions, and it seems improbable, according to the analysis conducted, that these first humans brought leprosy to West Africa. From West Africa, leprosy was then introduced to the Caribbean islands, Brazil and probably to other regions of South America through the slave trade in the 18th century, as isolates with the same profile as those from West Africa were discovered in these regions.
Moreover, the strain of M. leprae that is mostly responsible for the disease in the Americas is closer to the type present in Europe and North Africa, which indicates that colonialism and emigration from the Old Continent very clearly contributed to introducing leprosy to the New World. In fact, in the 18th and 19th centuries, when Scandinavian immigrants settled in the western United States, many cases of leprosy were reported, while a vast epidemic was simultaneously ravaging Norway. This hypothesis is supported by the presence today of a strain with the same genetic profile as the strain from Europe and North Africa in armadillos naturally infected in Louisiana (United States), which undoubtedly originated from human infection.
The authors conclude that M. leprae is a useful indicator for tracking the human migrations that led to modern populations. It is interesting to note that the greatest genetic variety of leprosy bacillus strains is found on islands such as the West Indies and New Caledonia, which reflects the passing and settlement of human populations from widely varying locations.
This study was made possible by the epidemiological tools developed by Institut Pasteur researchers for the leprosy bacillus study and by the partial genome sequencing of the Brazilian strain. There were the two basic reasons for choosing this strain: its geographic distance from the previously sequenced Indian strain and the significance of this disease in Brazil, the second most afflicted country after India. The comparison of these two strains has made it possible to discover minute genetic variations in the extremely stable M. leprae genome, and then to categorize the 175 strains examined, into four major genetic profile types that were correlated to the strains’ geographic origins.
This work received the financila support of the Institut Pasteur, the Association Française Raoul Follereau, Lepra, The Consortium National de recherche en Génomique (RNG programme), and the National Institutes of Health, National Institute of Allergy and Infectious Diseases.
Marc Monot (1), Nadine Honoré (1), Thierry Garnier (1), Romulo Araoz (1), Jean-Yves Coppée (2), Céline Lacroix (2), Samba Sow (3), John S. Spencer (4), Richard W. Truman (5), Diana L. Williams (5), Robert Gelber (6), Marcos Virmond (7), Béatrice Flageul (8), Sang-Nae Cho (9), Baohong Ji (10), Alberto Paniz-Mondolfi (11), Jacinto Convit (11), Saroj Young (12), Paul E. Fine (12), Voahangy Rasolofo (13), Patrick J. Brennan (4), and Stewart T. Cole (1)
1) Unité de Génétique Moléculaire Bactérienne, Institut Pasteur, Paris, France
2) PF2, Génopole, Institut Pasteur, Paris, France
3) Centre National d’Appuis à la lutte Contre la Maladie, Bamako, Mali
4) Department of Microbiology, Immunology, and Pathology, Colorado State University, Fort Collins, Colorado 80523-1682, USA
5) National Hansen’s Disease Program, DHHS/HRSA/BPHC, Lousiana State University, Baton Rouge, Lousiana 70894, USA
6) Leonard Wood Memorial Center for Leprosy Research, Cebu, Philippines
7) Instituto "Lauro de Souza Lima", Bauru, São Paulo, Brazil
8) Hôpital Saint-Louis, Paris, France
9) Yonsei University College of Medicine, Seoul, Republic of Korea
10) Bactériologie-Hygiène, Faculté de Médecine Pitié-Salpêtrière, Paris, France
11) Instituto de Biomedicina, Caracas, Venezuela
12) London School of Hygiene and Tropical Medicine, London, UK
13) Institut Pasteur de Madagascar, Antananarivo, Madagascar
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