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International teams led by researchers from the Max Planck Institute, the Institut Pasteur, and the Wellcome Trust Sanger Institute have just traced the evolutionary history of Salmonella Typhi, the bacterium responsible for typhoid fever, in a study published in the journal Science. This disease, which continues to exist in industrialised nations, affects twenty-one million people annually across the world. In particular, the researchers have suggested the importance of healthy carriers in spreading the bacterium, and have demonstrated the emergence of a strain resistant to a class of antibiotics commonly used in Asia. Beyond the public health questions this raises, the study has allowed tools to be developed that will help to improve epidemiological surveillance of typhoid fever throughout the world.
The bacterium responsible for typhoid fever, Salmonella enterica, serovar Typhi, is a bacterium strictly adapted to humans, transmitted by the oral-fecal route. Each year, it infects 21 million people across the world, and causes 200,000 deaths. Where does it come from? How does it evolve? What is the impact of antibiotics use on this evolution? What is the impact of asymptomatic carriers? The comprehensive epidemiology of typhoid fever remained relatively unknown until now.
In response to these questions, an extensive study on the population genetics of Salmonella typhi was launched by Philippe Roumagnac and Mark Achtman from the Molecular Biology department of the Max Planck Institute in Berlin, and François-Xavier Weill and Sylvain Brisse from the Biodiversity of Emerging Pathogenic Bacteria unit (also the National Reference Centre for Salmonella and WHO Collaborating Centre) at the Institut Pasteur in Paris, in collaboration with the Wellcome Trust Sanger Institute in Great Britain and several medical and research centres in Asia, in particular Vietnam.
Researchers chose 105 strains of Salmonella typhi in several international collections representative of this bacterial organism worldwide. They were able to take advantage of the exceptional collection of Salmonella from the Institut Pasteur’s National Reference Centre, which was assembled starting in the 1950s, and today contains more than 300,000 strains from around the world.
"Salmonella typhi are highly homogeneous bacteria", explains Achtman from the Max Planck Institute, "which means that standard molecular methods are very limited for studies on their populations". As a consequence, the researchers, working on 200 genes of the bacterium, have needed to elaborate new tools in order to successfully complete their research. "By developing an original method for screening particular mutations", explains Roumagnac from the Max Planck Institute, "we were able to reveal the markers that allowed us to draw up a phylogenetic tree for Salmonella typhi".
As a result, they were able to identify an ancestral strain from which all current strains are descended: it would have appeared between 43,000 and 10,000 BC, or after humans migrated outside Africa, but before the settling of the Neolithic period. Representatives of this ancestral strain are still found today on several continents, suggesting that the bacterium would originally have persisted within small populations of hunter-gatherers. How could such a virulent pathogen-fatal in 10% of cases when the infected person is not treated-not decimate these populations and, most of all, endure?
The researchers’ hypothesis is that the phenomenon of asymptomatic carriers allowed the bacterium to persist in human populations: some infected individuals can, after being cured, continue to excrete bacteria in their stools for decades. Asymptomatic carrying is well known, in particular the case of "N the Milker", who, between 1893 and 1909, infected more than 200 people in England; or the case of cook Mary Mallon, nicknamed "Typhoid Mary", in early 20th century America, who contaminated her "victims" unknowingly, although they were catalogued through the course of her movements.
"This asymptomatic carrying is probably much more widespread than we imagine", emphasised Dr. Weill, co-director of the NRC for Salmonella at the Institut Pasteur. "Even in France, typhoid fever can still strike, as proven by the contamination of a dozen customers of a Paris restaurant last July by a healthy carrier working in the kitchen. This fact prompts us to recall the importance of measures to combat oral-fecal transmission, in particular the simple act of washing one’s hands before cooking or eating."
The researchers’ study has also made possible the identification of several non-related strains resistant to fluoroquinolones in Asia, thanks to the analysis of nearly 300 Asian strains. They emerged perceptibly following the massive use of these antibiotics in this region at the beginning of the 1990s. In some places, 90% of bacteria are now resistant to this class of antibiotics. "The study raises a real problem in public health for Southeast Asia", Weill pointed out, "as other antibiotics could be used, but are more expensive and difficult to use. Moreover, a clone called H58, dominant in Asia, is beginning to be found in Africa."
The tools developed by the researchers will now allow better surveillance on a global scale of the emergence of resistant clones, in order to allow public health measures to be applied to limit the spread of these clones.
" Evolutionary history of Salmonella Typhi ", Science, November 24, 2006.
Philippe Roumagnac (1), François Xavier-Weill (2), Christiane Dolecek (2), Stephen Baker (4), Sylvain Brisse (2), Nguyen Tran Chin (5), Thi Anh Hong Le (6), Camilo J. Acosta (7), Jeremy Farrar (3), Gordon Dougan (4), Mark Achtman (1)
1. Max-Planck-Institute für Inkektionsbiologie, Molecular Biology and Pharmacology Departmen, Berlin, Germany; 2. Institut Pasteur,Biodiversity of Emerging Pathogenic Bacteria Unit , Paris, France; 3. Oxford University Clinical Research Unit, Hospital for Tropical Diseases, Ho Chi Minh Ville, Vietnam; 4. The Wellcome Trust Sanger Institute, Cambridge, UK; 5. Hospital for Tropical Diseases, Ho Chi Minh Ville, Vietnam; 5. National Institute of Hygiene and Epidemiology, Hanoi, Vietnam; 7. International Vaccine Institute, Seoul, Korea.
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