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With a third of the world's population infected, 2 million deaths and 8.5 million new cases each year, tuberculosis (TB) is the number two infectious disease in the world after AIDS, without sparing France, where 6300 new cases occurred last year. The prevalence of the resistance to antibiotics and the emergence of multiresistance are worrying at the international level, and is a risk for checkmating treatments in many countries.
Vaccines, treatments, diagnosis, and surveillance: on all of these fronts, the Institut Pasteur is seeking to improve the resources for fighting against the scourge. Several laboratories of international renown are conducting advanced research on its Paris campus, while worldwide, a TB Network brings together ten institutes from the International Network of Instituts Pasteur that are taking an active part in the national programmes in different countries to control TB.
The Institut Pasteur in Paris: a National Reference Centre
The National Reference Centre of Mycobacteria at the Institut Pasteur is one of two French centres in charge of epidemiological surveillance of TB in France, where each year about 6,000 new cases and 700 deaths are recorded. Each year it receives 2,000 samples to analyse, a tenth of which come from abroad, often sent by NGOs like Doctors Without Borders. Currently, a large study is underway in the Seine Saint-Denis department to characterize the circulating strains and thereby to understand exactly how individuals are infected: this work involves laboratory analyses like field surveys in affected families. It should be remembered that the Ile-de-France has 3-4 times more cases than the national average, and 5-6 times more within Paris. The NRC belongs to the network of laboratories set up by the WHO for the surveillance of resistance to TB antibiotics in the world.
The Instituts Pasteur in the world: an active network on the forefront of the fight
Algeria, Morocco, Tunisia, Ivory Coast, Central African Republic, Cameroon, Madagascar, Cambodia, Vietnam, Russia, etc.-the Instituts Pasteur present in these countries that are especially affected by TB have reference centres actively participating in diagnosis and surveillance of the disease. A number of them are involved in the National Programmes to Control TB, even managing them, like the Institut Pasteur of Algiers, which is the standard for the World Health Organization in the areas of Africa or Madagascar, one of the most affected countries.
Doing better than BCG
The only vaccine at our disposal against tuberculosis is BCG (Calmette-Guérin Bacillus, a vaccine developed at the Institut Pasteur in 1921). It is effective in nearly 90% of cases in preventing the serious forms of tuberculosis in children (tuberculous meningitis and disseminated form). But in adults, vaccinated individuals are only protected in half of the cases. As a result, vaccination by BCG is insufficient to prevent transmission of the disease, which is the only way of curbing the epidemic. To bring tuberculosis under control throughout the world, it is therefore necessary to develop more effective vaccines. Several teams from the Institut Pasteur in Paris are combining their efforts in this direction. Thanks to Franco-British efforts coordinated by Prof. Stewart Cole at the Institut Pasteur, the complete genome sequence of Mycobacterium bovis (BCG is a weakened form of this bacterium responsible for bovine tuberculosis)have been obtained in 2002, after the one of the bacterium responsible for tuberculosis (Mycobacterium tuberculosis) in 1998, considerably facilitating this research. Furthermore, the Institut Pasteur is now sequencing the BCG Pasteur strain, whose genome should be deciphered by the end of the year.
It is precisely due to the comparison of the genes of these mycobacteria that a good avenue for research is now being explored-adding genes lost during BCG development at the begining of the 20th century to give it a superior protective power. Results in animals for this improved BCG are encouraging. It still remains to the researchers to better define the targeted genes in order to build a BCG that is more
successful, without being more virulent.
Another avenue for research studied in Prof. Brigitte Gicquel’s laboratory consists in screening thousands of mutant tubercle bacilli, selecting those that do not multiply in the human target cells (macrophages), and that are therefore not pathogenic, before testing their protective power in mice. About a hundred mutants stemming from this screening will now be studied one by one.
In other respects, the receptor that allows the bacterium to attach itself to certain key cells of our defence system-a stage that engages our immune reactions-was discovered last year in the same laboratory : the studies conducted around this receptor could provide tools to modulate the organism’s defences, either during vaccination or during the illness.
In the meantime, an alternative, developed by Prof. Gilles Marchal’s staff, also consists in better administration of the BCG, for example rectally (suppositories), avoiding abscesses and syringe use in particular. The preliminary results obtained at the Institut Pasteur show the effectiveness of this course in animals.
Clinical trials over the world
In the world today, only one clinical trial (phase I) is under way, resulting from a European programme, the TB Vaccine Cluster, that was coordinated for four years by Prof. Brigitte Gicquel from the Institut Pasteur (now the coordinator of TB Ethics, an organisation of researchers, philosophers and experts in ethical questions responsible for considering the deployment of clinical trials throughout the world). The TB-VAC project funded by the European Commission and now coordinated in the Netherlands regroups most of the laboratories of the TB Vaccine Cluster project and sets up phase-I clinical trials. Two phase-I trials will be launched in the United States. This small number of trials illustrates the difficulty for the scientific community in developing new vaccines, which will only see the light of day several years from now.
Developing new tools is urgent
The method currently used for diagnosing the disease-examining sputum under the microscope-has not changed for a century, and it only permits diagnosing a third of the TB cases under the best conditions, even if it allows the diagnosis of the most contagious patients. The diagnostic of the patients whom sputum are negative needs 4 to 6 weeks of cultures. Testing for susceptibility to antibiotics made from theses cultures takes 3 to 4 more weeks. The lack of tools for a rapid and performing diagnostic is a major problem in controlling the epidemic, especially in a setting where an effective treatment exists. Pr Gilles Marchal at the Institut Pasteur has a number of promising leads that should eventually make it possible to improve and facilitate diagnosis: one consists in detecting molecules secreted precociously by the bacteria responsible for the infection; the other aims to reveal specific defence reactions of the patient that signal infection.
New molecules to fend off resistance
An effective treatment against tuberculosis does exist, a combination of four antibiotics. However, this is an unwieldy treatment that must be followed for at least six months. Moreover, the emergence of multi-resistant tubercle bacilli to these antibiotics, also the subject of significant molecular epidemiological studies at the Institut Pasteur, worries the medical authorities. For these reasons it now appears crucial to find new antibiotics to fight the infection. Historically, the Institut Pasteur has been committed in the search for new TB drugs, since the sulfonamides-among the first synthetic antibiotics to be used against TB in the 30s-were developed there.
Today, several laboratories are working in synergy. Brigitte Gicquel’s laboratory is seeking new therapeutic targets, particularly in the bacterial envelope, and others, specially Prof. Pierre-Etienne Bost’s laboratory, are testing active molecules on these targets in various ways. Two targets are already being investigated. One of the objectives is to obtain their structure in three dimensions (3D) by crystallography, then to make a ’molecular design’. Bioinformatics makes it possible to obtain the 3D structure of the target molecule on the computer and to research through the ’analytical drawing’ the ideal inhibitor molecule that could block this target. The candidates are then synthesized and tested. In addition, ’virtual screening’ methods make it possible to test entire libraries of virtual molecules. Parallel to this highly rational research, the anti-TB power of entire collections of molecules from ’combinatorial libraries’ is being tested. To accelerate this strategy, the Institut Pasteur is currently being equipped with a high-speed molecular screening platform that should be operational by the end of 2004: this will make it possible to test tens of thousands of molecules in several weeks, compared to the thousands currently tested in the same period of time. Starting next year, the Institut Pasteur could multiply its molecular screening capacities by a factor of 10.
The researchers thus hope to obtain through these various avenues more effective antibiotics that could then be administered for shorter period : indeed, the longer the treatment, the less the patient adhere, increasing the risk of therapeutic check and of resistance to antibiotics. Shortening the current treatment, on top of the logistical importance and the added comfort for the patient, will make it possible to considerably curb the development of the bacilli’s resistance to antibiotics.
A COALITION OF RESEARCHERS FOR A BETTER STRIKE FORCE
Besides the TB Network of the International Network of Instituts Pasteur, several teams from the Institut Pasteur in Paris have combined their efforts to increase the effectiveness of their research. In particular, a Major Horizontal ’TB’ Programme, coordinated by Prof. Stewart Cole, was launched in 2003: it brings together no less than 14 of the campus’s laboratories. The main ones involved are:
Bacterial Molecular Genetics Unit, directed by Stewart Cole
Mycobacterial Genetics Unit, directed by Brigitte Gicquel
Organic Chemistry Unit, directed by Pierre-Etienne Bost
Protein Folding and Modelling Unit, directed by Michel Goldberg
Structural Biochemistry Unit, directed by Pedro Alzari
National Reference Centre of Mycobacteria, directed by Véronique Vincent and Gilles Marchal
And technical platforms of the Institut Pasteur
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