With more than 1.5 million deaths and 8 million new cases per year, tuberculosis (TB) remains a major public health concern throughout the world. An increased number of multidrug resistant (MDR) and extremely drug resistant (XDR) Mycobacterium tuberculosis is a major concern (more details about TB). The fight against TB requires new strategies including the search for new drugs and new vaccines more efficient than the currently used BCG vaccine. The study of host-pathogen interactions within the context of human diversity will be instrumental for the discovery of new strategies.
Research strategies are oriented towards :
- The study of host-pathogen interactions with the aim to identify host and bacterial factors playing a role in infection, development of the disease or protection. Biomarkers resulting from these studies might provide information on the immune status of infected or vaccinated individuals and allow identifying persons that are either protected against the TB disease or at risk to develop the disease after infection.
- The identification of genes that play a role in the virulence of the bacilli, either in vitro or in vivo. Structural genes and regulators were discovered. Their functions are being studied. A loci involved in the interaction of the TB bacilli with phagocytes is located on horizontally transferred element. This opened the way to the study of horizontal transfer in M. tuberculosis : project horizontal transfer Mutant strains with an inactivation of the phoP/phoR two component regulatory system were shown to be attenuated and constitute promising vaccine candidate under clinical trials : project two component system PhoP/PhoQ.
- The identification of markers of TB strains that are characteristic of major M. tuberculosis strains families, thus corresponding to more adapted bacilli. Many of them correspond to SNPs affecting DNA repair genes. This opened the way to study genes involved in DNA repair and mycobacterial genome stability. New M. tuberculosis strain markers are being used to differentiate strains within major families and allow the detection of outbreaks. Together with the implementation of molecular probes for a rapid diagnosis and identification of drug resistances, molecular epidemiology could be used to identify MDR and even XDR TB outbreaks and alert public health authorities.
- Antibiotic resistances and drug screening. The characteristics of M. tuberculosis strains analysed in Africa, in Europe and in Asia showed that MDR strains accumulate additional antibiotic resistances with about 50% of them carrying pyrazinamide resistances. New drugs are under identification using phenotypic screening of chemical libraries and genomic approaches. Drugs used in clinic and new leads provided by partners of the EC NAREB project will be associated to nanocarriers with the aim to increase efficacy and lower side effects : NAREB project (Nanotherapeutics for Antibiotic Emerging Bacterial pathogens).