Final Report Summary - INTRACELLTB (A Chemical Genomics Approach of Intracellular Mycobacterium tuberculosis Towards Defining Specific Host Pathogen Interactions) The summary should be a stand-alone description of the project and its outcomes. This text should be as concise as possible and suitable for dissemination to non specialist audiences. Please notice that this summary will be published.Mycobacteria are the etiological agents of major diseases, plaguing and threatening the lives of millions of people throughout the world, including Tuberculosis (M. tuberculosis), Leprosy (M. leprae) and Buruli ulcer (M. ulcerans). The Koch bacillus, M. tuberculosis, is transmitted by aerosol and, in most cases, establishes infection in the lungs. In the case of M. ulcerans, transmission happens via insect bites and bacterial replication occurs within skin tissue. Surprisingly, subcutaneous nodules and ulcers, in the early infection stages, are painless so that patients seek remedy very late.An effective antibiotic arsenal that targets bacterial machinery has existed since the 1950s and is able to cure the mycobacterial diseases when caused by drug-sensitive strains. No satisfactory preventive measures against Tuberculosis (TB) and Buruli ulcer (BU) exist. The BCG vaccine confers protection only against disseminated forms of TB in young infants. The recent Phase II clinical trial of novel vaccine candidates failed and radical advances for novel vaccine development require a better understanding of the immunological correlates needed for protection.Concerning TB treatment, it is generally agreed that the key to improving lengthy antibiotic therapy relies on shortening its duration and making it more effective against multidrug resistant (MDR-TB) and extremely resistant strains (XDR-TB). The addition of fluoroquinolone-containing (moxifloxacin and gatifloxacin) regimens to the first line regimen has so far failed to shorten the duration of therapy. Despite massive drug discovery projects by pharmaceutical companies, and large public-private partnerships (PPPs), the new drugs for tuberculosis pipeline is sparse.Fighting these plagues can be only at the price of understanding, at the fundamental molecular levels, of the very diverse strategies evolved by these pathogens to complete successfully the various steps of infection. Diseases caused by mycobacteria, as well as by other microbes, can be associated with the various steps of the infective/growth processes, such as invasiveness into host cells, break of host defences and subversion of immune responses.In INTRACELLTB we identified novel molecular mechanisms involved in mycobacterium interactions with host cells. We identified key bacterial effectors and host proteins that are used by the mycobacterium to cause infections and to induce analgesia. Drug candidate that target the host pathways may ultimately contribute to the development of Host Directed Therapy aginst Tuberculosis and novel Analgesics.
