Tuberculosis remains among the most deadly health threats to humankind. This povertyrelated disease, caused by bacteria of the Mycobacterium tuberculosis complex, kills each year more than 1.5 million people. It is estimated that a further 2 billion individuals are latently infected with M. tuberculosis. Most of them will never develop any clinical symptoms, although 5 to 10% of these latently infected individuals are at risk to develop TB in their lifetime. During the last decades the situation worsened because of deteriorating socioeconomic conditions, the increased incidence of drug-resistant M.tuberculosis strains and the co-infection with HIV (a major risk factor for development of TB). Currently only one vaccine is available against TB, the Bacille of Calmette and Guérin (BCG). However, its efficacy is extremely variable against the contagious form of TB - pulmonary TB - in adults and adolescents (ranging from 0 to 80%). Therefore, to control and eliminate TB, a better vaccine, efficient drug treatments and more rapid and cheaper diagnostic techniques are needed.
In this PhD thesis we have attempted to provide additional information to reach this goal. Indeed, we investigated the inflammatory and adjuvant potential of mycolate esters
homologous of those found in the cell wall of M. tuberculosis. These mycolate esters vary in terms of sugar (trehalose, glucose and arabinose) and lipid (alpha-, methoxy-, keto-, wax-ester MAs) moieties. TDM, TMM, GMM and AraMM were found to be potent activators of BMDCs in vitro. This activation was shown to be dependent on the Mincle pathway. Our results demonstrated that the classes of MAs bound to sugar do not consistently impact the level of pro-inflammatory and adjuvant responses induced. Rather, the nature of the sugar and the number of acyl chains bound to it seem to dictate the affinity of the glycolipid for Mincle receptor in vitro. In vivo, we observed that TDM, TMM and GMM induce similar immune responses characterized by a production of antigen-specific IFN-γ and IL-17A. The immune responses induced by AraMM are dependent on the type of formulation. Indeed, AraMM in emulsion does not induce substantial level of Th1 while AraMM in DDA liposome induces Th1 immune response. This study increases our knowledge on host-pathogen interactions during M. tuberculosis infection by identifying the receptor involved in the recognition of several PAMPs. Furthermore, we showed that the activation of this receptor by these mycolate esters triggers the induction of protective Th1 and Th17 immune responses.
Téléchargement 7.57 Mo