Improving tuberculosis vaccination
Current preventive vaccination practice against tuberculosis consists of the Bacillus Calmette-Guerin (BCG) vaccine which is prepared from an attenuated bovine bacillus, the Mycobacterium bovis. However, the vaccine offers protection for only 15 years and at its best is 80 % effective. This is because apart from inducing protective immunity, the vaccine has an immunosuppressive effect. Research has shown that two mycobacterial glycolipids – lipoarabinomannan (LAM) and phenolic glycolipid (PGL) - play an important role in this immunosuppression and especially their mannose cap. To address this issue, the EU-funded project ‘A new approach for developing a less immunosuppressive tuberculosis vaccine’ (Immunovactb) focused on developing BCG strains lacking these surface glycolipids. Using an array of experimental procedures, project partners were able to determine the structure of the glycolipids and discover two genes (capA and capB) that were involved in the glycolipid cap biosynthesis. BCG mutants lacking one or both of these genes were characterised in vitro and in vivo to find that the mannose cap does not dominate the interaction of Mycobacteria with host dendritic cells. Nonetheless, compared to wild-type BCG, cap mutants triggered a greater cytokine release, indicating that the presence of mannose cap may have a slight immunosuppressive function. immunovactb scientists studied another structurally related group of mycobacteria glycolipids known as phosphatidylinositol mannosides (PIMs). These were found to interact with the mycobacterium-specific receptor on dendritic cells (DC-SIGN) but, similarly to what was seen for the cap genes, genetic removal of PIMs did not alter the bacterial interactions with the host immune cells. Furthermore, a third DC-SIGN ligand capsular alpha glucan was discovered with immunomodulatory properties. the Immunovactb project provided invaluable insight into the role of mycobacterial glycolipids in host immunosuppression. Manipulation of glycolipid expression is expected to improve the current M.bovis BCG vaccine and extend its protective effect against tuberculosis.
