Functional and dynamic exploration of the immune evasion mechanisms used by Mycobacterium strains during infection and vaccination. – IMAGING_TB

Tuberculosis (TB) is a disease caused by Mycobacterium tuberculosis (Mtb) and currently one third of the world’s population is latently infected with Mtb, in spite of the existence of a vaccine since 1921. This scenario is in a large part due to Mtb’s ability to adapt to current treatments, e.g. by developing multi-resistances to antibiotics. However we also lack a proper understanding of the immunological mechanisms subverted by Mtb to establish a chronic infection and of the reasons for the failure of the current vaccine to provide protection. Hence novel and cross-disciplinary approaches are required to identify at what level Mtb virulence factors or the current vaccine strain BCG prevent the induction of a protective immune response during infection and vaccination.

Here we will identify the mechanisms by which Mycobacterium strains subvert T cell immunity that is critical for the protection from fatal infection, in the context of an infection with virulent Mtb and of vaccination with the current vaccine strain (BCG) or a new attenuated Mtb strain that is a promising candidate for a new TB vaccine. To this purpose we will investigate a critical step for the initiation of T cell immunity against mycobacteria : the migration of infected dendritic cells to the draining lymph node.

Our approach will make use of a set of unique tools to gain new insights into the interaction between host factors and mycobacteria virulence factors. These include novel multiphoton microscopy studies of the cellular dynamics of the infectious process in the lung and cross-disciplinary approaches such as a high-throughput screen of a library of Mtb mutants for regulators of dendritic cell function.

This research proposal will benefit from the unique synergy between the expertise in Mycobacterium’s biology of the host institution and my immunological
expertise of T cell immunity and live multiphoton microscopy. Therefore, we foresee making significant contributions to the field of tuberculosis research that will be instrumental for the development of new vaccines and more efficient treatments of TB.