1999 Award Winner Dr. Jean Pieters Basel Institute for Immunology, Switzerland
The work of Jean Pieters
Despite a continuous exposure to various microorganisms, a healthy organism does not succumb to infections. One cell type that is especially important in surveying the host for invaders is the macrophage. Macrophages reside in virtually all organs and their function is to internalize circulating foreign material (including bacteria) in order to clear it from the circulation by a process called phagocytosis. After phagocytosis, internalized material is usually transferred to lysosomes, which are the organelles within a cell in which such material can be rapidly and completely destroyed. Several pathogenic bacteria, among which the Mycobacterium spp., which include the causative agents of diseases such as tuberculosis and leprosy, are efficiently phagocytosed by macrophages, but once inside the phagosome they resist delivery to lysosomes. As a consequence, these microorganisms cannot be degraded and hence survive in the so-called mycobacterial phagosome inside the macrophage. Dr. Pieters' laboratory is interested in understanding the mechanisms that are involved in host-pathogen interaction using the entry and survival of mycobacteria into macrophages as a model system. Using biochemical, molecular biological and immunological methods they have recently identified and characterized a host protein, termed TACO, that is actively recruited by mycobacteria and "coats" the phagosome, thereby blocking fusion of phagosomes with lysosomes. As a result, mycobacteria cannot be delivered to lysosomes, preventing their degradation and allowing them to survive within the macrophage. TACO, which stands for tryptophane aspartate contain-ing coat protein, because of the presence of so-called tryptophane-aspartate domains, is expressed in most macrophage cell types. The normal function of TACO is presently unknown; it is however likely that mycobacteria, during their long standing co-evolution with their host organisms, have evolved to make use of normal host cell mechanisms for their own benefit. Therefore, by analyzing the factors involved in host-pathogen interaction we hope to also gain more insight in the normal cell biological processes on going in the host. In addition, how mycobacteria can recruit and retain TACO is still unclear, and the genes expressed by the bacteria that mediate TACO retention have yet to be identified. Knowledge of the molecular mechanisms employed by mycobacteria, and possibly also by other pathogenic microorganisms that employ similar survival strategies to retain a TACO coat might prove to be useful for the development of novel anti-mycobacterial targets.