Spotlight on Mycobacteria and dendritic cells: will novel targets to fight tuberculosis emerge?

Abstract

Over thousands of years microbes and mammals have co-evolved, resulting in extraordinarily sophisticated molecular mechanisms permitting the organisms to survive together. Mycobacterium tuberculosis is one of the best examples of successful co-evolution, since the bacilli have infected one third of the human population, but in 90% of the cases without causing overt disease. Despite this, increasing incidence of Human Immunodeficiency Virus (HIV) infection and the emergence of drug-resistant strains means that tuberculosis is in fact an extremely serious emerging threat to global health. Decades of work have focused on the interaction of this pathogen with its established cellular host, the macrophage, but still novel therapeautics remain elusive. While the macrophage is clearly important, recent evidence suggests that understanding the role of dendritic cells, which are key regulators of immunity, may be a crucial step in identifying new means of controlling this disease. Novel technologies, in particular genome-wide transcriptome analyses, are advancing our ability to dissect the complex dynamic relationships between dendritic cells and mycobacteria, highlighting new areas for study that have not been previously explored.

Figure 1. Timeline of landmark events in TB history with mankind since 5000BC

MDR TB, multi-drug resistant tuberculosis; XDR TB, extremely drug-resistant TB

Figure 2. The process of normal phagosome maturation is differentially affected by M.tb. in DCs and MFs

The normal process of phagocytosis (for killed mycobacteria, or non-mycobacterial cargoes) involves gradual maturation of the nascent phagosome. Coronin 1 expression is transient, and the loss of this protein combined with the switch of Rab5 to Rab7 expression, and the acquisition of syntaxin 6, promotes maturation of the phagosome and finally lysosomal fusion. In MFs the M.tb. phagosome is arrested at an early stage of maturation, and retains the expression of coronin 1 with Rab5. Interaction with early/recycling endosomes is encouraged by the expression of Rab11, and this gives mycobacteria access to transferrin-bound iron. Lipids are also an important energy source for mycobacteria, and can be acquired through interaction with the endoplasmic reticulum/biosynthetic pathway, which is detected by the presence of calnexin and Grp78 on the phagosome membrane. In comparison to MFs, far less is known about the mycobacterial phagosome in DCs. What is understood is that the phagosome is similarly arrested and retains coronin 1 expression, but exhibits far fewer interactions with the host intracellular trafficking machinery (based on the data of Tailleux et al, 2003a).