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.

Investigation of Functional Activity of Cells in Granulomatous Inflammatory Lesions from Mice with Latent Tuberculous Infection in the NewEx VivoModel

“…However, dendritic cells in the mouse granulomas made up from 5% to 25% of the granuloma macrophage population. Therefore, our studies confirm that dendritic cells are for some reason absolutely required for granulomas [7, 35, 36]. It is presumed that dendritic cells, as some of the main antigen-presenting immune cells, can both stimulate and suppress the immune response during tuberculous infection [7].…”

“…Therefore, some of the activated macrophages and maturated dendritic cells of mouse granulomas did not manage to destroy intracellular BCG-mycobacteria. This observation disagrees on the issue that activated macrophages and maturated inflammatory dendritic cells must successfully destroy intracellular bacilli [3–5, 7, 12, 35, 36]. Basically the impact of granuloma cells infected by intracellular mycobacteria to the process of synthesis of proinflammatory cytokines, growth factors, the phagocytic receptors, and costimulatory molecules, is needed to be studied.…”

“…It is presumed that dendritic cells, as some of the main antigen-presenting immune cells, can both stimulate and suppress the immune response during tuberculous infection [7]. Dendritic cells are considered the principal disseminators of infection to animal organs and tissues, which results in miliary tuberculosis [7, 35, 36]. However, the factors accounting for the role of the dendritic cells in the granulomas and whether this role is subject to change during latent tuberculous infection have yet to be known.…”

“…As is known, to be able to ingest bacteria, the host's cells should have phagocytic receptors clustered on their membranes [13]. Therefore, the microdomain organization of the phagocytic receptors CD11b, CD11c, CD14, and CD16/CD32 on the surface of mouse granuloma cells suggested that the macrophages and dendritic cells were probably in a position to ingest mycobacteria in the granulomas and then have various signal transduction pathways activated [7, 8, 13, 35–37]. Detected differences in the amount of granuloma macrophages with CD11c and CD16/CD32 and dendritic cells with CD11c in Gran/1 and Gran/2 granulomas are held to imply expression modulation of these markers during the process initiation and growth of granulomatous inflammation in mice after being infected with BCG vaccine, though these findings demand for more investigations.…”

Innate Immune Gene Polymorphisms in Tuberculosis

“…However, an integrated understanding of the concerted genetic factors underlying an individual's susceptibility to TB remains elusive. We can look forward to significant progress with the combined use of large-scale technologies that enable full sequencing of genomes and transcriptomes and functional genomics approaches (153,158,171,246), leading to a systems biology analysis of host-pathogen interaction dynamics (47). In particular, we believe that further progress is needed with new approaches in the following areas.…”