Mycobacterium tuberculosis: Rewiring host cell signaling to promote infection

Abstract

The ability of Mycobacterium tuberculosis to cause disease hinges upon successfully thwarting the innate defenses of the macrophage host cell. The pathogen's trump card is its armory of virulence factors that throw normal host cell signaling into disarray. This process of subverting the macrophage begins upon entry into the cell, when M. tuberculosis actively inhibits the fusion of the bacilli-laden phagosomes with lysosomes. The pathogen then modulates an array of host signal transduction pathways, which dampens the macrophage's host-protective cytokine response, while simultaneously adapting host cell metabolism to stimulate lipid body accumulation. Mycobacterium tuberculosis also renovates the surface of its innate host cells by altering the expression of key molecules required for full activation of the adaptive immune response. Finally, the pathogen coordinates its exit from the host cell by shifting the balance from the host-protective apoptotic cell death program toward a lytic form of host cell death. Thus, M. tuberculosis exploits its extensive repertoire of virulence factors in order to orchestrate the infection process to facilitate its growth, dissemination, and entry into latency. This review offers critical insights into the most recent advances in our knowledge of how M. tuberculosis manipulates host cell signaling. An appreciation of such interactions between the pathogen and host is critical for guiding novel therapies and understanding the factors that lead to the development of active disease in only a subset of exposed individuals.

Keywords: host-pathogen interactions; macrophages; virulence factors.

Figure 1

Mycobacterium tuberculosis manipulates essential components of the macrophage antimicrobial response. Mycobacterial virulence factors such as ESX‐1, PtpA, and SecA2 interfere with the ability of lysosomes to kill phagocytosed M. tuberculosis, thereby establishing a secure, intracellular replicative niche. The pathogen then disables NF‐κB and MAPK signal transduction pathways, blunting the macrophage's host‐protective cytokine response. However, bacilli may eventually burst from phagosomes to activate host cytosolic DNA sensors, either directly by shedding their own DNA, or indirectly by inducing mitochondrial stress and DNA release. The consequence of this is the transcriptional induction of type I IFNs, which are detrimental to the host

Figure 2

Mycobacterium tuberculosis alters host cell metabolism to promote “foamy” macrophages containing lipid bodies. Mycobacterial cell wall components can stimulate lipid body accumulation in a partially TLR2‐dependent manner. The virulence factor ESAT‐6 also promotes glycolytic flux by stimulating the translocation of GLUT‐1 glucose transporters to the cell surface to enhance glucose uptake, and by directly modulating the activity of key glycolytic enzymes. This promotes the accumulation of dihydroxyacetone phosphate (DHAP) and acetyl CoA, which can both be used as substrates for triacylglycerol (TAG) synthesis. Acetyl CoA is also converted into D‐3‐hydroxybutyrate (3HB), which activates the G protein coupled receptor GPR109A. This inhibits the phosphorylation of perilipin, thereby restricting the translocation of hormone‐sensitive lipase (HSL) to lipid bodies, and preventing their degradation. Mycobacterium tuberculosis also inhibits autophagic degradation of lipid bodies by inducing miR‐33 expression. The pathogen can reside within these lipid bodies and acquire a protective dormancy phenotype, or can utilize the lipids as a source of nutrients by secreting the hydrolytic Msh1 protein

Figure 3

Mycobacterium tuberculosis modulates the macrophage death modality to promote dissemination and interfere with adaptive immunity. PE‐PGRS47A obstructs autophagosomal processing of mycobacteria, and therefore the presentation of M. tuberculosis peptides by MHC class II. Other virulence factors reduce the expression of cell surface molecules required for antigen presentation. Through a variety of reported mechanisms, M. tuberculosis also inhibits macrophage apoptosis, a process which would otherwise result in mycobacterial killing and facilitate priming of adaptive immunity. The pathogen exits the host cell and disseminates by inducing a lytic form of death. The processes leading to this are poorly understood and may involve secretion of tuberculosis necrotizing toxin (TNT)