Mycobacterium tuberculosis-macrophage interaction: Molecular updates

Abstract

Mycobacterium tuberculosis (Mtb), the causative agent of Tuberculosis (TB), remains a pathogen of great interest on a global scale. This airborne pathogen affects the lungs, where it interacts with macrophages. Acidic pH, oxidative and nitrosative stressors, and food restrictions make the macrophage's internal milieu unfriendly to foreign bodies. Mtb subverts the host immune system and causes infection due to its genetic arsenal and secreted effector proteins. In vivo and in vitro research have examined Mtb-host macrophage interaction. This interaction is a crucial stage in Mtb infection because lung macrophages are the first immune cells Mtb encounters in the host. This review summarizes Mtb effectors that interact with macrophages. It also examines how macrophages control and eliminate Mtb and how Mtb manipulates macrophage defense mechanisms for its own survival. Understanding these mechanisms is crucial for TB prevention, diagnosis, and treatment.

Keywords: Mycobacterium tuberculosis; host macrophage; immune control; immune evasion; intracellular pathogen; molecular interaction; tuberculosis control.

Figure 1

Activation of macrophage immune mechanisms to control Mtb infection. Crucial intracellular processes, such as autophagy, apoptosis, pyroptosis, and inflammation associated with the secretion of antimicrobial compounds (NO, iNOS, ROS) are induced following Mtb infection. Extrinsic or intrinsic activation of apoptosis by Mtb intracellular or extracellular effectors respectively leads to Mtb control. Mtb control is also achieved by efficient phagosome maturation and fusion to the lysosome (phagolysosome), coupled with reduced availability of calories characterized by the shift from FAO to glycolysis. Finally, the secretion of soluble factors through inflammasome and pyroptosis activation, or the production of ROS or RNS via the NF-kB pathway or through sphingomyelinases restrict the pathogen progression in the macrophage as well. FAO, fatty acid oxidation, Casp, caspase, ER, endoplasmic reticulum. Section 4 provides more details.

Figure 2

Manipulation of macrophage intracellular processes by Mtb. Via the secretion of its virulence factors, Mtb subverts crucial host processes. Mtb inhibits phagosome maturation via the MSH pathway, inhibits ubiquitination by acting as host ubiquitin-like enzymes or interfering with host ubiquitin ligases, reduces the secretion of pro-inflammatory cytokines by blocking inflammasome and pyroptosis, limits the generation of ROS or NO by interfering with sphingolipids or via the activation of the transcription factor WhiB3 or the lipid-associated gene cluster (Lip-Y, Icl-1, and tgs-1). Moreover, the promotion of ferroptosis via increased Fe²⁺ concentration or lipid peroxidation is a risk factor for individuals infected by Mtb. Finally, Mtb survival is also reached by inhibiting apoptosis while promoting necrosis. Section 5 provides more details.