Molecular basis of mycobacterial survival in macrophages

Abstract

Macrophages play an essential role in the immune system by ingesting and degrading invading pathogens, initiating an inflammatory response and instructing adaptive immune cells, and resolving inflammation to restore homeostasis. More interesting is the fact that some bacteria have evolved to use macrophages as a natural habitat and tools of spread in the host, e.g., Mycobacterium tuberculosis (Mtb) and some non-tuberculous mycobacteria (NTM). Mtb is considered one of humanity's most successful pathogens and is the causal agent of tuberculosis, while NTMs cause opportunistic infections all of which are of significant public health concern. Here, we describe mechanisms by which intracellular pathogens, with an emphasis on mycobacteria, manipulate macrophage functions to circumvent killing and live inside these cells even under considerable immunological pressure. Such macrophage functions include the selective evasion or engagement of pattern recognition receptors, production of cytokines, reactive oxygen and nitrogen species, phagosome maturation, as well as other killing mechanisms like autophagy and cell death. A clear understanding of host responses elicited by a specific pathogen and strategies employed by the microbe to evade or exploit these is of significant importance for the development of effective vaccines and targeted immunotherapy against persistent intracellular infections like tuberculosis.

Keywords: Immune evasion; Inflammatory signaling; Intracellular pathogens; Phagocytosis; Phagosome maturation; Tuberculosis.

Fig. 1

Schematic illustration of the different bacterial cell walls and their associated PAMPs. Left Gram-negative bacterial cell wall consists of a thin layer of peptidoglycan in the periplasmic space between the inner and outer lipid membranes. The outer membrane contains lipopolysaccharides on its outer leaflet and transport channels, such as porins. Centre Gram-positive bacteria lack an outer membrane but have a single lipid membrane surrounded by a cell wall composed of a thick layer of peptidoglycan and lipoteichoic acid, which is anchored to the cell membrane by diacylglycerol. Right Mycobacteria spp cell wall components surround a lipid membrane and include thin peptidoglycan and arabinogalactan layers, and a thick layer of mycolic acids. Glycolipids, porins and lipoarabinomannan and its variants, which are anchored to the cell membrane by diacylglycerol, are also important components. In addition, these bacteria secrete proteins and nucleic acids are also recognized by host PRRs

Fig. 2

Mycobacterial phagocytosis and interference with phagosomal maturation and autophagy. Mycobacteria enter the cell through passive phagocytosis and there is a great deal of redundancy in receptor usage, once inside the macrophage phagosomes normally fuse with lysosomes for degradation of the content. Pathogenic mycobacteria are known to interfere with phagosome maturation and take residence within a macrophage compartment. Our research indicates that the compartment may be in the endosomal recycling pathway. Within macrophages mycobacteria experience iron starvation, but can access iron through interaction with endosomes providing them with transferrin-iron. Mycobacteria can be detected by various factors on membranes and cytosol, and autophagy, a mechanism whereby the bacterium or the compartment is wrapped by a double membrane into an autophagosome that will fuse with lysosomes for degradation. Recent studies have shown that phagosomal escape of Mtb or at least permeabilisation of the phagosome triggers autophagy. Some mycobacteria, e.g., M. avium, may escape phagosomal degradation and signaling even when fused with late endosomes or lysosomes, although the mechanisms around this remain elusive. Mycobacterial evasion and survival strategies, in particular, mycobacterial iron acquisition, and also mycobacterial proteins that may interfere with phagosomal maturation and autophagy are illustrated in red lines