Macrophage Signaling Pathways in Pulmonary Nontuberculous Mycobacteria Infections

Abstract

The incidence and prevalence of nontuberculous mycobacteria (NTM) lung disease is rising worldwide and accounts for most clinical cases of NTM disease. NTM infections occur in both immunocompetent and immunocompromised hosts. Macrophages are the primary host cells that initiate an immune response to NTM. Defining the molecular events that govern the control of infection within macrophages is fundamental to understanding the pathogenesis of NTM disease. Here, we review key macrophage host signaling pathways that contribute to the host immune response to pulmonary NTM infections. In this review, we focus primarily on NTM that are known to cause lung disease, including Mycobacterium avium intracellulare, M. abscessus, and M. kansasii.

Keywords: Mycobacterium abscessus; Mycobacterium avium; autophagy; inflammasome; macrophage.

Figure 1.

Phagosomal maturation and autophagy. Nontuberculous mycobacteria (NTM) are taken up by the macrophage by phagocytosis. The bacteria aggregate into social phagosomes, with more than one bacillus within each phagosome. Tight apposition between the mycobacterial cell wall and the phagosomal membrane prevents phagosomal maturation and is a virulence mechanism by which NTM can survive intracellularly. As phagosomes mature, the pH becomes increasingly more acidic in an attempt to curb, and even kill, bacterial growth. The mature phagosomes fuse with lysosomes, and hydrolases degrade mycobacterial components, initiating autophagy and resulting in phagolysosome fusion with autophagosomes. The presence of cholesterol enables NTM to survive by keeping the bacteria closely apposed to the phagosomal membrane, thus preventing phagosomal fusion with lysosomes. Occasionally, NTM can also escape from late phagosomes or phagolysosomes and survive in a separate compartment within the cell.