Autophagy in the fight against tuberculosis

Abstract

Tuberculosis (TB), a chronic infectious disease mainly caused by the tubercle bacillus Mycobacterium tuberculosis, is one of the world's deadliest diseases that has afflicted humanity since ancient times. Although the number of people falling ill with TB each year is declining, its incidence in many developing countries is still a major cause of concern. Upon invading host cells by phagocytosis, M. tuberculosis can replicate within infected cells by arresting the maturation of the phagosome whose function is to target the pathogen for elimination. Host cells have mechanisms of controlling this evasion by inducing autophagy, an elaborate cellular process that targets bacteria for progressive elimination, decreasing bacterial loads within infected cells. In addition, autophagy activation also aids in the control of inflammation, contributing to a more efficient innate immune response against M. tuberculosis. Several innovative TB therapies have been envisaged based on autophagy manipulation, with some of them revealing high potential for future clinical trials and eventual implementation in healthcare systems. Thus, this review highlights the recent advances on the innate immune response regulation by autophagy upon M. tuberculosis infection and the promising new autophagy-based therapies for TB.

FIG. 1.

The autophagy pathway and its main regulators. Autophagy is typically subdivided in different steps: (i) vesicle nucleation/initiation, (ii) phagophore elongation, (iii) autophagosome maturation, (iv) autophagosome/lysosome fusion, and (v) cargo degradation. Following AMPK activation and/or mTORC1 inhibition (by factors such as nutrient depletion and energetic stress), the complex formed by ULK1/2, FIP200, and ATG13 is activated, which in turn activates the VPS34 complex by phosphorylation. Both complexes regulate the nucleation/initiation step of autophagy, with VPS34 providing PI3P to the phagophore, which is likely to assist the recruitment of WIPI to the phagophore. On the other hand, membrane expansion depends on ATG9, which is postulated to supply lipid bilayers to the phagophore, and on two ubiquitin-like conjugation systems that conjugate LC3 and ATG12 to PE and ATG5, respectively. The ATG12-ATG5 complex further interacts with ATG16L1, presumably at the surface of the autophagosome membrane. LC3-II seems to be involved in the elongation and closure of the autophagosome membrane, as well as in the recruitment of cargo to the phagophore. Subsequently, the autophagosome fuses with the lysosome, forming the autolysosome, where degradation of the autophagosomal contents occurs. AMPK, AMP-activated protein kinase; FIP200, focal adhesion kinase family-interacting protein of 200 kDa; mTORC1, mechanistic target of rapamycin complex 1; PE, phosphatidylethanolamine; ULK, unc-51-like kinase.

FIG. 2.

M. tuberculosis clearance by autophagy. M. tuberculosis invades macrophages by phagocytosis and arrests the maturation of the phagosome by excluding late endosome and lysosome markers (i.e., RAB7, V-ATPase, VPS33b, LAMP1) from the phagosome and by promoting the retention of early endosome markers (i.e., RAB5) in the phagocytic compartment. Host cells have developed ways of overcoming the evasion of M. tuberculosis from the phagocytic pathway by taking advantage of some intrinsic M. tuberculosis mechanisms. For instance, phagosomal permeabilization induced by the bacterial ESX-1/ESAT-6 system allows the host protein STING to recognize extracellular bacterial DNA, which then promotes ubiquitin marking of bacteria (mostly through K63-linkage chain formation by the E3 ligase Parkin). Ubiquitin is then recognized by autophagy adaptors, such as P62, which deliver the bacilli to autophagosomes. TBK-1-induced phosphorylation of Ser403 of P62 increases the affinity of P62 to ubiquitin. Autophagosomes are subsequently fused to lysosomes, where degradation of mycobacteria occurs. LAMP1, lysosomal-associated membrane protein 1; STING, stimulator of the interferon gene; TBK-1, TANK-binding kinase 1.

FIG. 3.

Cross talk between autophagy and inflammation during M. tuberculosis infection. Autophagy activation in macrophages is controlled by membrane and intracellular innate immune receptors, as well as by several inflammatory cytokines released by Th1 and Th2 cells upon M. tuberculosis infection. The receptors, TLR2, TLR4, TLR9, and NOD2, and the proinflammatory cytokines, TNF-α, IFN-γ, IL-2, IL-6, and CCL2, promote autophagy activation. On the other hand, the anti-inflammatory cytokines, IL-4 and IL-13, appear to inhibit IFN-γ-induced autophagy activation. However, cytokine expression and secretion are also regulated by autophagy. For instance, IL-1α, IL-1β, and IL-18 are negatively regulated by autophagy, while TNF-α is upregulated by this mechanism. IFN-γ, interferon-γ; IL, interleukin; NOD2, NOD-like receptor 2; Th1, T helper 1; Th2, T helper 2; TLR, Toll-like receptor; TNF-α, tumor necrosis factor-α.