Virulence Factors of Mycobacterium tuberculosis as Modulators of Cell Death Mechanisms

Abstract

Mycobacterium tuberculosis (Mtb) modulates diverse cell death pathways to escape the host immune responses and favor its dissemination, a complex process of interest in pathogenesis-related studies. The main virulence factors of Mtb that alter cell death pathways are classified according to their origin as either non-protein (for instance, lipomannan) or protein (such as the PE family and ESX secretion system). The 38 kDa lipoprotein, ESAT-6 (early antigen-secreted protein 6 kDa), and another secreted protein, tuberculosis necrotizing toxin (TNT), induces necroptosis, thereby allowing mycobacteria to survive inside the cell. The inhibition of pyroptosis by blocking inflammasome activation by Zmp1 and PknF is another pathway that aids the intracellular replication of Mtb. Autophagy inhibition is another mechanism that allows Mtb to escape the immune response. The enhanced intracellular survival (Eis) protein, other proteins, such as ESX-1, SecA2, SapM, PE6, and certain microRNAs, also facilitate Mtb host immune escape process. In summary, Mtb affects the microenvironment of cell death to avoid an effective immune response and facilitate its spread. A thorough study of these pathways would help identify therapeutic targets to prevent the survival of mycobacteria in the host.

Keywords: apoptosis; cell death; necroptosis; necrosis; pyroptosis; tuberculosis; virulence factors.

Figure 1

Major virulent factors of Mtb involved in cell death mechanisms. (a) Mycobacterial virulence proteins are mainly secreted through one of the essential secretion systems, ESX. ESX1, ESX3, and ESX5 are localized across the membrane, where proteins, such as ESAT-6, CFP-10, PE_PGRS, PtpA, SapM, PknG, and PknE, are delivered (left). (b) Non-proteins are glycolipids and phospholipids forming mycobacterial membrane structures. LAM (lipoarabinomannan), ManLAM (mannose-capped LAM), PDIM (phthiocerol dimycocerosate), and PIMs (Phosphatidyl-myo-inositol mannosides) are inserted in the cell wall (right). TDM, trehalose mono, and di mycolate; PGL, phenolic glycolipid.

Figure 2

Mycobacterium tuberculosis and apoptosis modulation. The mycobacteria or its virulence factors may modulate apoptosis, both intrinsic and extrinsic pathways at different levels, as inductors (red arrows) or inhibitors (black inhibitors). (a) Apoptosis may be detonated via TNF and FasL impacting initiator caspases-8 and -9 and effector caspases-3 and -7. (b) The intrinsic pathway also may control mycobacteria infection at the mitochondria level, cytochrome c released, and apoptosome formation by activating caspases-9 and -3. (c) TNF death signal may be blocked at DISC formation and caspase-8 activation. (d) The proapoptotic protein BAX may be down-regulated with the H37Ra strain. (e) Mycobacteria may stabilize the anti-apoptotic Bcl-2. (f) Up-regulation at the gene level of FasL and caspases may be done during mycobacteria infection; (g) down-regulation of IL-12 expression and TNF has also been reported.

Figure 3

Mycobacterium tuberculosis and the necrotic-like cell death modulation. The mycobacteria or its virulence factors may modulate pyroptosis, necroptosis, and ferroptosis pathways at different levels as inducers (red arrows) or inhibitors (black inhibitors). For example, Mtb through ESAT-6, LpqH activates inflammasome, favoring pyroptosis, while Zmp1 and PknF inhibit it. The Mtb ESX-1 secretion system, secreted protein ESAT-6, TNT, and PDIM lipid induce necroptosis. Meanwhile, multiple factors inhibit or activate ferroptosis, including the HO-1 enzyme, the SOCS1 protein, and the PI3K/Akt/mTORC1 signaling pathway, which act at different levels and points regulating the cell death pathway. PtpA favors ferroptosis by inhibiting GPX4 expression, a ferroptosis regulator.

Figure 4

Overview of cell death pathways modulated by Mtb through their virulence factors. Mtb can use its various virulence factors as inductors (red arrows) or inhibitors (black inhibitors) of diverse cell death mechanisms to orchestrate the infection process; as well, it allows it to disseminate and replicate for its survival.