Table 2.
List of Mtb factors associated with host cell death
Actions on host | Mtb Protein/Factor | Remarks | Cell Type | Reference |
---|---|---|---|---|
Apoptosis inducers | Lipomannan (LM); lipoarabinomannan (LAM); mannosylated lipoarabinomannan (manLAM) | Induces apoptosis and IL-12 secretion | Human THP-1 | (47) |
Glycolipoprotein (p19; LpqH) | Induces apoptosis through TLR-2 and mitochondrial apoptosis-inducing factor | THP-1/CHO expressing TLR2 | (48) | |
Mycolactone | Causes apoptosis in guinea pig ulcers and tissue culture cells | macrophage cells J774A.1/guinea pig model | (49) | |
Periplasmic phosphate-specific transporter; 38-kDa lipoprotein (Pst-S1) | Causes TNF-α and FasL-mediated caspase-dependent apoptosis and upregulation of cell-death receptors TNFR1, TNFR2, and Fas and TLR2 | THP-1 macrophages | (50) | |
Early Secreting Antigen Target-6kDa (ESAT-6)-family (esxA, esxT and esxL) | Induces apoptosis through activation of caspase gene expression | THP-1 macrophages | (51) | |
PE-PGRS33 | Induces apoptosis through TLR2 pathway | RAW 264.7 and HEK293 cells | (52) | |
Rv0183 | Induces inflammation and apoptosis in RAW macrophages | Macrophage RAW264.7 cells | (53) | |
Rv0901 | Overexpression induces macrophage apoptosis | THP-1 macrophages | (54) | |
Rv3499c (Mce4A) | Induces apoptosis mediated by TNF-α | THP-1 macrophages | (55) | |
PPE37 | C-terminal domain induces apoptosis | THP-1 macrophages | (56) | |
PE9 (Rv1088)/PE10 (Rv1089) | Induces apoptosis by TLR4 pathway | THP-1 macrophages | (57) | |
PE_PGRS41 | Enhances intracellular survival | THP-1 macrophages | (58) | |
PE13/Rv1195 | Increases intracellular survival by activating the p38-ERK pathway | THP-1 macrophages | (59) | |
PE_PGRS18 | Enhances intracellular survival | THP-1 macrophages | (60) | |
Apoptosis inhibitors | NADH-quinone oxidoreductase subunit G (NuoG) | Inhibits apoptosis of infected host cells | BALB/c or SCID/Ncr (BALB/c mice) | (61) |
Protein Phosphatase 2 Phosphatase Activator (PtpA ) | Inhibits phagosome acidification and maturation. Interacts with tripartite motif containing 27 (TRIM27) and suppresses apoptosis |
THP-1 macrophages | (62) | |
DUF732 domain-containing protein kinase (Rv3354) | Targets the metalloprotease resulting in suppression of apoptosis; destabilizes regulatory cullin-RING ubiquitin E3 enzymatic activity; inhibits constitutive photomorphogenesis 9 (cop9) signaling | THP-1 macrophages | (63) | |
MPT64 (Rv1980c) | Inhibits apoptosis of macrophages through the NF-kB-miRNA21-Bcl-2 pathway | RAW264.7 macrophages | (64) | |
Protein Kinase E (pknE) | Mutation increases the expression of genes involved in apoptosis | THP-1 macrophages | (65) | |
Rv2456c | Inhibits apoptosis through NF-κB and extends the survival of Mtb. | Human epithelial cells (A549) & THP-1 macrophages | (66) | |
GroEL2 (Rv0440) | Blocks macrophage apoptosis via interaction with mitochondrial mortalin | THP-1 and RAW 264.7 cell lines | (37) | |
SecA2 (Rv1821) | Controls(?) secretion of a specific subset of proteins and blocks macrophage apoptosis | C57BL/6 mice | (67) | |
Oligopeptide transporter subunit (OppD) | Transports Mtb and induces apoptosis | THP-1 macrophages | (68) | |
Rv3654c/Rv3655c | Interacts with AL017 and blocks the extrinsic pathway | U937 monocyte-derived macrophage | (69) | |
Necrosis inducers | ESAT-6 | Results in necrosis of human macrophages mediated by pyrin domain-containing protein-3 (NLRP3) | THP-1 macrophages | (70) |
Channel protein with necrosis-inducing toxin (CpnT /Rv3903c) | Induce necrosis of human macrophages through its secreted C-terminal domain known as tuberculosis necrotizing toxin (TNT) | RAW 264.7 macrophages | (71) | |
THP-1 macrophages | ||||
PE25/PPE41 | Recombinant form induces necrosis | RAW 264.7 macrophages | (72) | |
Rv2626c | High levels of necrosis were observed in THP-1 macrophages infected with MtbH37Rv over-expressing Rv2626c | THP-1 macrophages | (73) | |
PPE68 | Inactivation decreases necrosis | THP-1 macrophages | (73) | |
PPE31 | Shortens the life of macrophages infected by Mtb over-expressing PPE31 and promotes mycobacterial survival | RAW264.7 macrophages | (74) | |
Pyroptosis inhibitors | Rv3364c | Binds to the cathepsin G, inhibiting its enzymatic activity and the downstream signal caspase-1. | Human monocytic cell line U937-derived macrophages | (75) |
Inhibits host pyroptosis | ||||
Pyroptosis inducers | Rv1579c/EST12 | Binds to RACK1 to recruit the deubiquitinase UCHL5 leading to NLRP3 inflammasome activation that promotes pyroptosis | Human monocytic THP-1 and mouse BMDMs | (76) |
Zinc metalloprotease 1 (Zmp-1/Rv0198c) | Deletion triggers activation of caspase-1/IL-1β inflammasome leading to pyroptosis signaling and improved mycobacterial clearance | J774A and RAW 264.7 macrophages | (77) | |
Autophagy inhibitors | Enhanced intracellular survival (Eis) | Infection with Mtb-Δeis elevates ROS generation and renders the cells highly sensitive to autophagy activation | THP-1 macrophages Mouse BMDM |
(78) |
ESAT-6 | Transient expression of the ESAT-6/CFP-10 fusion inhibits autophagosome formation by decreasing expression levels of ATG genes | RAW264.7 macrophages | (79) | |
PtpA | Interacts with active-phosphorylated vacuolar protein sorting 33B (VPS33B) and inhibits phagosome-lysosome fusion, impacting autophagy | THP-1 | (80) | |
PknG | Inhibits phagosome-lysosome fusion, impacting autophagy | J774 macrophage cells | (81) | |
ETosis | ESAT-6 | Induces a high level of intracellular Ca2+ leading to the formation of NETs characterized by extracellular DNA and myeloperoxidase | Neutrophils from healthy volunteers | (82) |
Mycobacterium tuberculosis (Mtb) modulates several types of host cell death upon infection. A list of different Mtb factors and their regulatory role in host cell death are tabulated. TLR2, Toll-like receptor 2; TNFR, tumor necrosis factor-alpha receptor.