Table 1.
Host factors modulated by Mtb in various cell death modalities
| Cell Death Pathways | Host Factor | Remarks | Cell Type | Reference |
|---|---|---|---|---|
| Apoptosis | Bcl-2 (B-cell lymphoma-2) | Integral outer mitochondrial membrane protein that blocks apoptosis; upregulated over 2.5-fold following 48 h infection of Mtb | Human alveolar MΦ, alveolar epithelial cells, murine models | (29, 30) |
| Bax (Bcl-2 associated X) | Apoptosis regulator protein; downregulated > 2-fold following Mtb infection | Human alveolar MΦ, alveolar epithelial cells, murine models | (29, 30) | |
| Bad (Bcl-2 agonist of cell death) | Promotes apoptosis by forming heterodimers with Bcl-xl and Bcl-2; downregulated > 2-fold following Mtb infection | Human alveolar MΦ and alveolar epithelial cells | (29) | |
| Bim (Bcl-2 interacting mediator) | Proapoptotic Bcl-2 family protein; upregulated after 24, 48, and 72 h after Mtb infection | Mouse MΦ J774 | (31) | |
| Bcl-w (Bcl-2l2) | Acts as anti- and proapoptotic regulator; upregulated 1.8–2-fold following Mtb infection | Human alveolar MΦ | (32) | |
| Calreticulin | Modulates Mtb survival through endoplasmic reticulum stress-mediated apoptosis; upregulated following Mtb infection | THP-1 MΦ | (33) | |
| Elongation factor 1-alpha (eEF1α) | Modulates TNF-α dependent apoptosis; down-regulated > 2-fold following pathogenic Mtb infection | Human alveolar MΦ | (32) | |
| Interferon gamma (IFN-γ) | Activates nitric oxide-induced apoptosis; upregulated following mycobacterial infection | Mouse MΦ | (34) | |
| Tumor necrosis factor-alpha (TNF-α) | Modulates apoptosis and other cell death pathways; expression is inversely proportional to mycobacterial virulence | BALB/c mouse MΦ | (35) | |
| Myeloid leukemia-1 (Mcl-1) | Provide resistance to apoptosis; upregulated as early as 4 h and peaked (∼6-fold) at 24 h after infection | THP-1 MΦ | (36) | |
| Mitochondrial mortalin | Modulates macrophage apoptosis signaling by interaction with mitochondrial mortalin; upregulated during Mtb infection. | THP-1 and RAW 264.7 MΦ | (37) | |
| Nuclear factor kappa-B (NFκB) | Regulates apoptosis following Mtb- antigen stimulation; upregulated during Mtb infection. | HeLa cells | (38) | |
| RAD23 homolog B | Modulates TNF-α dependent apoptosis; downregulated > 2-fold following pathogenic Mtb infection. | Human alveolar MΦ | (32) | |
| Retinoblastoma (Rb) | Regulates apoptosis; upregulated over 2.5-fold after 48 h of Mtb infection | Human alveolar MΦ and alveolar epithelial cells | (29) | |
| Superoxide dismutase-2 (SOD2) | Modulates TNF-α dependent apoptosis; downregulated 1.8 to 2.0-fold after 48 h post-Mtb infection | Human alveolar MΦ | (32) | |
| Toll-like receptor 2 (TLR-2) | Induces macrophage death; upregulated in Mtb infection | Mouse MΦ | (39) | |
| Lymphocyte activation gene-3 (LAG-3) | Immunomodulator that affects host cell apoptosis; induced nearly 100-fold following Mtb infection. | Macaque blood derived MΦ/T cell co-culture | (40) | |
| Kruppel-type zinc finger (ZK1) protein | Modulates TNF-α dependent apoptosis; downregulated > 2-fold following Mtb infection. | Human alveolar MΦ | (32) | |
| Gasdermin-D (GSDMD) | Mediates apoptosis but not IL-1β secretion in Mtb-infected macrophages | Human MΦ, PBMCs | (41) | |
| Pyroptosis | NOD-, LRR-. and pyrin domain-containing protein 3 (NLRP3) | Activation of the NLRP3 inflammasome to modulate inflammatory disease pathogenicity | Immune cells (T cells) | (42) |
| Caspase-1 (CASP-1) | CASP-1 activation leads to chromosomal DNA damage through an endonuclease | H9C2 cardiomyocytes | (43) | |
| Necroptosis | Receptor-interacting serine/threonine-protein kinase 3 (RIPK3) | RIPK3 complex recruits and phosphorylates MLKL to form the necrosome | Mouse embryonic fibroblasts (MEFs) | (44, 45) |
| Mixed lineage kinase domain-like (MLKL) | Initiates necroptotic cell death by allowing ion influx, cell swelling, and membrane lysis followed by the uncontrollable release of intracellular material | Mouse embryonic fibroblasts (MEFs) | (45, 46) |
Several host factors/proteins regulated following Mtb infection in different cell death modes and their fold expression are listed. MΦ, macrophages; Mtb, Mycobacterium tuberculosis; NOD, nucleotide binding oligomerization domain; PBMCs, peripheral blood mononuclear cells.