Table 3.
Deficiency or excess of specific components that impairs host control of Mtb.
| Component | Deficiency (component beneficial to host) | Excess (component harmful) |
|---|---|---|
| Epithelioid macrophages | Absolute Stat 6 depletion prevents epithelioid macrophage differentiation, increasing Mtb growth in granulomas (36, 37). | Excessive formation may create a “wall” that prevents immune cell influx into granulomas whereas some disruption increases immune access and promote host survival (35). |
| TH1 (IFNγ) | Natural examples are individuals with advanced HIV infection (73, 249) or with genetic defect in IFNγ-IL-12 axis (Medelian Susceptibility to Mycobacterial Diseases) who are vulnerable to systemic mycobacterial infections (250, 253) due to CD4+IFNγ+ deficiency resulting in massive Mtb burden and necrotic macrophage death ( Figure 4A ). Deficiency of IFNγ may also augment IL-17 production, inducing neutrophil influx (258). Appropriate IFNγ production induces IDO-1 that inhibits excessive IL-17 production, limiting excessive neutrophil influx (91) ( Figure 4C ). | Excess TH1 (IFNγ) results in secondary excess in TNF (207). TNF activates RIP1 and RIP3, induces robust reactive oxygen species, programmed necrosis (necroptosis), and TB cavitation (76, 77) ( Figure 4B ). IFNγ also increases CXCR3 (a receptor for several angiostatic chemokines), causing hypoxia and granuloma necrosis (211). Excess IFNγ-induced IDO-1 (259) can also inhibit iBALT formation. |
| TH2/Stat6 | TH2 cells are required for granuloma formation as TH2 deficiency results in failed epithelioid transformation and increased Mtb burden (37, 78). | Excess TH2 results in insufficient host-protective immunity causing granuloma necrosis, increased delayed-type hypersensitivity to TNF, cavitation, perinecrotic fibrotic capsule, and Mtb transmission (79–81). |
| TNF | Mice in which either TNF is neutralized by a monoclonal antibody or have genetic disruption of the 55 kDa TNF receptor are more susceptible to Mtb (147, 260). Humans treated with anti-TNF antibody for autoimmune are highly susceptible to TB (141–143). | TNF activates RIP1 and RIP3 and induces production of reactive oxygen intermediates, resulting in activation of BAX, and initiation of a mitochondrial mediated cascade that induces cyclophilin-D-mediated necroptosis (76, 261). TNF also causes anorexia and cachexia (262). |
| IL-12 | Deficiency of IL-12 or defect in IL-12 receptor subunit is associated with predisposition to mycobacterial infections (250–253). | Depending on the Mtb lineage, the ancestral human IL-12B allele may be associated with more severe TB (suggesting co-evolution of humans and Mtb) (136). |
| IL-17 | Insufficient IL-17 increases (sequentially) HIF-1α expression, hypoxic necrotic granuloma formation, & severity of TB (87). IL-17 also required for initial formation of protective iBALT (89, 90, 119). IL-17 triggers the production of chemokines that recruit CD4+IFNγ+ T cells (88). | Excess TH17 and IL-17 production increases influx of neutrophils, augmenting granuloma necrosis (91, 92). Sustained & prolonged IL-17 production in iBALT lesions could result in chronic inflammatory & pathologic iBALT (119). |
| MMPs | MMPs facilitate leucocyte recruitment, cytokine and chemokine processing, defensin activation and matrix remodeling (181). Inhibition of MMPs in BALB/c mice was deleterious, resulting in decreased IL-1 and IL-2 expression, premature increase in IL-4, delayed granuloma formation, & more rapid progression of TB (263). In contrast, inhibition of MMPs in C57BL/6 mice was salubrious, resulting in increased fibrosis of the granulomas, decreased leukocyte recruitment (to the granulomas), & decreased numbers of Mtb in the lungs & blood in early disease (264). | Excess MMP may lead to immunopathology that leads to Mtb dissemination or persistence (181). MMP-9 helps mediate intercellular spread of M. marinum (60, 182). |
| Hypoxia | The beneficial, seemingly paradoxical, effects of hypoxia to the host are that hypoxia can: (i) impair the growth of Mtb as evinced by Mtb-infected mice, guinea pigs, & rabbits controlled the TB significantly better when breathing 10% O2 (vs. 21% O2) (265); (ii) induce expression of HIF-1α, augmenting phagocytes to kill Mtb in part through impaired ability to activate autophagy (158, 162) (see also HIF-1α below); (iii) recruit immune cells to infection site through induction of the chemokine receptor CXCR4 for CD4+ T cells (164) & neovascularization (165). | Hypoxia induces necrosis of immune cells in granulomas & of pulmonary tissues (211, 266), causing increased disease severity and provide a niche for Mtb (87). Hypoxia also induces secretion of MMP-1 causing lung destruction and cavities (218). |
| HIF-1α | Hypoxia-induced HIF-1α enhances glycolysis to generate ATP quickly, increases angiogenesis (267), coordinates antimicrobial responses of macrophages such as production of inflammatory cytokines (268), and induces greater M1 macrophage and TH1 cell phenotypes (154, 162, 163) to kill Mtb and other bacteria including pyogenic bacteria and Mycobacterium avium (159, 160, 166). | HIF-1α, although induced by hypoxia, has also been shown to induce hypoxic TB granulomas (87), to inhibit apoptosis of Mtb-infected foamy macrophages (impairing killing of intracellular Mtb) (154), and induce MMP-1 (a collagenase that may cause tissue destruction) (218). |
| Aerobic glycolysis | Aerobic glycolysis skews macrophages and T cells toward the M1 and TH1 (IFNγ-producing) phenotypes, augmenting immune cells to control Mtb infection (161, 163). Lactate produced from glycolysis increases autophagy and killing of Mtb (39, 41) | Indirect evidence that the more TB-resistant cynomolgus macaques have less positive PET-CT lesions (see above discussions). Post-translational modification of proteins by lactate may also lead to excessive inflammation (269). |
| IDO-1 activity | IDO-1 expression in granulomas is found mainly in the rim that surrounds the central necrosis (270). IDO-1 catabolizes tryptophan into kynurenine. Since tryptophan is normally required for Mtb growth, absence of IDO-1 would theoretically provide excess fuel for Mtb growth (271). Insufficient IDO-1 would increase IL-17, resulting in increased neutrophil influx into and cause necrosis of the granulomas ( Figure 7 ). | Increased IDO-1 activity is a predictor of death in Mtb-infected hosts (272). Excess IDO-1 activity would decreased proliferation of CD4+ and CD8+ T cells (132). Reduced remodeling of granuloma resulting in decreased influx of CD4+ T cells to the granuloma core ( Figure 7 ) (132, 271).. Nevertheless, in the NHP model, (modest) inhibition of IDO-1 results in both reduced Mtb burden and disease severity ( Figure 7 ) (132, 271). |
| HO-1 activity | HO-1 is protective and promotes granuloma formation in M. avium infection (273). In mice, HO-1 deficiency leads to increased susceptibility to Mtb infection with increased bacterial loads and mortality due, in part, to failure to mount a protective TH1-mediated granulomatous response (274, 275). HO-1 catalyzes the oxidation of heme (as seen with TB hemorrhage) to produce iron, biliverdin, and carbon monoxide that have anti-oxidant, anti-inflammatory, and anti-apoptotic properties to attenuate TB immunopathology (276, 277). | Treatment of macrophages or mice with a HO-1 inhibitor leads to enhanced control of mycobacterial replication (278, 279); it is believed that HO-1 expression increases iron availability in activated macrophages, which benefits Mtb growth (276). HO-1 levels correlate directly with the level of active TB but this relationship by itself does not inform whether HO-1 is host-protective or not (280). |
| Immune checkpoint | C57BL/6 mice with genetic disruption of the PD-1 gene are more susceptible to Mtb infection with both severe pathology and greater Mtb burden (213, 214, 216). The PD-L1 gene knockout mice do not have as severe TB than the PD-1 knockout mice, perhaps because PD-L2 gene is still intact ( Figure 6 ) (213, 281). See above for more detailed discussion. | BALB/c mice with genetic disruption of TIM3 gene were more resistant to Mtb (256). Similarly, administration of an anti-CTLA-4 antibody enhanced mycobacterium-specific T cell proliferation as well as a decrease in M. bovis-BCG burden (257). |
| LTA4H activity | Individuals with the CC genotype of LTA4H possess an anti-inflammatory (decreased LTB4:LXA4 ratio) and have poorer TB outcome. See above for more detailed discussion. | Individuals with the TT genotype of LTA4H possess a pro-inflammatory phenotype (increased LTB4:LXA4 ratio) and have poorer TB outcome. |
| NFκB | NFκB-mediated responses are critical for restricting bacterial growth in a granuloma (282). | In excess, NFκB may also cause injurious inflammation and cell necrosis (282) and may inhibit apoptosis and autophagy of Mtb-infected macrophages (50). |
| TGFβ | In conjunction with IL-23, TGFβ promotes the expansion of TH17 cells, which are important for early control of Mtb infection (86). | TGFβ negatively impacts IFNγ-producing CD4+ T cells in granulomas, impairing control of Mtb (83, 101). |
CTLA-4, cytotoxic T lymphocyte-associated protein 4; HIF-1α, hypoxia-inducible factor-1 alpha; HO-1, heme oxygenase-1; IDO-1, indoleamine 2,3-dioxygenase; IL-12, interleukin-12; IL-17, interleukin-17; LTA4H, leukotriene A4 hydrolase; LTB4, leukotriene B4; LXA4, lipoxin A4; MMPs, matrix metalloproteinases; NFκB, nuclear factor-kappa B; PD-1, programmed cell death protein-1; TGFβ, transforming growth factor-beta; TIM3, T cell immunoglobulin and mucin domain-containing protein 3; TNF, tumor necrosis factor.