Mechanisms of lung damage in tuberculosis: implications for chronic obstructive pulmonary disease

Abstract

Pulmonary tuberculosis is increasingly recognized as a risk factor for COPD. Severe lung function impairment has been reported in post-TB patients. Despite increasing evidence to support the association between TB and COPD, only a few studies describe the immunological basis of COPD among TB patients following successful treatment completion. In this review, we draw on well-elaborated Mycobacterium tuberculosis-induced immune mechanisms in the lungs to highlight shared mechanisms for COPD pathogenesis in the setting of tuberculosis disease. We further examine how such mechanisms could be exploited to guide COPD therapeutics.

Keywords: COPD - chronic obstructive pulmonary disease; Tuberculosis; adaptive immunity; host-directed therapy (HDT); innate immunity.

Figure 1

Immune-mediated mechanisms of TB-associated COPD. Alveolar macrophages engulf M.tb in the alveolar space. 2. Infected alveolar macrophages migrate from the alveolar space into the interstitium in an IL-1R-dependent manner. 3. M.tb replicate within alveolar macrophages. 4. M.tb induce infected macrophage apoptosis and expression of host lytic proteins in an ESX-1-dependent manner. 5. Newly recruited alveolar macrophages engulf infected cell debris. 6. Lung infiltrating neutrophils move by chemotaxis towards the growing granuloma, engulfing dying infected cells and killing bacteria through NETosis and release of lytic enzymes. 7. M.tb-specific T cells arrive at the granuloma and produce IFN-γ to enhance the microbicidal activity of alveolar macrophages. However, activated T cells are walled off from accessing the inner core of the granuloma, and their effect is dampened by the cytokine TGFβ. 8. Alveolar macrophage necrosis leads to granuloma rupture and release of M.tb into the extracellular space. Subsequent induction of lytic proteins causes granuloma cavitation and release of Mtb into the airways. 9. In the post-TB stage following treatment, extensive lung fibrosis and emphysema reduces lung compliance and are observed as reduced lung function. 10-11. Extensive fibrosis and calcification further reduce lung compliance and worsens COPD. 12. Periodic insults such as bacterial, viral, and fungal infections and air pollution or smoking trigger periodic COPD exacerbations after that. Created with Biorender.com.

Figure 2

Targets for host-directed therapy (HDTs) for TB-associated COPD. A select list of immune-based therapies could offer benefits for patients with TB-associated COPD. Several agents have been developed or are under development that target (i) the innate immune sensors such as Toll-like receptors (TLRs) and their signaling pathway; (ii) the inflammasome activation pathway, their executioner Gasdermin D and pro-inflammatory cytokines IL-1β and IL-18; the cGAS-STING pathway and their effector cytokines, type I interferons as well as (iv) pro-inflammatory cytokines such as IL-6, TNF, IL1β and type I and II interferons. Such agents include antagonists of TLRs, NLRP3, and STING; inhibitors of the signaling molecules and enzymes such as tyrosine kinase (Tyk), PI3 kinase (PI3K), Phosphokinase C (PKCθ), phospholipase C (PLCγ), calcineurin, IP3, DAG, NFAT, and NEMO. Cytokine antagonists include anti-IL6, anti-TNF, IL-1R inhibitors, and inhibitors of type I interferons. Other agents target acute inflammation, such as corticosteroids, disease-modifying antirheumatic drugs (DMARDs), anti-TNF, Phosphodiesterase 4 (PDE4) inhibitors, Leukotriene BLT1-receptor antagonists, anti-TNF- therapies, TNFα-converting enzyme inhibitors, statins, PPARγ inhibitors, COX selective and non-selective inhibitors, TGFβ-1 receptor kinase antagonists, anti-IL-8 neutralizing antibody, CXCR2 inhibitors, CXCR3 antagonists, anti-Reactive Oxygen Species (ROS), anti-ICAM/VCAM and anti-CXCL5/8 and inhibitors. Other molecules target macrophage phagocytic receptors, autophagy, executioner machinery, and phagosome maturation. These include metformin, Imatinib as enhancers of phagosome maturation and autophagy induction, mammalian target of rapamycin (mTOR) inhibitors, Vitamin D, and inhibitors of lytic proteins and enzymes in phagolysosomes. cDCs, T and B cell activation also contribute molecules that orchestrate tissue damage. Such molecules can be targeted for therapeutic purposes. These include inducers of DC maturation like FLT3L, immune checkpoint inhibitors, inducers of Treg cells, inducers of iNOS, inhibitors of granzymes, anti-TGFβ, and finally, inhibitors of chromatin remodeling such as HDAC inhibitors. Created with Biorender.com.