Targeting Molecular Inflammatory Pathways in Granuloma as Host-Directed Therapies for Tuberculosis

Abstract

Globally, more than 10 million people developed active tuberculosis (TB), with 1.4 million deaths in 2020. In addition, the emergence of drug-resistant strains in many regions of the world threatens national TB control programs. This requires an understanding of host-pathogen interactions and finding novel treatments including host-directed therapies (HDTs) is of utter importance to tackle the TB epidemic. Mycobacterium tuberculosis (Mtb), the causative agent for TB, mainly infects the lungs causing inflammatory processes leading to immune activation and the development and formation of granulomas. During TB disease progression, the mononuclear inflammatory cell infiltrates which form the central structure of granulomas undergo cellular changes to form epithelioid cells, multinucleated giant cells and foamy macrophages. Granulomas further contain neutrophils, NK cells, dendritic cells and an outer layer composed of T and B lymphocytes and fibroblasts. This complex granulomatous host response can be modulated by Mtb to induce pathological changes damaging host lung tissues ultimately benefiting the persistence and survival of Mtb within host macrophages. The development of cavities is likely to enhance inter-host transmission and caseum could facilitate the dissemination of Mtb to other organs inducing disease progression. This review explores host targets and molecular pathways in the inflammatory granuloma host immune response that may be beneficial as target candidates for HDTs against TB.

Keywords: granuloma; host-directed drug therapy; inflammation; lung pathology; tuberculosis.

Figure 1

Host-directed drugs targeting molecular pathways within lung granulomas. 1) TNF blockers such as soluble TNF receptor 2 fusion protein, etanercept and phosphodiesterase inhibitors (Sildenafil, Cilostazol, CC-3052, and CC-11050) reduce lung inflammation and pulmonary pathology. 2) The antidiabetic drug metformin inhibits mitochondrial respiratory-chain complex 1 and increases AMPK levels. Metformin reduces lung pathology and in Mtb-infected macrophages induces mitochondrial ROS and increases phagolysosome fusion. 3) Histone deacetylase Sirtuin 1 activators (Resveratrol, SRT1720) and Sirtuin 2 inhibitor (AGK2) dampen lung pathology, increase phagolysosome fusion and autophagy. 4) Broad-spectrum metalloproteinase (MMP) inhibitor, Marimastat, enhances anti-tubercular drug delivery and reduces blood vessel leakage. Doxycycline reduces lung lesion sizes. 5) Statins, cholesterol-lowering drugs, reduce lung pathology. In macrophages, statins induce autophagy and increase phagosome maturation. 6) The antioxidant N-acetylcysteine (NAC) decreases pro-inflammatory cytokines, reduces tuberculous granuloma lesions, necrosis, pulmonary infiltrates, and cavity size. 7) Carbamazepine, a sodium channel blocker, decreases lung lesions and induces autophagy in macrophages. 8) Vitamin D and Vitamin A metabolite (all-trans retinoic acid, ATRA), PGE2 and Zileuton, Anakinra and Linezolid induce smaller lung lesions. 9) VEGF blocker (Bevacizumab) reduces angiogenesis and induces functionally better vascularized granulomas. 10) Nonsteroidal anti-inflammatory drugs (Ibuprofen and Aspirin) block cyclooxygenases and reduce lung lesion sizes. 11) The amino acid _L-isoleucine decreases pulmonary pathology through the induction of β-defensins. 12) Lactate dehydrogenase A inhibitor (FX11) restricts necrotic lung lesions. 13) The IDO inhibitor, 1-methyl-tryptophan, results in the reorganization of granuloma architecture increasing lymphocyte recruitment into the lesion core. 1-13) All listed HDT candidates reduce mycobacterial burden except for bevacizumab. TNF, Tumor Necrosis Factor; AMPK, AMP-activated protein kinase; Sirtuin, Silent mating type information regulation 2 homolog; ROS, Reactive Oxygen Species; MMP, metalloproteinases; VEGF, Vascular endothelial growth factor; COX, cyclooxygenases; LDHA, Lactate dehydrogenase A; FX11, 7-Benzyl-2;3-dihydroxy-6-methyl-4-propyl-naphthalene-1-carboxylic; IDO, indoleamine 2;3-dioxygenase; ATRA, All-trans retinoic acid; PGE2, Prostaglandin E2. Image of the granuloma structure adapted from reference (3), Nature Publishing Group. Image of the blood vessel structure adapted from reference (8), Wiley Publishing Group (8).