Table 2.
Developmental pipeline of host-directed therapies for adjunct treatment of drug-sensitive and drug-resistant tuberculosis, by host pathway
| Class or type | Mechanism of action | Host effect | Developmental stage for tuberculosis | |
|---|---|---|---|---|
| Mitochondrial respiration and fatty acid oxidation | ||||
| Metformin92, 93, 94 | Biguanide | Interrupts the mitochondrial respiratory chain and induces ROS production; increases mitochondrial biogenesis and respiration | Enhanced killing of intracellular Mycobacterium tuberculosis via ROS production; improved control of bacterial burden and reduced lung pathology in mice; enhanced T-cell responses; might improve maintenance of memory CD8 T cells via increased FAO; promotes generation of CD8 T-cell memory against tumour engraftment in experimental TRAF6-deficient mice by restoring FAO, possibly via AMPK activation; increases mitochondrial biogenesis and hence respiration in rabbit renal proximal tubular cells | Preclinical |
| Niraparib95 | PARP inhibitor | Inhibition of PARP-1 and PARP-2 activity, and impairs repair of DNA single strand breaks | Restores mitochondrial respiratory function in human myotubes, also by improved FAO; might promote maintenance of antituberculosis memory CD8 T cells | Preclinical |
| Interleukin 1596, 97 | Cytokine | Involved in maintenance and possibly proliferation of CD8 T cells | Increases mitochondrial mass and FAO in memory CD8 T cells to prolong survival in experimental mice | Preclinical |
| Arachidonic acid metabolism | ||||
| Aspirin98 | NSAID | Increased lipoxin A4 production to reduce TNFα levels and achieve eicosanoid balance during chronic inflammation | Dampening of TNFα-induced hyperinflammation to aid tissue repair and control burden of M tuberculosis | Preclinical |
| Zileuton99 | Leukotriene synthesis inhibitor | Blocks leukotriene production by disrupting lipooxygenase activity; promotes prostaglandin production via cyclooxygenase activation | Increases PGE2 levels and augments interleukin-1β-mediated immune control of tuberculosis in mice; promotes reduced lung M tuberculosis burden and pathology | Preclinical |
| Ibuprofen100, 101 | NSAID | Blocks production of prostaglandins possibly by inhibiting cyclooxygenase activity | Reduces lung pathology and mycobacterial burden in a highly susceptible mouse model of tuberculosis | Clinical (early phase) |
| Corticosteroid metabolism | ||||
| Prednisone102 | Glucocorticoid receptor antagonist | Forms a complex with glucocorticoid receptor and triggers transcription of several important host genes (ie, iNOS, cyclooxygenase-2, collagenase) | Use in patients with community-acquired pneumonia showed improved survival; results in patients with tuberculosis require further validation | Clinical (mid-late phase) |
| Histone acetylation | ||||
| Valproic acid and vorinostat41, 103 | Histone deacetylase inhibitor | Acetylation of lysine residues on histones to promote DNA unwinding and gene transcription | Valproic acid and vorinostat can activate latent HIV reservoirs and increase ART efficacy as well as CD8 T-cell activity; both drugs can improve efficacy of isoniazid and rifampicin against intracellular M tuberculosis | Preclinical |
| Phenylbutyrate104, 105 | Histone deacetylase inhibitor | Acetylation of lysine residues on histones to promote DNA unwinding and gene transcription | Augments vitamin D3 activity, cathelicidin production, and MAPK signalling to kill intracellular M tuberculosis | Clinical (early phase) |
| Host cell cytotoxicity | ||||
| Cyclophosphamide106, 107 | Alkylating agent | CYP450 metabolism of cyclophosphamide produces chemical species that can alkylate DNA guanine to reduce cell proliferation. Cells highly expressing ALDH are resistant to cyclophosphamide | Abrogation of regulatory T-cell responses, and potentiation of RCC vaccine candidate efficacy in clinical trials, with induction of CD8 T-cell responses; might increase efficacy of the BCG vaccine | Not yet tested in tuberculosis |
| Etoposide108, 109 | Topoisomerase inhibitor | Blockade of DNA topoisomerase II to prevent re-ligation of nascent DNA strands | Depletion of pathogenic inflammatory T cells in influenza-induced HLH | Preclinical |
| Modulation of ion efflux channels | ||||
| Verapamil110 | Calcium-channel blocker | Modulation of voltage-gated calcium-channel activity for maintenance of cellular ionic homeostasis | Improves efficacy of conventional and novel antituberculosis drugs in M tuberculosis-infected mice | Preclinical |
| Carbamazepine111 | Sodium-channel blocker | Anticonvulsant; acts via voltage-gated sodium-channel downmodulation and activation of GABA receptors for reduced sensitivity to neuropathic pain. Activates AMPK to induce autophagy | Shown to induce inositol depletion-dependent autophagic killing of intracellular M tuberculosis in macrophages; augments reduced lung pathology and improved immune responses in the mouse model of tuberculosis | Preclinical |
| Statins112, 113 | Inhibitors of 3-hydroxy-3-methylglutaryl coenzyme reductase | Block biosynthesis of endogenous cholesterol | Simvastatin can reduce M tuberculosis CFUs (human macrophages and mice) | Preclinical |
| Inhibition of tyrosine kinases | ||||
| Imatinib mesylate114 | Inhibitor of BCR-ABL tyrosine kinase | Induces apoptotic death of cancerous B cells, and cells expressing related kinases | Reduces CFU load and pathology in lungs of M tuberculosis-infected mice; induces myelopoiesis | Preclinical (about to enter early phase clinical trials) |
| Innate immune defences | ||||
| Vitamin D3115, 116 | Vitamin | Induces cathelicidin production, improves antigen processing and presentation, augments response to interferon-γ signalling | Kills intracellular M tuberculosis and improves T-cell responses | Clinical (late phase) |
| Immune activation | ||||
| GM-CSF, interleukin 2, and interferon γ117 | Cytokine | Contribute to proliferation and activation of macrophages, dendritic cells, monocytes, T cells | Variable results but with a generally positive outcome following treatment, coupled with reduction in sputum AFB | Clinical (mid-late phase) |
| Immune checkpoint inhibition | ||||
| Ipilimumab (anti-CTLA-4)118, 119 | Monoclonal antibody | Blockade of CTLA-4 to undo T-cell exhaustion; restores interleukin-2 secretion and signalling | CTLA-4 inhibition in melanoma increases CD8 T-cell activity and tumour regression; might improve CD8 T-cell activity against M tuberculosis-infected cells | Preclinical |
| Nivolumab or pembrolizumab (anti-PD-1)120, 121, 122 | Monoclonal antibody | Blockade of PD-1 to restore lymphocyte functionality. Also, PD-L1 blockade on the surface of APCs contributes to T-cell activation | PD-1 blockade potentiates in-vitro killing of M tuberculosis-infected macrophages by CD4 T cells in an interferon-γ-dependent manner and prevents apoptosis of T cells; downregulation of PD-1 on CD4 T cells is commensurate with antituberculosis treatment | Preclinical |
| Anti-Tim3123, 124 | Monoclonal antibody | Modulation of Tim3–Gal9 interaction to induce targeted T-cell responses | M tuberculosis-infected human CD14 monocytes shown to have reduced Tim3 expression with extent of tuberculosis disease in patients; Tim3–Gal9 interaction induces interleukin-1β-driven immune control of M tuberculosis infection in vitro | Preclinical |
| Anti-LAG3125, 126 | Monoclonal antibody | Blockade of LAG3 to abrogate regulatory T-cell interaction with activated effector CD4 and CD8 T cells | Blockade of LAG3 can potentiate targeted CD8 CTL responses in patients with solid tumours. In tuberculosis, low LAG3 expression may be reflective of successful containment of tuberculosis infection | Preclinical |
| Cytokine neutralisation | ||||
| Adalimumab (anti-TNFα)127 | Monoclonal antibody | Removal of excess TNFα from tissue and circulation | Successfully used salvage therapy in a patient with severe pulmonary tuberculosis | Clinical (compassionate use) |
| Siltuximab (anti-interleukin 6)128, 129 | Monoclonal antibody | Removal of excess interleukin 6 from tissue and circulation | Effective against arthritis and Castleman's disease; used prospectively in patients with HIV/tuberculosis co-infection may reduce mortality from tuberculosis-associated IRIS | Preclinical |
| Angiogenesis inhibition | ||||
| Bevacizumab (anti-VEGF)130, 131 | Monoclonal antibody | Blockade of VEGF-induced neovascularisation in tissue | Disrupts neovascularisation within lung granulomas in a rabbit model of tuberculosis; improves small-molecule penetration into granulomas and increases air supply, might therefore improve antituberculosis drug efficacy | Preclinical |
| Reduction of inflammation and improved tissue regeneration | ||||
| BM-MSCs132 | Cell-based therapy | BM-MSCs can reduce destructive inflammation, regenerate tissue, and restore positive modulation of immune responses, secretion of soluble factors, and activation of regulatory T cells | Autologous MSC reinfusion in a phase 1 trial in Belarus of patients with multidrug-resistant tuberculosis was safe and reconstituted anti-M tuberculosis T cell responses; a phase 1 study is underway in Durban, South Africa | Clinical (early phase) |
ROS=reactive oxygen species. FAO=fatty acid oxidation. TRAF6=tumour necrosis factor receptor-associated factor 6. AMPK=5' adenosine monophosphate-activated protein kinase. PARP=poly (ADP-ribose) polymerase. NSAID=non-steroidal anti-inflammatory drug. TNFα=tumour necrosis factor α. PGE2=prostaglandin E2. iNOS=inducible nitric oxide synthase. ART=antiretroviral therapy. MAPK=mitogen-activated protein kinase. CYP450=cytochrome P450. ALDH=aldehyde dehydrogenase. RCC=renal cell carcinoma. HLH=haemophagocytic lymphohistiocytosis. GABA=γ-aminobutyric acid. CFUs=colony forming units. GM-CSF=granulocyte-macrophage colony-stimulating factor. AFB=acid-fast bacilli. CTLA-4=cytotoxic-T-lymphocyte-associated antigen 4. PD-1=programmed cell death 1. PD-L1=programmed death-ligand 1. APCs=antigen-presenting cells. Tim3=T-cell immunoglobulin and mucin-domain containing-3. Gal9=galectin 9. LAG3=lymphocyte-activation gene 3. IRIS=immune reconstitution inflammatory syndrome. VEGF=vascular endothelial growth factor. BM-MSCs=bone marrow-derived mesenchymal stromal cells. BCR-ABL=breakpoint cluster-Abelson tyrosine kinase.