Skip to main content

Advertisement

SpringerLink
Log in

Host-directed therapy against tuberculosis: Concept and recent developments

  • Review
  • Published:
Journal of Biosciences Aims and scope Submit manuscript

Abstract

Tuberculosis (TB) continues to remain at the forefront of the infectious disease burden globally, albeit with some aberrations during the COVID-19 pandemic. Among many factors, the emergence of drug resistance or antimicrobial resistance (AMR) has necessitated a renewed focus on developing novel and repurposed drugs against TB. Host-directed therapy (HDT) has emerged as an attractive alternative and a complementary strategy to the conventional antibiotic-based therapy of tuberculosis since HDT enjoys the advantage of disarming the pathogen of its ability to develop drug resistance. Considering the imminent threat of AMR across the spectrum of bacterial pathogens, HDT promises to overcome the drug shortage against superbugs. While all these make HDT a very attractive strategy, identifying the right set of host targets to develop HDT remains a challenge, despite remarkable development in the field over the past decade. In this review, we examine the host mechanisms, that either inadvertently or through targeted perturbation by the pathogen, help TB pathogenesis, and we discuss the latest developments in the targeting of some of the key pathways to achieve newer TB therapeutics.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Figure 1

Similar content being viewed by others

References

  • Aguib Y, Heiseke A, Gilch S, et al. 2009 Autophagy induction by trehalose counteracts cellular prion infection. Autophagy 5 361–369

    Article  CAS  PubMed  Google Scholar 

  • Al-Saeedi M and Al-Hajoj S 2017 Diversity and evolution of drug resistance mechanisms in Mycobacterium tuberculosis. Infect. Drug Resist. 10 333–342

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Arcaroli J, Quackenbush K, Dasari A, et al. 2012 Biomarker-driven trial in metastatic pancreas cancer: feasibility in a multicenter study of saracatinib, an oral Src inhibitor, in previously treated pancreatic cancer. Cancer Med. 1 207–217

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Bao Y, Wang L and Sun J 2021 A small protein but with diverse roles: a review of EsxA in Mycobacterium-host interaction. Cells 10 1645

  • Billig S, Schneefeld M, Huber C, et al. 2017 Lactate oxidation facilitates growth of Mycobacterium tuberculosis in human macrophages. Sci. Rep. 7 6484

    Article  PubMed  PubMed Central  Google Scholar 

  • Bohme J, Martinez N, Li S, et al. 2020 Metformin enhances antimycobacterial responses by educating CD8+ T-cell immunometabolic circuits. Nat. Commun. 11 5225

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Brogden KA 2005 Antimicrobial peptides: pore formers or metabolic inhibitors in bacteria? Nat. Rev. Microbiol. 3 238–250

    Article  CAS  PubMed  Google Scholar 

  • Burton EA, Plattner R and Pendergast AM 2003 Abl tyrosine kinases are required for infection by Shigella flexneri. EMBO J. 22 5471–5479

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Bussi C and Gutierrez MG 2019 Mycobacterium tuberculosis infection of host cells in space and time. FEMS Microbiol. Rev. 43 341–361

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Buter J, Cheng TY, Ghanem M, et al. 2019 Mycobacterium tuberculosis releases an antacid that remodels phagosomes. Nat. Chem. Biol. 15 889–899

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Campagno KE and Mitchell CH 2021 The P2X(7) Receptor in microglial cells modulates the endolysosomal axis, autophagy, and phagocytosis. Front. Cell Neurosci. 15 645244

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Cannon LL, Oladimeji KE and Goon DT 2021 Socio-economic drivers of drug-resistant tuberculosis in Africa: a scoping review. BMC Public Health 21 488

    Article  PubMed  PubMed Central  Google Scholar 

  • Castillo EF, Dekonenko A, Arko-Mensah J, et al. 2012 Autophagy protects against active tuberculosis by suppressing bacterial burden and inflammation. Proc. Natl. Acad. Sci. USA 109 E3168-3176

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Castillo K, Nassif M, Valenzuela V, et al. 2013 Trehalose delays the progression of amyotrophic lateral sclerosis by enhancing autophagy in motoneurons. Autophagy 9 1308–1320

    Article  CAS  PubMed  Google Scholar 

  • Cerni S, Shafer D, To K, et al. 2019 Investigating the role of Everolimus in mTOR inhibition and autophagy promotion as a potential host-directed therapeutic target in Mycobacterium tuberculosis infection. J. Clin. Med. 8 232

  • Chai Q, Wang X, Qiang L, et al. 2019 A Mycobacterium tuberculosis surface protein recruits ubiquitin to trigger host xenophagy. Nat. Commun. 10 1973

    Article  PubMed  PubMed Central  Google Scholar 

  • Chandra P, Ghanwat S, Matta SK, et al. 2015 Mycobacterium tuberculosis inhibits RAB7 recruitment to selectively modulate autophagy flux in macrophages. Sci. Rep. 5 16320

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Chandra P and Kumar D 2016 Selective autophagy gets more selective: Uncoupling of autophagy flux and xenophagy flux in Mycobacterium tuberculosis-infected macrophages. Autophagy 12 608–609

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Chandra P, Rajmani RS, Verma G, et al. 2016 Targeting drug-sensitive and -resistant strains of Mycobacterium tuberculosis by inhibition of src family kinases lowers disease burden and pathology. mSphere 1 e00043-15

  • Chauhan K, Kalam H, Dutt R, et al. 2019 RNA Splicing: a new paradigm in host-pathogen interactions. J. Mol. Biol. 431 1565–1575

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Coussens AK, Naude CE, Goliath R, et al. 2015 High-dose vitamin D3 reduces deficiency caused by low UVB exposure and limits HIV-1 replication in urban Southern Africans. Proc. Natl. Acad. Sci. USA 112 8052–8057

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Cumming BM, Addicott KW, et al. 2018 Mycobacterium tuberculosis induces decelerated bioenergetic metabolism in human macrophages. eLife 7 e39169

  • DeBosch BJ, Heitmeier MR, Mayer AL, et al. 2016 Trehalose inhibits solute carrier 2A (SLC2A) proteins to induce autophagy and prevent hepatic steatosis. Sci. Signal. 9 ra21

  • Deretic V 2008 Autophagy, an immunologic magic bullet: Mycobacterium tuberculosis phagosome maturation block and how to bypass it. Future Microbiol. 3 517–524

    Article  CAS  PubMed  Google Scholar 

  • Deretic V and Fratti RA 1999 Mycobacterium tuberculosis phagosome. Mol. Microbiol. 31 1603–1609

    Article  CAS  PubMed  Google Scholar 

  • Deretic V, Saitoh T and Akira S 2013 Autophagy in infection, inflammation and immunity. Nat. Rev. Immunol. 13 722–737

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Deretic V, Via LE, Fratti RA, et al. 1997 Mycobacterial phagosome maturation, rab proteins, and intracellular trafficking. Electrophoresis 18 2542–2547

    Article  CAS  PubMed  Google Scholar 

  • Duan L, Yi M, Chen J, et al. 2016 Mycobacterium tuberculosis EIS gene inhibits macrophage autophagy through up-regulation of IL-10 by increasing the acetylation of histone H3. Biochem. Biophys. Res. Commun. 473 1229–1234

    Article  CAS  PubMed  Google Scholar 

  • Duong M, Islam S, Rangarajan S, et al. 2019 Mortality and cardiovascular and respiratory morbidity in individuals with impaired FEV(1) (PURE): an international, community-based cohort study. Lancet Glob. Health 7 e613–e623

    Article  PubMed  Google Scholar 

  • Ernst JD 1998 Macrophage receptors for Mycobacterium tuberculosis. Infect Immun 66 1277–1281

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Feltcher ME, Sullivan JT and Braunstein M 2010 Protein export systems of Mycobacterium tuberculosis: novel targets for drug development? Future Microbiol. 5 1581–1597

    Article  CAS  PubMed  Google Scholar 

  • Feng Y, He D, Yao Z, et al. 2014 The machinery of macroautophagy. Cell Res. 24 24–41

    Article  CAS  PubMed  Google Scholar 

  • Fielding AK, Rowe JM, Buck G, et al. 2014 UKALLXII/ECOG2993: addition of imatinib to a standard treatment regimen enhances long-term outcomes in Philadelphia positive acute lymphoblastic leukemia. Blood 123 843–850

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Fratti RA, Backer JM, Gruenberg J, et al. 2001 Role of phosphatidylinositol 3-kinase and Rab5 effectors in phagosomal biogenesis and mycobacterial phagosome maturation arrest. J. Cell Biol. 154 631–644

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Fratti RA, Chua J, Vergne I, et al. 2003 Mycobacterium tuberculosis glycosylated phosphatidylinositol causes phagosome maturation arrest. Proc. Natl. Acad. Sci. USA 100 5437–5442

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Gandhi NR, Nunn P, Dheda K, et al. 2010 Multidrug-resistant and extensively drug-resistant tuberculosis: a threat to global control of tuberculosis. Lancet 375 1830–1843

    Article  PubMed  Google Scholar 

  • Gao LY, Guo S, McLaughlin B, et al. 2004 A mycobacterial virulence gene cluster extending RD1 is required for cytolysis, bacterial spreading and ESAT-6 secretion. Mol. Microbiol. 53 1677–1693

    Article  CAS  PubMed  Google Scholar 

  • Gedde MM, Higgins DE, Tilney LG, et al. 2000 Role of listeriolysin O in cell-to-cell spread of Listeria monocytogenes. Infect. Immun. 68 999–1003

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Giver CRP, Shaw PA, Fletcher H, et al. 2019 IMPACT-TB: A phase II trial assessing the capacity of low dose imatinib to induce myelopoiesis and enhance host antimicrobial immunity against tuberculosis. Blood 134 1050

  • Guinn KM, Hickey MJ, Mathur SK, et al. 2004 Individual RD1-region genes are required for export of ESAT-6/CFP-10 and for virulence of Mycobacterium tuberculosis. Mol. Microbiol. 51 359–370

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Gutierrez MG, Master SS, Singh SB, et al. 2004 Autophagy is a defense mechanism inhibiting BCG and Mycobacterium tuberculosis survival in infected macrophages. Cell 119 753–766

    Article  CAS  PubMed  Google Scholar 

  • Hawn TR, Matheson AI, Maley SN, Vandal O. Host-directed therapeutics for tuberculosis: can we harness the host? Microbiol. Mol. Biol. Rev. 77 608–627

  • Huang L, Nazarova EV, Tan S, et al. 2018 Growth of Mycobacterium tuberculosis in vivo segregates with host macrophage metabolism and ontogeny. J. Exp. Med. 215 1135–1152

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Iqbal N and Iqbal N 2014 Imatinib: a breakthrough of targeted therapy in cancer. Chemother. Res. Pract. 2014 357027

    PubMed  PubMed Central  Google Scholar 

  • Jain N, Kalam H, Singh L, et al. 2020 Mesenchymal stem cells offer a drug-tolerant and immune-privileged niche to Mycobacterium tuberculosis. Nat. Commun. 11 3062

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Jayachandran R, Sundaramurthy V, Combaluzier B, et al. 2007 Survival of mycobacteria in macrophages is mediated by coronin 1-dependent activation of calcineurin. Cell 130 37–50

    Article  CAS  PubMed  Google Scholar 

  • Kalam H, Fontana MF and Kumar D 2017 Alternate splicing of transcripts shape macrophage response to Mycobacterium tuberculosis infection. PLoS Pathog. 13 e1006236

    Article  PubMed  PubMed Central  Google Scholar 

  • Kalam H, Singh K, Chauhan K, et al. 2018 Alternate splicing of transcripts upon Mycobacterium tuberculosis infection impacts the expression of functional protein domains. IUBMB Life 70 845–854

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Kamada Y, Funakoshi T, Shintani T, et al. 2000 Tor-mediated induction of autophagy via an Apg1 protein kinase complex. J. Cell Biol. 150 1507–1513

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Karim AF, Chandra P, Chopra A, et al. 2011 Express path analysis identifies a tyrosine kinase Src-centric network regulating divergent host responses to Mycobacterium tuberculosis infection. J. Biol. Chem. 286 40307–40319

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Karakousis PC, Chaisson RE and Martinson N 2022 StAT-TB (statin adjunctive therapy for TB): A phase 2b dose-finding study of Pravastatin in adults with tuberculosis (https://clinicaltrials.gov/study/NCT03882177)

  • Kaufmann SH, Lange C, Rao M, et al. 2014 Progress in tuberculosis vaccine development and host-directed therapies–a state of the art review. Lancet Respir. Med. 2 301–320

    Article  CAS  PubMed  Google Scholar 

  • Khadela A, Chavda VP, Postwala H, et al. 2022 Epigenetics in tuberculosis: immunomodulation of host immune response. Vaccines 10 1740

  • Khosla S, Sharma G and Yaseen I 2016 Learning epigenetic regulation from mycobacteria. Microb. Cell. 3 92–94

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Kim JS, Kim YR and Yang CS 2020 Host-directed therapy in tuberculosis: targeting host metabolism. Front. Immunol. 11 1790

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Klionsky DJ, Abdel-Aziz AK, Abdelfatah S, et al. 2021 Guidelines for the use and interpretation of assays for monitoring autophagy. Autophagy 17 1–382

    Article  PubMed  PubMed Central  Google Scholar 

  • Klug-Micu GM, Stenger S, Sommer A, et al. 2013 CD40 ligand and interferon-gamma induce an antimicrobial response against Mycobacterium tuberculosis in human monocytes. Immunology 139 121–128

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Koster S, Upadhyay S, Chandra P, et al. 2017 Mycobacterium tuberculosis is protected from NADPH oxidase and LC3-associated phagocytosis by the LCP protein CpsA. Proc. Natl. Acad. Sci. USA 114 E8711–E8720

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Koul A, Herget T, Klebl B, et al. 2004 Interplay between mycobacteria and host signalling pathways. Nat. Rev. Microbiol. 2 189–202

    Article  CAS  PubMed  Google Scholar 

  • Kroesen VM, Rodriguez-Martinez P, Garcia E, et al. 2018 A beneficial effect of low-dose aspirin in a murine model of active tuberculosis. Front. Immunol. 9 798

    Article  PubMed  PubMed Central  Google Scholar 

  • Kumar D, Nath L, Kamal MA, et al. 2010 Genome-wide analysis of the host intracellular network that regulates survival of Mycobacterium tuberculosis. Cell 140 731–743

    Article  CAS  PubMed  Google Scholar 

  • Laaberki MH, Pfeffer J, Clarke AJ, et al. 2011 O-Acetylation of peptidoglycan is required for proper cell separation and S-layer anchoring in Bacillus anthracis. J. Biol. Chem. 286 5278–5288

    Article  CAS  PubMed  Google Scholar 

  • Lachmandas E, Beigier-Bompadre M, Cheng SC, et al. 2016 Rewiring cellular metabolism via the AKT/mTOR pathway contributes to host defence against Mycobacterium tuberculosis in human and murine cells. Eur. J. Immunol. 46 2574–2586

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Lee HJ, Woo Y, Hahn TW, et al. 2020 Formation and maturation of the phagosome: a key mechanism in innate immunity against intracellular bacterial infection. Microorganisms 8 1298

  • Liu CH, Liu H and Ge B 2017 Innate immunity in tuberculosis: host defense vs pathogen evasion. Cell Mol. Immunol. 14 963–975

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Liu PT, Stenger S, Li H, et al. 2006 Toll-like receptor triggering of a vitamin D-mediated human antimicrobial response. Science 311 1770–1773

    Article  CAS  PubMed  Google Scholar 

  • Loewenberg S 2012 India reports cases of totally drug-resistant tuberculosis. Lancet 379 205

    Article  PubMed  Google Scholar 

  • Looney M, Lorenc R, Halushka MK, et al. 2021 Key macrophage responses to infection with Mycobacterium tuberculosis are co-regulated by microRNAs and DNA methylation. Front. Immunol. 12 685237

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • MacGurn JA and Cox JS 2007 A genetic screen for Mycobacterium tuberculosis mutants defective for phagosome maturation arrest identifies components of the ESX-1 secretion system. Infect. Immun. 75 2668–2678

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Malik ZA, Denning GM and Kusner DJ 2000 Inhibition of Ca2+ signaling by Mycobacterium tuberculosis is associated with reduced phagosome-lysosome fusion and increased survival within human macrophages. J. Exp. Med. 191 287–302

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Martineau AR, Newton SM, Wilkinson KA, et al. 2007 Neutrophil-mediated innate immune resistance to mycobacteria. J. Clin. Invest. 117 1988–1994

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Matta SK and Kumar D 2015 AKT mediated glycolytic shift regulates autophagy in classically activated macrophages. Int. J. Biochem. Cell Biol. 66 121–133

    Article  CAS  PubMed  Google Scholar 

  • Miotto P, Cirillo DM and Migliori GB 2015 Drug resistance in Mycobacterium tuberculosis: molecular mechanisms challenging fluoroquinolones and pyrazinamide effectiveness. Chest 147 1135–1143

    Article  PubMed  Google Scholar 

  • Mishra R, Kohli S, Malhotra N, et al. 2019 Targeting redox heterogeneity to counteract drug tolerance in replicating Mycobacterium tuberculosis. Sci. Transl. Med. 11 eaaw6635

  • Mizunoe Y, Kobayashi M, Sudo Y, et al. 2018 Trehalose protects against oxidative stress by regulating the Keap1-Nrf2 and autophagy pathways. Redox Biol. 15 115–124

    Article  CAS  PubMed  Google Scholar 

  • Moreira JD, Koch BEV, van Veen S, et al. 2020 Functional inhibition of host histone deacetylases (HDACs) enhances in vitro and in vivo antimycobacterial activity in human macrophages and in zebrafish. Front. Immunol. 11 36

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Morishita H and Mizushima N 2019 Diverse cellular roles of autophagy. Annu. Rev. Cell Dev. Biol. 35 453–475

    Article  CAS  PubMed  Google Scholar 

  • Naftalin CM, Verma R, Gurumurthy M, et al. 2018 Adjunctive use of celecoxib with anti-tuberculosis drugs: evaluation in a whole-blood bactericidal activity model. Sci. Rep. 8 13491

    Article  PubMed  PubMed Central  Google Scholar 

  • Napier RJ, Rafi W, Cheruvu M, et al. 2011 Imatinib-sensitive tyrosine kinases regulate mycobacterial pathogenesis and represent therapeutic targets against tuberculosis. Cell Host Microbe 10 475–485

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Nau GJ, Richmond JF, Schlesinger A, et al. 2002 Human macrophage activation programs induced by bacterial pathogens. Proc. Natl. Acad. Sci. USA 99 1503–1508

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Nguyen L and Pieters J 2009 Mycobacterial subversion of chemotherapeutic reagents and host defense tactics: challenges in tuberculosis drug development. Annu. Rev. Pharmacol. Toxicol. 49 427–453

    Article  CAS  PubMed  Google Scholar 

  • Nieto RL, Mehaffy C and Dobos KM 2016 Comparing isogenic strains of Beijing genotype Mycobacterium tuberculosis after acquisition of Isoniazid resistance: A proteomics approach. Proteomics 16 1376–1380

    Article  Google Scholar 

  • Nieto-Patlan E, Serafin-Lopez J, Wong-Baeza I, et al. 2019 Valproic acid promotes a decrease in mycobacterial survival by enhancing nitric oxide production in macrophages stimulated with IFN-gamma. Tuberculosis 114 123–126

    Article  CAS  PubMed  Google Scholar 

  • Padmapriydarsini C, Mamulwar M, Mohan A, et al. 2022 Randomized trial of metformin with anti-tuberculosis drugs for early sputum conversion in adults with pulmonary tuberculosis. Clin. Infect. Dis. 75 425–434

    Article  PubMed  Google Scholar 

  • Paik S, Kim JK, Chung C, et al. 2019 Autophagy: A new strategy for host-directed therapy of tuberculosis. Virulence 10 448–459

    Article  CAS  PubMed  Google Scholar 

  • Parida SK, Axelsson-Robertson R, Rao MV, et al. 2015 Totally drug-resistant tuberculosis and adjunct therapies. J. Intern. Med. 277 388–405

    Article  CAS  PubMed  Google Scholar 

  • Parihar SP, Guler R, Khutlang R, et al. 2014 Statin therapy reduces the mycobacterium tuberculosis burden in human macrophages and in mice by enhancing autophagy and phagosome maturation. J. Infect. Dis. 209 754–763

    Article  CAS  PubMed  Google Scholar 

  • Park JH, Shim D, Kim KES, et al. 2021 Understanding metabolic regulation between host and pathogens: new opportunities for the development of improved therapeutic strategies against Mycobacterium tuberculosis infection. Front. Cell Infect. Microbiol. 11 635335

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Patel U, Rajasingh S, Samanta S, et al. 2017 Macrophage polarization in response to epigenetic modifiers during infection and inflammation. Drug Discov. Today 22 186–193

    Article  CAS  PubMed  Google Scholar 

  • Queval CJ, Brosch R and Simeone R 2017 The macrophage: a disputed fortress in the battle against Mycobacterium tuberculosis. Front. Microbiol. 8 2284

    Article  PubMed  PubMed Central  Google Scholar 

  • Rayasam GV and Balganesh TS 2015 Exploring the potential of adjunct therapy in tuberculosis. Trends Pharmacol. Sci. 36 506–513

    Article  CAS  PubMed  Google Scholar 

  • Rekha RS, Rao Muvva SS, Wan M, et al. 2015 Phenylbutyrate induces LL-37-dependent autophagy and intracellular killing of Mycobacterium tuberculosis in human macrophages. Autophagy 11 1688–1699

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Richards AB, Krakowka S, Dexter LB, et al. 2002 Trehalose: a review of properties, history of use and human tolerance, and results of multiple safety studies. Food Chem. Toxicol. 40 871–898

    Article  CAS  PubMed  Google Scholar 

  • Roy S, Schmeier S, Kaczkowski B, et al. 2018 Transcriptional landscape of Mycobacterium tuberculosis infection in macrophages. Sci. Rep. 8 6758

    Article  PubMed  PubMed Central  Google Scholar 

  • Sarkar S, Davies JE, Huang Z, et al. 2007 Trehalose, a novel mTOR-independent autophagy enhancer, accelerates the clearance of mutant huntingtin and alpha-synuclein. J. Biol. Chem. 282 5641–5652

    Article  CAS  PubMed  Google Scholar 

  • Schwegmann A and Brombacher F 2008 Host-directed drug targeting of factors hijacked by pathogens. Sci. Signal. 1 re8

  • Seung KJ, Keshavjee S and Rich ML 2015 Multidrug-resistant tuberculosis and extensively drug-resistant tuberculosis. Cold Spring Harb. Perspect. Med. 5 a017863

    Article  PubMed  PubMed Central  Google Scholar 

  • Sharma V, Makhdoomi M, Singh L, et al. 2021 Trehalose limits opportunistic mycobacterial survival during HIV co-infection by reversing HIV-mediated autophagy block. Autophagy 17 476–495

    Article  CAS  PubMed  Google Scholar 

  • Shimada T, Park BG, Wolf AJ, et al. 2010 Staphylococcus aureus evades lysozyme-based peptidoglycan digestion that links phagocytosis, inflammasome activation, and IL-1beta secretion. Cell Host Microbe 7 38–49

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Silver RF, Walrath J, Lee H, et al. 2009 Human alveolar macrophage gene responses to Mycobacterium tuberculosis strains H37Ra and H37Rv. Am. J. Respir Cell Mol. Biol. 40 491–504

    Article  CAS  PubMed  Google Scholar 

  • Simeone R, Sayes F, Lawaree E, et al. 2021 Breaching the phagosome, the case of the tuberculosis agent. Cell. Microbiol. 23 e13344

    Article  CAS  PubMed  Google Scholar 

  • Singhal A, Jie L, Kumar P, et al. 2014 Metformin as adjunct antituberculosis therapy. Sci. Transl. Med. 6 263ra159

  • Smith J, Manoranjan J, Pan M, et al. 2008 Evidence for pore formation in host cell membranes by ESX-1-secreted ESAT-6 and its role in Mycobacterium marinum escape from the vacuole. Infect. Immun. 76 5478–5487

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Sogi KM, Lien KA, Johnson JR, et al. 2017 The tyrosine kinase inhibitor Gefitinib restricts Mycobacterium tuberculosis growth through increased lysosomal biogenesis and modulation of cytokine signaling. ACS Infect. Dis. 3 564–574

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Sorgi CA, Soares EM, Rosada RS, et al. 2020 Eicosanoid pathway on host resistance and inflammation during Mycobacterium tuberculosis infection is comprised by LTB(4) reduction but not PGE(2) increment. Biochim. Biophys. Acta Mol. Basis Dis. 1866 165574

    Article  CAS  PubMed  Google Scholar 

  • Su VY, Pan SW, Yen YF, et al. 2021 Statin use and impact on tuberculosis risk. Expert Rev. Anti. Infect. Ther. 19 1093–1098

    Article  CAS  PubMed  Google Scholar 

  • Subbian S, Koo MS, Tsenova L, et al. 2016a Pharmacologic Inhibition of host phosphodiesterase-4 improves isoniazid-mediated clearance of Mycobacterium tuberculosis. Front. Immunol. 7 238

    Article  PubMed  PubMed Central  Google Scholar 

  • Subbian S, Tsenova L, Holloway J, et al. 2016b Adjunctive phosphodiesterase-4 inhibitor therapy improves antibiotic response to pulmonary tuberculosis in a rabbit model. EBioMedicine 4 104–114

    Article  PubMed  PubMed Central  Google Scholar 

  • Suchindran S, Brouwer ES and Van Rie A 2009 Is HIV infection a risk factor for multi-drug resistant tuberculosis? A systematic review. PLos One 4 e5561

    Article  PubMed  PubMed Central  Google Scholar 

  • Sui J, Qiao W, Xiang X, et al. 2022 Epigenetic changes in Mycobacterium tuberculosis and its host provide potential targets or biomarkers for drug discovery and clinical diagnosis. Pharmacol. Res. 179 106195

    Article  CAS  PubMed  Google Scholar 

  • Stop TB Partnership 2023 Global Plan to End TB 2023-2030 (https://www.stoptb.org/global-plan-to-end-tb/global-plan-to-end-tb-2023-2030)

  • Tahir F, Bin Arif T, Ahmed J, et al. 2020 Anti-tuberculous effects of statin therapy: a review of literature. Cureus 12 e7404

    PubMed  PubMed Central  Google Scholar 

  • Tal MC, Sasai M, Lee HK, et al. 2009 Absence of autophagy results in reactive oxygen species-dependent amplification of RLR signaling. Proc. Natl Acad. Sci. USA 106 2770–2775

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Tammer I, Brandt S, Hartig R, et al. 2007 Activation of Abl by Helicobacter pylori: a novel kinase for CagA and crucial mediator of host cell scattering. Gastroenterology 132 1309–1319

    Article  CAS  PubMed  Google Scholar 

  • Torres Ortiz A, Coronel J, Vidal JR, et al. 2021 Genomic signatures of pre-resistance in Mycobacterium tuberculosis. Nat. Commun. 12 7312

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Valdor R and Macian F 2012 Autophagy and the regulation of the immune response. Pharmacol. Res. 66 475–483

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • van der Wel N, Hava D, Houben D, et al. 2007 M. tuberculosis and M. leprae translocate from the phagolysosome to the cytosol in myeloid cells. Cell 129 1287–1298

    Article  PubMed  Google Scholar 

  • Vandal OH, Pierini LM, Schnappinger D, et al. 2008 A membrane protein preserves intrabacterial pH in intraphagosomal Mycobacterium tuberculosis. Nat. Med. 14 849–854

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Vergne I, Chua J and Deretic V 2003a Mycobacterium tuberculosis phagosome maturation arrest: selective targeting of PI3P-dependent membrane trafficking. Traffic 4 600–606

    Article  CAS  PubMed  Google Scholar 

  • Vergne I, Chua J and Deretic V 2003b Tuberculosis toxin blocking phagosome maturation inhibits a novel Ca2+/calmodulin-PI3K hVPS34 cascade. J. Exp. Med. 198 653–659

    Article  PubMed  PubMed Central  Google Scholar 

  • Vieira OV, Botelho RJ and Grinstein S 2002 Phagosome maturation: aging gracefully. Biochem. J. 366 689–704

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Viollet B, Guigas B, Sanz Garcia N, et al. 2012 Cellular and molecular mechanisms of metformin: an overview. Clin. Sci. 122 253–270

    Article  CAS  Google Scholar 

  • Wallis RS, Ginindza S, Beattie T, et al. 2021 Adjunctive host-directed therapies for pulmonary tuberculosis: a prospective, open-label, phase 2, randomised controlled trial. Lancet Respir. Med. 9 897–908

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Wang W, Du Z, Ni M, et al. 2020 Aspirin enhances the clinical efficacy of anti-tuberculosis therapy in pulmonary tuberculosis in patients with type 2 diabetes mellitus. Infect. Dis. 52 721–729

    Article  Google Scholar 

  • Watson RO, Manzanillo PS and Cox JS 2012 Extracellular M. tuberculosis DNA targets bacteria for autophagy by activating the host DNA-sensing pathway. Cell 150 803–815

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Willcox PA and Ferguson AD 1989 Chronic obstructive airways disease following treated pulmonary tuberculosis. Respir. Med. 83 195–198

    Article  CAS  PubMed  Google Scholar 

  • Wirth SE, Krywy JA, Aldridge BB, et al. 2012 Polar assembly and scaffolding proteins of the virulence-associated ESX-1 secretory apparatus in mycobacteria. Mol. Microbiol. 83 654–664

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Wong CO, Gregory S, Hu H, et al. 2017 Lysosomal degradation is required for sustained phagocytosis of bacteria by macrophages. Cell Host Microbe 21 719–730 e716

  • Wong D, Bach H, Sun J, et al. 2011 Mycobacterium tuberculosis protein tyrosine phosphatase (PtpA) excludes host vacuolar-H+-ATPase to inhibit phagosome acidification. Proc. Natl. Acad. Sci. USA 108 19371–19376

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • World Health Organization 2010 Treatment of tuberculosis: guidelines 4th edition (World Health Organization)

  • World Health Organisation 2022 Global Tuberculosis Report 2022 (https://www.who.int/teams/global-tuberculosis-programme/tb-reports/global-tuberculosis-report-2022)

  • Yaseen I, Choudhury M, Sritharan M, et al. 2018 Histone methyltransferase SUV39H1 participates in host defense by methylating mycobacterial histone-like protein HupB. EMBO J. 37 183–200

    Article  CAS  PubMed  Google Scholar 

  • Young C, Walzl G and Du Plessis N 2020 Therapeutic host-directed strategies to improve outcome in tuberculosis. Mucosal Immunol. 13 190–204

    Article  CAS  PubMed  Google Scholar 

  • Yuk JM, Shin DM, Lee HM, et al. 2009 Vitamin D3 induces autophagy in human monocytes/macrophages via cathelicidin. Cell Host Microbe 6 231–243

    Article  CAS  PubMed  Google Scholar 

  • Zheng L, Leung ET, Wong HK, et al. 2016 Unraveling methylation changes of host macrophages in Mycobacterium tuberculosis infection. Tuberculosis 98 139–148

    Article  CAS  PubMed  Google Scholar 

  • Zhou G, Myers R, Li Y, et al. 2001 Role of AMP-activated protein kinase in mechanism of metformin action. J. Clin. Invest. 108 1167–1174

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

The authors acknowledge Ms Shaina Jamwal for help with the figure.

Funding

This work was supported by an extramural grant from the Science and Engineering Research Board (SERB), Government of India (EMR/2016/000026), to DK. The DK lab is supported by the Department of Biotechnology-Wellcome Trust India Alliance Senior Fellowship (IA/S/17/1/503071) and the Flagship program from the Department of Biotechnology, Government of India (BT/IC-06/003/91-Flagship Program).

Author information

Authors and Affiliations

  1. Cellular Immunology Group, International Centre for Genetic Engineering and Biotechnology, Aruna Asaf Ali Marg, New Delhi, 110067, India

    Sonakshi Udinia & Dhiraj Kumar

  2. School of Biotechnology, Kalinga Institute of Industrial Technology (KIIT), Bhubaneswar, 751024, India

    Sonakshi Udinia & Mrutyunjay Suar

Authors
  1. Sonakshi Udinia
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Mrutyunjay Suar
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Dhiraj Kumar
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

Writing original draft, SU and DK; Writing review and editing, SU, MS, and DK.

Corresponding author

Correspondence to Dhiraj Kumar.

Ethics declarations

Conflict of interest

No conflict of interest.

Additional information

Corresponding editor: Umesh Varshney

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Udinia, S., Suar, M. & Kumar, D. Host-directed therapy against tuberculosis: Concept and recent developments. J Biosci 48, 54 (2023). https://doi.org/10.1007/s12038-023-00374-y

Download citation

  • Received:

  • Accepted:

  • Published:

  • DOI: https://doi.org/10.1007/s12038-023-00374-y

Keywords

Search

Navigation