title: NOD-2 and TLR-4 Signaling Reinforces the Efficacy of Dendritic Cells and Reduces the Dose of TB Drugs against Mycobacterium tuberculosis.
abstract: Tuberculosis (TB) is one of the leading killer infectious diseases. TB patients are inflicted with devastating side effects and the toxicity of a lengthy drug regime, accentuating an urgent need to explore newer and safer treatment methods. Recently, an improved understanding of host-pathogen interaction has opened new avenues for TB treatment, including immunotherapy. This has emboldened us to devise a novel strategy to restrict Mycobacterium tuberculosis(Mtb) growth by activating dendritic cells (DCs) through the NOD-2 and TLR-4 molecules of innate immunity. Triggered DCs show a robust release of cytokines and nitric oxide, autophagy and improved migration towards the lymph nodes, and consequently impede the intracellular survival of Mtb. Of note, this approach enhanced the efficacy of TB drugs by reducing their dose to a 5-fold lesser concentration than recommended. In vivo administration of ligands of NOD-2 (NOD-2L) and TLR-4 (TLR-4L) substantially increased the pool of effector memory CD4 and CD8 T cells. Additionally, NOD-2L and TLR-4L, in conjunction with the reduced dose of isoniazid, substantially declined the Mtb burden in the lungs. In the future, adjunct therapy involving NOD-2L, TLR-4L and TB drugs may have enough potential to reduce the dose and duration of treatment of TB patients.
authors.affiliation: Institute of Microbial Technology, Council of Scientific and Industrial Research, Chandigarh, India.
authors.forename: Nargis
authors.initials: N
authors.lastname: Khan
authors.forename: Susanta
authors.initials: S
authors.lastname: Pahari
authors.forename: Aurobind
authors.initials: A
authors.lastname: Vidyarthi
authors.forename: Mohammad
authors.initials: M
authors.lastname: Aqdas
authors.forename: Javed N
authors.initials: JN
authors.lastname: Agrewala
mesh_terms: D000818:Animals; D000995:Antitubercular Agents / Q000627:therapeutic use; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D002454:Cell Differentiation; D048708:Cell Growth Processes; D002478:Cells, Cultured; D003713:Dendritic Cells / Q000276:immunology* / Q000382:microbiology; D007113:Immunity, Innate; D008168:Lung / Q000276:immunology* / Q000382:microbiology; D008213:Lymphocyte Activation; D051379:Mice; D008810:Mice, Inbred C57BL; D009169:Mycobacterium tuberculosis / Q000502:physiology*; D053473:Nod2 Signaling Adaptor Protein / Q000378:metabolism; D015398:Signal Transduction; D051197:Toll-Like Receptor 4 / Q000378:metabolism; D014376:Tuberculosis / Q000188:drug therapy / Q000276:immunology*
chemical_list: D000995:Antitubercular Agents; D053473:Nod2 Signaling Adaptor Protein; C495945:Nod2 protein, mouse; C493487:Tlr4 protein, mouse; D051197:Toll-Like Receptor 4