title: A novel therapeutic strategy of lipidated promiscuous peptide against Mycobacterium tuberculosis by eliciting Th1 and Th17 immunity of host.
abstract: Regardless of the fact that potent drug-regimen is currently available, tuberculosis continues to kill 1.5 million people annually. Tuberculosis patients are not only inflicted by the trauma of disease but they also suffer from the harmful side-effects, immune suppression and drug resistance instigated by prolonged therapy. It is an exigency to introduce radical changes in the existing drug-regime and discover safer and better therapeutic measures. Hence, we designed a novel therapeutic strategy by reinforcing the efficacy of drugs to kill Mtb by concurrently boosting host immunity by L91. L91 is chimera of promiscuous epitope of Acr1 antigen of Mtb and TLR-2 agonist Pam2Cys. The adjunct therapy using drugs and L91 (D-L91) significantly declined the bacterial load in Mtb infected animals. The mechanism involved was through enhancement of IFN-γ(+)TNF-α(+) polyfunctional Th1 cells and IL-17A(+)IFN-γ(+) Th17 cells, enduring memory CD4 T cells and downregulation of PD-1. The down-regulation of PD-1 prevents CD4 T cells from undergoing exhaustion and improves their function against Mtb. Importantly, the immune response observed in animals could be replicated using T cells of tuberculosis patients on drug therapy. In future, D-L91 therapy can invigorate drugs potency to treat tuberculosis patients and reduce the dose and duration of drug-regime.
authors.affiliation: CSIR-Institute of Microbial Technology, Chandigarh, India.
authors.forename: Pradeep K
authors.initials: PK
authors.lastname: Rai
authors.affiliation: CSIR-Institute of Microbial Technology, Chandigarh, India.
authors.forename: Sathi Babu
authors.initials: SB
authors.lastname: Chodisetti
authors.affiliation: CSIR-Institute of Microbial Technology, Chandigarh, India.
authors.forename: Sajid
authors.initials: S
authors.lastname: Nadeem
authors.affiliation: CSIR-Institute of Microbial Technology, Chandigarh, India.
authors.forename: Sudeep K
authors.initials: SK
authors.lastname: Maurya
authors.affiliation: CSIR-Institute of Microbial Technology, Chandigarh, India.
authors.forename: Uthaman
authors.initials: U
authors.lastname: Gowthaman
authors.affiliation: Department of Microbiology and Immunology, Peter Doherty Institute for Infection and Immunity, The University of Melbourne, Parkville 3010, Victoria, Australia.
authors.forename: Weiguang
authors.initials: W
authors.lastname: Zeng
authors.affiliation: Department of Pulmonary Medicine, Government Medical College and Hospital, Chandigarh, India.
authors.forename: Ashok K
authors.initials: AK
authors.lastname: Janmeja
authors.affiliation: Department of Microbiology and Immunology, Peter Doherty Institute for Infection and Immunity, The University of Melbourne, Parkville 3010, Victoria, Australia.
authors.forename: David C
authors.initials: DC
authors.lastname: Jackson
authors.affiliation: CSIR-Institute of Microbial Technology, Chandigarh, India.
authors.forename: Javed N
authors.initials: JN
authors.lastname: Agrewala
mesh_terms: D000818:Animals; D058491:Bacterial Load / Q000187:drug effects; D001426:Bacterial Proteins / Q000737:chemistry / Q000276:immunology; D004195:Disease Models, Animal; D004357:Drug Synergism; D000939:Epitopes / Q000276:immunology; D006801:Humans; D007371:Interferon-gamma / Q000378:metabolism; D020381:Interleukin-17 / Q000378:metabolism; D055666:Lipopeptides / Q000737:chemistry; D051379:Mice; D009169:Mycobacterium tuberculosis / Q000187:drug effects* / Q000276:immunology; D010455:Peptides / Q000737:chemistry / Q000276:immunology* / Q000494:pharmacology; D018417:Th1 Cells / Q000276:immunology*; D058504:Th17 Cells / Q000276:immunology*; D014376:Tuberculosis / Q000188:drug therapy* / Q000276:immunology; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
chemical_list: D001426:Bacterial Proteins; D000939:Epitopes; D020381:Interleukin-17; D055666:Lipopeptides; D010455:Peptides; C552442:S-(2,3-bis(palmitoyloxy)propyl)cysteine; D014409:Tumor Necrosis Factor-alpha; D007371:Interferon-gamma