A novel peptide interferes with <i>Mycobacterium tuberculosis</i> virulence and survival

Samuchiwal, Sachin K.; Tousif, Sultan; Singh, Dhiraj Kumar; Kumar, Arun; Ghosh, Anamika; Bhalla, Kuhulika; Prakash, Prem; Kumar, Sushil; Trivedi, Ashish Chandra; Bhattacharyya, Maitree; Das, Gobardhan; Ranganathan, Anand

doi:10.1016/j.fob.2014.08.001

Cited by 4 publications

(3 citation statements)

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“…Indeed, fewer studies have been reported using human MΦs compared to mouse MΦs. Human MΦs secrete NO at lower levels, show marked functional and phenotypic heterogeneity among tissues, and likely differ in their antimicrobial mechanisms [7][8][9] . This difference is reflected by the nearuniform susceptibility of most mouse strains to low-dose aerosol infection with Mtb versus the differential susceptibility of humans to active disease.…”

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Human M1 macrophages express unique innate immune response genes after mycobacterial infection to defend against tuberculosis

et al. 2022

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Mycobacterium tuberculosis (Mtb) is responsible for approximately 1.5 million deaths each year. Though 10% of patients develop tuberculosis (TB) after infection, 90% of these infections are latent. Further, mice are nearly uniformly susceptible to Mtb but their M1-polarized macrophages (M1-MΦs) can inhibit Mtb in vitro, suggesting that M1-MΦs may be able to regulate anti-TB immunity. We sought to determine whether human MΦ heterogeneity contributes to TB immunity. Here we show that IFN-γ-programmed M1-MΦs degrade Mtb through increased expression of innate immunity regulatory genes (Inregs). In contrast, IL-4-programmed M2-polarized MΦs (M2-MΦs) are permissive for Mtb proliferation and exhibit reduced Inregs expression. M1-MΦs and M2-MΦs express pro- and anti-inflammatory cytokine-chemokines, respectively, and M1-MΦs show nitric oxide and autophagy-dependent degradation of Mtb, leading to increased antigen presentation to T cells through an ATG-RAB7-cathepsin pathway. Despite Mtb infection, M1-MΦs show increased histone acetylation at the ATG5 promoter and pro-autophagy phenotypes, while increased histone deacetylases lead to decreased autophagy in M2-MΦs. Finally, Mtb-infected neonatal macaques express human Inregs in their lymph nodes and macrophages, suggesting that M1 and M2 phenotypes can mediate immunity to TB in both humans and macaques. We conclude that human MФ subsets show unique patterns of gene expression that enable differential control of TB after infection. These genes could serve as targets for diagnosis and immunotherapy of TB.

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Human M1 macrophages express unique innate immune response genes after mycobacterial infection to defend against tuberculosis

et al. 2022

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“…Most of the peptides like Human neutrophil defensins (HNPs), Protegrin-1 (PG-1) ( 28 ), Polydim ( 29 ), Pin 2 ( 30 ), Bacteriocins ( 31 ) etc. act on Mycobacterium by disrupting its cell envelope either by forming pore or increases permeabilization by causing membrane depolarization ( 32 ) or by disrupting cell wall biosynthetic pathway ( 33 , 34 ). Beside this several anti-TB peptide perform its inhibition activity by targeting specific enzyme like Mycosin protease-1 (MycP1) ( 35 ), ClpC1 ATPase ( 36 , 37 ), ClpP1P2 peptidase ( 38 ), etc.…”

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confidence: 99%

AntiTbPdb: a knowledgebase of anti-tubercular peptides

Usmani

Kumar

et al. 2018

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Tuberculosis is a global menace, caused by Mycobacterium tuberculosis, responsible for millions of premature deaths every year. In the era of drug-resistant tuberculosis, peptide-based therapeutics may provide alternate to small molecule based drugs. In order to create knowledgebase, AntiTbPdb (http://webs.iiitd.edu.in/raghava/antitbpdb/), experimentally validated anti-tubercular and anti-mycobacterial peptides were compiled from literature. We curate 10 652 research articles and 35 patents to extract anti-tubercular peptides and annotate these peptides manually. This knowledgebase has 1010 entries, each entry provides extensive information about an anti-tubercular peptide such as sequence, chemical modification, chirality, nature and source of origin. The tertiary structure of these anti-tubercular peptides containing natural as well as chemically modified residues was predicted using PEPstrMOD and I-TASSER. In addition to structural information, database maintains other properties of peptides like physiochemical properties. Numerous web-based tools have been integrated for data retrieval, browsing, sequence similarity search and peptide mapping. In order to assist wide range of user, we developed a responsive website suitable for smartphone, tablet and desktop. Database URL: http://webs.iiitd.edu.in/raghava/antitbpdb/

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“…ESAT-6 possesses membrane lytic activity due to its helix-turn-helix structure and hydrophobic nature, an attribute that helps M.tb escape phagolysosome, cell-to-cell spread and dissemination. ESAT-6 can alter host defense by decreasing MHC-II expression on macrophages, granuloma formation and decreasing ROS production to aid in intramacrophagial M.tb survival [6]. ESAT-6 or CFP-10/ESAT-6 complex is also known to attenuate host innate immune response by inhibiting production of IL-12, TNF-α, and apoptosis inhibition in M.tb infected macrophages to achieve greater vial load and cell-cell spread [7,8].…”

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ESAT-6: A Perfect Warfare or A Weak Link in Armor

S¹

2017

MOJI

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Submit Manuscript | http://medcraveonline.com responsible for the substandard efficacy of BCG [2]. Considerable efforts are being made to generate recombinant BCG (rBCG) but with little headway. Causative agent of TB Mycobacterium tuberculosis (M.tb) is remarkably skillful in eluding host defense and modulating immune response for its own benefits. An interesting approach for combating TB is to target M.tb virulence factors [3]. One such key protein is ESAT-6, encoded by region of difference 1 (RD1), the region absent from BCG and most attenuated mycobacterial strains [4,5].Role of ESAT-6 in M.tb virulence has been highlighted in this editorial. ESAT-6 possesses membrane lytic activity due to its helix-turn-helix structure and hydrophobic nature, an attribute that helps M.tb escape phagolysosome, cell-to-cell spread and dissemination. ESAT-6 can alter host defense by decreasing MHC-II expression on macrophages, granuloma formation and decreasing ROS production to aid in intramacrophagial M.tb survival [6]. ESAT-6 or CFP-10/ESAT-6 complex is also known to attenuate host innate immune response by inhibiting production of IL-12, TNF-α, and apoptosis inhibition in M.tb infected macrophages to achieve greater vial load and cell-cell spread [7,8]. ESAT-6 is also supposed to bind to T-cell surface and belittles T-cell immunity by inhibiting T-cell proliferation and activation [9]. As we know the production of the proinflammatory cytokine TNF-α is critical for controlling M.tb infection as it induces apoptosis via TNF-α receptor1 (TNFR1) signaling. Therefore ESAT-6 and CFP-10/ ESAT-6 complex inhibit apoptosis of infected cells by decreasing TNF-α production to attain bacterial buildup and dissemination. There is a large body of literature suggesting that M.tb virulence and modulation of host defense in an intricate communication of M.tb and host proteins, and targeting these interactions can offer a pivotal tool in fight against TB. ESAT-6 has been gaining more and more popularity over the time as one such candidate to be targeted for antitubercular therapeutics development.Widespread efforts are being made to improve current BCG vaccine or to develop new TB vaccines. An in trend approach is to develop efficacious vaccines by combining ESAT-6 with other M.tb virulence determining proteins. Several rBCG strains have been created that express ESAT-6 fusion proteins along with other M.tb proteins like Ag85B, Rv3620c, TNF-and Rv2608, complement RD1, or combine ESAT-6 with Antigen 85 family and superoxide dismutase (SOD), interestingly these new rBCG vaccines demonstrate a strong T-cell response and high expression of Th1 cytokines in experimental animals [10,11]. Even chimeric DNA vaccines are also underway and one such example is developed by combining ESAT-6 gene from M.tb and kinesin motor domain gene of Leishmania donovani, which resulted in robust IFN-γ and IL-2 production in mice. While another nanoparticle based chimeric DNA vaccine contains Ag85A, ESAT-6 and IL-21 construct [11]. On another front, an strong ESAT-6 b...

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A novel peptide interferes with Mycobacterium tuberculosis virulence and survival

Cited by 4 publications

References 31 publications

Human M1 macrophages express unique innate immune response genes after mycobacterial infection to defend against tuberculosis

Human M1 macrophages express unique innate immune response genes after mycobacterial infection to defend against tuberculosis

AntiTbPdb: a knowledgebase of anti-tubercular peptides

ESAT-6: A Perfect Warfare or A Weak Link in Armor

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