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peptides and tuberculosis

Joel D Ernst, Amber Cornelius, Ludovic Desvignes, Jacqueline Tavs, Brian A Norris
Infection with M. tuberculosis is associated with inconsistent and incomplete elimination of the bacteria, despite development of antigen-specific T cell responses. One mechanism employed by M. tuberculosis is to limit availability of antigen for activation of CD4 T cells. We examined the utility of systemic administration of epitope peptides to activate pre-existing T cells in mice infected with M. tuberculosis. We found that systemic peptide administration: 1) selectively activates T cells specific for the epitope peptide; 2) loads MHC class II on lung macrophages and dendritic cells; 3) activates CD4 T cells in the lung parenchyma; 4) has little antimycobacterial activity...
March 14, 2018: Journal of Infectious Diseases
Cheleka A M Mpande, One B Dintwe, Munyaradzi Musvosvi, Simbarashe Mabwe, Nicole Bilek, Mark Hatherill, Elisa Nemes, Thomas J Scriba
Background: Maintenance of long-lasting immunity is thought to depend on stem cell memory T cells (TSCM ), which have superior self-renewing capacity, longevity and proliferative potential compared with central memory (TCM ) or effector (TEFF ) T cells. Our knowledge of TSCM derives primarily from studies of virus-specific CD8+ TSCM . We aimed to determine if infection with Mycobacterium tuberculosis ( M. tb ), the etiological agent of tuberculosis, generates antigen-specific CD4+ TSCM and to characterize their functional ontology...
2018: Frontiers in Immunology
Wendy E Whatney, Neel R Gandhi, Cecilia S Lindestam Arlehamn, Azhar Nizam, Hao Wu, Melanie J Quezada, Angela Campbell, Salim Allana, Mbuyi Madeleine Kabongo, Jeremiah Khayumbi, Benson Muchiri, Joshua Ongalo, Joan Tonui, Loren E Sasser, Tawania J Fergus, Gregory Sadat Ouma, Samuel Gurrion Ouma, Allison A Beck, Mark J Mulligan, Alawode Oladele, Deepak Kaushal, Kevin P Cain, Lance Waller, Henry M Blumberg, John D Altman, Joel D Ernst, Jyothi Rengarajan, Cheryl L Day
Antigen-specific CD4 and CD8 T cells are important components of the immune response to Mycobacterium tuberculosis , yet little information is currently known regarding how the breadth, specificity, phenotype, and function of M. tuberculosis -specific T cells correlate with M. tuberculosis infection outcome in humans. To facilitate evaluation of human M. tuberculosis -specific T cell responses targeting multiple different Ags, we sought to develop a high throughput and reproducible T cell response spectrum assay requiring low blood sample volumes...
March 14, 2018: Journal of Immunology: Official Journal of the American Association of Immunologists
Divya Arora, Yogesh Chawla, Basanti Malakar, Archana Singh, Vinay Kumar Nandicoori
The cell wall of Mycobacterium tuberculosis (Mtb) is a complex structure that protects the pathogen in hostile environments. Peptidoglycan (PG), which helps determine the morphology of the cell envelope, undergoes substantial remodeling under stress. This meshwork of linear chains of sugars, crosslinked through attached peptides, is generated through the sequential action of enzymes termed transglycosylases and transpeptidases. The Mtb genome encodes two classical transglycosylases and four transpeptidases, the functions of which are not fully elucidated...
March 12, 2018: Journal of Biological Chemistry
Søren Heissel, Jakob Bunkenborg, Max Per Kristiansen, Anne Fich Holmbjerg, Marie Grimstrup, Ejvind Mørtz, Thomas Kofoed, Peter Højrup
Recombinantly expressed biopharmaceutical proteins often undergo a series of purification steps with the aim of removing contaminating material. Depending on the application of the protein, there are various requirements for the degree of purity, but host cell proteins (HCPs) will in general remain in small amounts. LC-MS has emerged as an orthogonal technique, capable of providing detailed information regarding the individual proteins. The aim of this case study was to characterize the HCPs associated with a biopharmaceutical protein, provided by Statens Serum Institut (DK), which is used in the field of tuberculosis and has not previously been studied by LC-MS...
March 8, 2018: Protein Expression and Purification
Kuppan Gokulan, Sangeeta Khare, Carl E Cerniglia, Steven L Foley, Kottayil I Varughese
The final step of peptidoglycan (PG) synthesis in all bacteria is the formation of cross-linkage between PG-stems. The cross-linking between amino acids in different PG chains gives the peptidoglycan cell wall a 3-dimensional structure and adds strength and rigidity to it. There are two distinct types of cross-linkages in bacterial cell walls. D,D-transpeptidase (D,D-TPs) generate the classical 4➔3 cross-linkages and the L,D-transpeptidase (L,D-TPs) generate the 3➔3 non-classical peptide cross-linkages...
March 9, 2018: AAPS Journal
Alfonsina D'Amato, Gleb Zilberstein, Svetlana Zilberstein, Mikhail Ivanovich Golovan, Anastasiya Anatolyevna Zhuravleva, Pier Giorgio Righetti
Five different letters and post cards as well as the shirt worn by Anton Chekhov on his death bed, stored in A. Chekhov's museum in Melikhovo (nearby Moscow), have been analyzed by applying to these surfaces EVA (an ethyl vinyl acetate foil studded with crushed strong anion and cation exchangers and with C8 resins) diskettes. Three different eluates (under acidic and basic conditions and with acetonitrile) were analyzed by high resolution mass spectrometry. The environmental microbiota present on samples and the Mycobacterium tuberculosis strain were described by a meta-proteomics approach...
March 9, 2018: Proteomics
Violeta D Alvarez-Jiménez, Kahiry Leyva-Paredes, Mariano García-Martínez, Luis Vázquez-Flores, Víctor Gabriel García-Paredes, Marcia Campillo-Navarro, Israel Romo-Cruz, Víctor Hugo Rosales-García, Jessica Castañeda-Casimiro, Sirenia González-Pozos, José Manuel Hernández, Carlos Wong-Baeza, Blanca Estela García-Pérez, Vianney Ortiz-Navarrete, Sergio Estrada-Parra, Jeanet Serafín-López, Isabel Wong-Baeza, Rommel Chacón-Salinas, Iris Estrada-García
Tuberculosis is an infectious disease caused by Mycobacterium tuberculosis (Mtb). In the lungs, macrophages and neutrophils are the first immune cells that have contact with the infecting mycobacteria. Neutrophils are phagocytic cells that kill microorganisms through several mechanisms, which include the lytic enzymes and antimicrobial peptides that are found in their lysosomes, and the production of reactive oxygen species. Neutrophils also release extracellular vesicles (EVs) (100-1,000 nm in diameter) to the extracellular milieu; these EVs consist of a lipid bilayer surrounding a hydrophilic core and participate in intercellular communication...
2018: Frontiers in Immunology
Christian David Sánchez-Barinas, Marisol Ocampo, Magnolia Vanegas, Jeimmy Johana Castañeda-Ramirez, Manuel Alfonso Patarroyo, Manuel Elkin Patarroyo
Mycobacterium tuberculosis is the causative agent of tuberculosis, a disease causing major mortality worldwide. As part of a systematic methodology for studying M. tuberculosis surface proteins which might be involved in host-pathogen interactions, our group found that LpqG surface protein (Rv3623) found in M. tuberculosis complex strains was located on the mycobacterial envelope and that peptide 16661 (21 SGCDSHNSGSLGADPRQVTVY40 ) had high specific binding to U937 monocyte-derived macrophages and inhibited mycobacterial entry to such cells in a concentration-dependent way...
February 27, 2018: Molecules: a Journal of Synthetic Chemistry and Natural Product Chemistry
Jinjing Tan, Xiaoguang Wu, Suting Chen, Meng Gu, Hairong Huang, Wentao Yue
BACKGROUND: Serological antibodies tests for tuberculosis (TB) are widely used in developing countries. They appear to have some advantages- faster, simple and could be used for extrapulmonary TB. However, most of current commercial TB serological tests are failed to provide sufficient sensitivity and specificity. Improved serological biomarkers were essential. In this study, we present an approach using peptide array to discover new immunodiagnostic biomarkers based on immunodominant epitopes of TB antigens...
March 1, 2018: BMC Immunology
Kavita Bansal, Mohammad Aqdas, Munish Kumar, Rajni Bala, Sanpreet Singh, Javed Naim Agrewala, O P Katare, Rohit Kumar Sharma, Nishima Wangoo
Peptide based drug delivery system has found a mainstay in contemporary medicinal field resulting in the design and development of better pharmaceutical formulations. However, most of the available reports employ tedious multiple reaction steps for the conjugation of bioactive cationic peptides with drug delivery vehicles. To overcome these limitations, the present work describes a one-step approach for facile and time efficient synthesis of highly cationic cell penetrating peptide functionalized gold nanoparticles and their intracellular delivery...
February 28, 2018: Bioconjugate Chemistry
Rui Yang, Enzhuo Yang, Ling Shen, Robert L Modlin, Hongbo Shen, Zheng W Chen
The ability of Mycobacterium tuberculosis to block host antimicrobial responses in infected cells provides a key mechanism for disease pathogenesis. The immune system has evolved to overcome this blockade to restrict the infection, but it is not clear whether two key innate cytokines (IL-12/IL-18) involved in host defense can enhance antimycobacterial mechanisms. In this study, we demonstrated that the combination of IL-12 and IL-18 triggered an antimicrobial response against mycobacteria in infected macrophages (THP-1 and human primary monocyte-derived macrophages) and pulmonary epithelial A549 cells...
February 16, 2018: Journal of Immunology: Official Journal of the American Association of Immunologists
Lissa S Tsutsumi, John M Elmore, Uyen T Dang, Miranda J Wallace, Ravikanthreddy Marreddy, Robin B Lee, Ghee T Tan, J Hurdle, Richard E Lee, Dianqing Sun
Herein we report the antibacterial structure-activity relationships of cyclic hexapeptide wollamide analogs derived from solid-phase library synthesis. Wollamide B, a cyclic hexapeptide natural product, has been previously found to have activity against Mycobacterium bovis. To further evaluate its antimycobacterial/antibacterial potential, 27 peptides including wollamides A/B, and desotamide B, were synthesized and subsequently tested against a panel of clinically significant bacterial pathogens. Biological evaluation revealed that the cyclic scaffold, amide functionality in position I, tryptophan residue in position V, and the original stereochemistry pattern of the core scaffold were key for antituberculosis and/or antibacterial activity...
February 12, 2018: ACS Combinatorial Science
Paige M E Hawkins, Andrew M Giltrap, Gayathri Nagalingam, Warwick J Britton, Richard J Payne
The first total synthesis of the potent anti-mycobacterial cyclic depsipeptide natural product ecumicin is described. Synthesis was achieved via a solid-phase strategy, incorporating the synthetic non-proteinogenic amino acids N-methyl-4-methoxy-l-tryptophan and threo-β-hydroxy-l-phenylalanine into the growing linear peptide chain. The synthesis employed key on-resin esterification and dimethylation steps as well as a final macrolactamization between the unusual N-methyl-4-methoxy-l-tryptophan unit and a bulky N-methyl-l-valine residue...
February 7, 2018: Organic Letters
Flora Ngadjeua, Emmanuelle Braud, Saidbakhrom Saidjalolov, Laura Iannazzo, Dirk Schnappinger, Sabine Ehrt, Jean-Emmanuel Hugonnet, Dominique Mengin-Lecreulx, Delphine Patin Patin, Mélanie Ethève-Quelquejeu, Matthieu Fonvielle, Michel Arthur
The bacterial cell wall peptidoglycan contains unusual L and D amino acids assembled in branched peptides. Insight into the biosynthesis of the polymer has been hampered by limited access to substrates and to suitable polymerization assays. Here we report the full synthesis of the peptide stem of peptidoglycan precursors from two pathogenic bacteria, Enterococcus faecium and Mycobacterium tuberculosis, and the development of a sensitive post-derivatization assay for their cross-linking by L,D-transpeptidases...
February 1, 2018: Chemistry: a European Journal
Zhigang Xu, Dezhou Li, Xinyu Chen, Zhiliang Duan, Jiayuan Mao, Jinsheng Wen
Objective To identify Mycobacterium tuberculosis ESAT-6 protein esxN-specific HLA-A*0201-restricted CTL epitopes and assess the diagnostic potential of the identified epitopes in pulmonary tuberculosis. Methods The esxN-specific HLA-A*0201-restricted CTL epitopes were predicted by the T epitope prediction software SYFPEITHI and further synthesized. The binding affinity of the candidate epitopes for HLA-A*0201 was detected using MHC-peptide complex stabilization assay. The immunogenicity of candidate epitopes were assessed using ELISPOT in HLA-A*0201 transgenic mice...
December 2017: Xi Bao Yu Fen Zi Mian Yi Xue za Zhi, Chinese Journal of Cellular and Molecular Immunology
Fadhil Ahsan, Jeroen Maertzdorf, Ute Guhlich-Bornhof, Stefan H E Kaufmann, Pedro Moura-Alves
Mycobacterium tuberculosis (Mtb) is a life-threatening pathogen in humans. Bacterial infection of macrophages usually triggers strong innate immune mechanisms, including IL-1 cytokine secretion. The newer member of the IL-1 family, IL-36, was recently shown to be involved in cellular defense against Mtb. To unveil the underlying mechanism of IL-36 induced antibacterial activity, we analyzed its role in the regulation of cholesterol metabolism, together with the involvement of Liver X Receptor (LXR) in this process...
January 24, 2018: Scientific Reports
Anish Parmar, Rajamani Lakshminarayanan, Abhishek Iyer, Venkatesh Mayandi, Eunice Tze Leng Goh, Daniel G Lloyd, Madhavi Latha S Chalasani, Navin Kumar Verma, Stephen H Prior, Roger W Beuerman, Annemieke Madder, Edward J Taylor, Ishwar Singh
The cyclic depsipeptide, teixobactin kills a number of Gram positive bacteria including Methicillin-resistant Staphylococcus aureus (MRSA) and Mycobacterium tuberculosis without detectable resistance. To date, teixobactin is the only molecule in its class which has shown in vivo antibacterial efficacy. There have been no in vivo evaluation studies on teixobactin analogues. In this work, we have designed and synthesized 10 new in vivo ready teixobactin analogues. These analogues showed highly potent antibacterial activity against Staphylococcus aureus, MRSA, and vancomycin-resistant Enterococci (VRE) in vitro...
January 24, 2018: Journal of Medicinal Chemistry
Andrea Figueroa-Montiel, Johanna Bernáldez, Samanta Jiménez, Beatrix Ueberhide, Luis Javier González, Alexei Licea-Navarro
Mycobacterium tuberculosis is the etiological agent of tuberculosis, an airborne infectious disease that is a leading cause of human morbidity and mortality worldwide. We report here the first conotoxin that is able to inhibit the growth of M. tuberculosis at a concentration similar to that of two other drugs that are currently used in clinics. Furthermore, it is also the first conopeptide that has been isolated from the venom of Conasprella ximenes. The venom gland transcriptome of C. ximenes was sequenced to construct a database with 24,284 non-redundant transcripts...
January 23, 2018: Toxins
Chang Liu, Christopher J Lyon, Yang Bu, Zaian Deng, Elisabetta Walters, Yan Li, Liqun Zhang, Anneke C Hesseling, Edward A Graviss, Ye Hu
BACKGROUND: The diagnosis of active tuberculosis (TB)10 cases primarily relies on methods that detect Mycobacterium tuberculosis (Mtb) bacilli or their DNA in patient samples (e.g., mycobacterial culture and Xpert MTB/RIF assays), but these tests have low clinical sensitivity for patients with paucibacillary TB disease. Our goal was to evaluate the clinical performance of a newly developed assay that can rapidly diagnose active TB cases by direct detection of Mtb-derived antigens in patients' blood samples...
January 18, 2018: Clinical Chemistry
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