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  1. Article ; Online: CD1

    D. Branch Moody / Sara Suliman

    F1000Research, Vol

    From Molecules to Diseases [version 1; referees: 3 approved]

    2017  Volume 6

    Abstract: The human cluster of differentiation (CD)1 system for antigen display is comprised of four types of antigen-presenting molecules, each with a distinct functional niche: CD1a, CD1b, CD1c, and CD1d. Whereas CD1 proteins were thought solely to influence T- ... ...

    Abstract The human cluster of differentiation (CD)1 system for antigen display is comprised of four types of antigen-presenting molecules, each with a distinct functional niche: CD1a, CD1b, CD1c, and CD1d. Whereas CD1 proteins were thought solely to influence T-cell responses through display of amphipathic lipids, recent studies emphasize the role of direct contacts between the T-cell receptor and CD1 itself. Moving from molecules to diseases, new research approaches emphasize human CD1-transgenic mouse models and the study of human polyclonal T cells in vivo or ex vivo in disease states. Whereas the high genetic diversity of major histocompatibility complex (MHC)-encoded antigen-presenting molecules provides a major hurdle for designing antigens that activate T cells in all humans, the simple population genetics of the CD1 system offers the prospect of discovering or designing broadly acting immunomodulatory agents.
    Keywords Antigen Processing & Recognition ; Immunity to Infections ; Immunomodulation ; Innate Immunity ; Leukocyte Signaling & Gene Expression ; Medical Microbiology ; Medicine ; R ; Science ; Q
    Language English
    Publishing date 2017-10-01T00:00:00Z
    Publisher F1000 Research Ltd
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  2. Article ; Online: 24780 Investigating the role of mycobacterial lipid antigens and CD1-restricted T cells in host-protective tuberculosis immunity using a guinea pig model

    Macallister Harris / James Dilisio / Hadley Gary / Edward Chan / D. Branch Moody / Brendan Podell

    Journal of Clinical and Translational Science, Vol 5, Pp 114-

    2021  Volume 115

    Abstract: ABSTRACT IMPACT: Examining lipid immunity for Mycobacterium tuberculosis in a translatable Guinea pig model may serve as a critical foundation for the creation of an efficacious human lipid based vaccine against tuberculosis. OBJECTIVES/GOALS: CD1 is a ... ...

    Abstract ABSTRACT IMPACT: Examining lipid immunity for Mycobacterium tuberculosis in a translatable Guinea pig model may serve as a critical foundation for the creation of an efficacious human lipid based vaccine against tuberculosis. OBJECTIVES/GOALS: CD1 is a group of glycoproteins on antigen-presenting cells (APCs) that present lipid antigens to T cells. Mycobacterium tuberculosis (Mtb) has a lipid-rich cell wall which is essential for the pathogenesis of tuberculosis. Our goal is to determine the frequency, phenotypes, and functionality of CD1 T cells against Mtb using the guinea pig model. METHODS/STUDY POPULATION: Guinea pigs serve as the best translational model for CD1 immunology as they have both group 1 and group 2 CD1 complexes, comparable to human CD1. We performed ex-vivo and in-vivo experiments to analyze lipid antigen-specific CD1 T cell responses with Mtb infection. Assays to detect lipid-specific CD1 T cell activation include cellular proliferation, cytotoxicity assays, and interferon-gamma (IFNγ) release assay (Elispot) using both synthetic and Mtb-derived lipids. We isolated and characterized CD1 T cells using tetramerized CD1 complexes loaded with specific Mtb lipids. Spatial interaction between lipid loaded CD1 APCs with CD1 T cells were demonstrated by immunohistochemistry (IHC). Lastly, we will investigate the impact of lipid-based immunology via knockdown and overexpression of CD1 complexes. RESULTS/ANTICIPATED RESULTS: The cytotoxicity assay demonstrated that the CD1b1 and CD1b3 complexes play roles in the presentation of Mtb lipids, specifically glucose monomycolate, and mycolic acid, as noted by T cell killing of fibroblasts that express specific CD1 complexes that can present Mtb lipids. Similarly, cellular proliferation exhibited lipid specific T cell proliferation. IFNγ production by the stimulated CD1-restricted T cells (Elispot) was weak indicating CD1 T cells may not produce IFNγ. IHC successfully showed CD1 APCs in lungs and spleens of infected guinea pigs. It is anticipated that ...
    Keywords Medicine ; R
    Subject code 572
    Language English
    Publishing date 2021-03-01T00:00:00Z
    Publisher Cambridge University Press
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  3. Article ; Online: Efficient and precise single-cell reference atlas mapping with Symphony

    Joyce B. Kang / Aparna Nathan / Kathryn Weinand / Fan Zhang / Nghia Millard / Laurie Rumker / D. Branch Moody / Ilya Korsunsky / Soumya Raychaudhuri

    Nature Communications, Vol 12, Iss 1, Pp 1-

    2021  Volume 21

    Abstract: The number of single-cell RNA-seq datasets generated is increasing rapidly, making methods that map cell types to well-curated references increasingly important. Here, the authors propose an accurate method for mapping single cells onto a reference atlas ...

    Abstract The number of single-cell RNA-seq datasets generated is increasing rapidly, making methods that map cell types to well-curated references increasingly important. Here, the authors propose an accurate method for mapping single cells onto a reference atlas in seconds.
    Keywords Science ; Q
    Language English
    Publishing date 2021-10-01T00:00:00Z
    Publisher Nature Portfolio
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  4. Article ; Online: A periplasmic cinched protein is required for siderophore secretion and virulence of Mycobacterium tuberculosis

    Lei Zhang / James E. Kent / Meredith Whitaker / David C. Young / Dominik Herrmann / Alexander E. Aleshin / Ying-Hui Ko / Gino Cingolani / Jamil S. Saad / D. Branch Moody / Francesca M. Marassi / Sabine Ehrt / Michael Niederweis

    Nature Communications, Vol 13, Iss 1, Pp 1-

    2022  Volume 13

    Abstract: The pathogen Mycobacterium tuberculosis uses the siderophores called mycobactins and carboxymycobactins to acquire iron from the host. Here, Zhang et al. identify a protein that is important for siderophore secretion and for the pathogen’s growth in low- ... ...

    Abstract The pathogen Mycobacterium tuberculosis uses the siderophores called mycobactins and carboxymycobactins to acquire iron from the host. Here, Zhang et al. identify a protein that is important for siderophore secretion and for the pathogen’s growth in low-iron medium.
    Keywords Science ; Q
    Language English
    Publishing date 2022-04-01T00:00:00Z
    Publisher Nature Portfolio
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  5. Article ; Online: Protein kinases PknA and PknB independently and coordinately regulate essential Mycobacterium tuberculosis physiologies and antimicrobial susceptibility.

    Jumei Zeng / John Platig / Tan-Yun Cheng / Saima Ahmed / Yara Skaf / Lakshmi-Prasad Potluri / Daniel Schwartz / Hanno Steen / D Branch Moody / Robert N Husson

    PLoS Pathogens, Vol 16, Iss 4, p e

    2020  Volume 1008452

    Abstract: The Mycobacterium tuberculosis Ser/Thr protein kinases PknA and PknB are essential for growth and have been proposed as possible drug targets. We used a titratable conditional depletion system to investigate the functions of these kinases. Depletion of ... ...

    Abstract The Mycobacterium tuberculosis Ser/Thr protein kinases PknA and PknB are essential for growth and have been proposed as possible drug targets. We used a titratable conditional depletion system to investigate the functions of these kinases. Depletion of PknA or PknB or both kinases resulted in growth arrest, shortening of cells, and time-dependent loss of acid-fast staining with a concomitant decrease in mycolate synthesis and accumulation of trehalose monomycolate. Depletion of PknA and/or PknB resulted in markedly increased susceptibility to β-lactam antibiotics, and to the key tuberculosis drug rifampin. Phosphoproteomic analysis showed extensive changes in protein phosphorylation in response to PknA depletion and comparatively fewer changes with PknB depletion. These results identify candidate substrates of each kinase and suggest specific and coordinate roles for PknA and PknB in regulating multiple essential physiologies. These findings support these kinases as targets for new antituberculosis drugs and provide a valuable resource for targeted investigation of mechanisms by which protein phosphorylation regulates pathways required for growth and virulence in M. tuberculosis.
    Keywords Immunologic diseases. Allergy ; RC581-607 ; Biology (General) ; QH301-705.5
    Subject code 571 ; 572
    Language English
    Publishing date 2020-04-01T00:00:00Z
    Publisher Public Library of Science (PLoS)
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  6. Article ; Online: Synthetic mycobacterial diacyl trehaloses reveal differential recognition by human T cell receptors and the C-type lectin Mincle

    Josephine F. Reijneveld / Mira Holzheimer / David C. Young / Kattya Lopez / Sara Suliman / Judith Jimenez / Roger Calderon / Leonid Lecca / Megan B. Murray / Eri Ishikawa / Sho Yamasaki / Adriaan J. Minnaard / D. Branch Moody / Ildiko Van Rhijn

    Scientific Reports, Vol 11, Iss 1, Pp 1-

    2021  Volume 10

    Abstract: Abstract The cell wall of Mycobacterium tuberculosis is composed of diverse glycolipids which potentially interact with the human immune system. To overcome difficulties in obtaining pure compounds from bacterial extracts, we recently synthesized three ... ...

    Abstract Abstract The cell wall of Mycobacterium tuberculosis is composed of diverse glycolipids which potentially interact with the human immune system. To overcome difficulties in obtaining pure compounds from bacterial extracts, we recently synthesized three forms of mycobacterial diacyltrehalose (DAT) that differ in their fatty acid composition, DAT1, DAT2, and DAT3. To study the potential recognition of DATs by human T cells, we treated the lipid-binding antigen presenting molecule CD1b with synthetic DATs and looked for T cells that bound the complex. DAT1- and DAT2-treated CD1b tetramers were recognized by T cells, but DAT3-treated CD1b tetramers were not. A T cell line derived using CD1b-DAT2 tetramers showed that there is no cross-reactivity between DATs in an IFN-γ release assay, suggesting that the chemical structure of the fatty acid at the 3-position determines recognition by T cells. In contrast with the lack of recognition of DAT3 by human T cells, DAT3, but not DAT1 or DAT2, activates Mincle. Thus, we show that the mycobacterial lipid DAT can be both an antigen for T cells and an agonist for the innate Mincle receptor, and that small chemical differences determine recognition by different parts of the immune system.
    Keywords Medicine ; R ; Science ; Q
    Language English
    Publishing date 2021-01-01T00:00:00Z
    Publisher Nature Portfolio
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  7. Article ; Online: Effects of BCG vaccination on donor unrestricted T cells in two prospective cohort studies

    Anele Gela / Melissa Murphy / Miguel Rodo / Kate Hadley / Willem A. Hanekom / W.Henry Boom / John L. Johnson / Daniel F. Hoft / Simone A. Joosten / Tom H.M. Ottenhoff / Sara Suliman / D.Branch Moody / David M. Lewinsohn / Mark Hatherill / Chetan Seshadri / Elisa Nemes / Thomas J. Scriba / Libby Briel / Hellen Veldtsman /
    Nondumiso Khomba / Bernadette Pienaar / Hadn Africa / Marcia Steyn

    EBioMedicine, Vol 76, Iss , Pp 103839- (2022)

    2022  

    Abstract: Summary: Background: Non-protein antigen classes can be presented to T cells by near-monomorphic antigen-presenting molecules such as CD1, MR1, and butyrophilin 3A1. Such T cells, referred to as donor unrestricted T (DURT) cells, typically express ... ...

    Abstract Summary: Background: Non-protein antigen classes can be presented to T cells by near-monomorphic antigen-presenting molecules such as CD1, MR1, and butyrophilin 3A1. Such T cells, referred to as donor unrestricted T (DURT) cells, typically express stereotypic T cell receptors. The near-unrestricted nature of DURT cell antigen recognition is of particular interest for vaccine development, and we sought to define the roles of DURT cells, including MR1-restricted MAIT cells, CD1b-restricted glucose monomycolate (GMM)-specific T cells, CD1d-restricted NKT cells, and γδ T cells, in vaccination against Mycobacterium tuberculosis. Methods: We compared and characterized DURT cells following primary bacille Calmette-Guerin (BCG) vaccination in a cohort of vaccinated and unvaccinated infants, as well as before and after BCG-revaccination in adults. Findings: BCG (re)vaccination did not modulate peripheral blood frequencies, T cell activation or memory profiles of MAIT cells, CD1b-restricted GMM-specific and germline-encoded mycolyl-reactive (GEM) cells or CD1d-restricted NKT cells. By contrast, primary BCG vaccination was associated with increased frequencies of γδ T cells as well as a novel subset of CD26+CD161+TRAV1-2− IFN-γ-expressing CD4+ T cells in infants. Interpretation: Our findings, that most DURT cell populations were not modulated by BCG, do not preclude a role of BCG in modulating other qualitative aspects of DURT cells. More studies are required to understand the full potential of DURT cells in new TB vaccine strategies. Funding: Aeras, the National Institutes of Health, and the Bill and Melinda Gates Foundation.
    Keywords BCG ; Tuberculosis ; Vaccination ; Unconventional T cells ; Memory ; Medicine ; R ; Medicine (General) ; R5-920
    Subject code 610 ; 570
    Language English
    Publishing date 2022-02-01T00:00:00Z
    Publisher Elsevier
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  8. Article ; Online: A terpene nucleoside from M. tuberculosis induces lysosomal lipid storage in foamy macrophages

    Melissa Bedard / Sanne van der Niet / Elliott M. Bernard / Gregory Babunovic / Tan-Yun Cheng / Beren Aylan / Anita E. Grootemaat / Sahadevan Raman / Laure Botella / Eri Ishikawa / Mary P. O’Sullivan / Seónadh O’Leary / Jacob A. Mayfield / Jeffrey Buter / Adriaan J. Minnaard / Sarah M. Fortune / Leon O. Murphy / Daniel S. Ory / Joseph Keane /
    Sho Yamasaki / Maximiliano G. Gutierrez / Nicole van der Wel / D. Branch Moody

    The Journal of Clinical Investigation, Vol 133, Iss

    2023  Volume 6

    Abstract: Induction of lipid-laden foamy macrophages is a cellular hallmark of tuberculosis (TB) disease, which involves the transformation of infected phagolysosomes from a site of killing into a nutrient-rich replicative niche. Here, we show that a terpenyl ... ...

    Abstract Induction of lipid-laden foamy macrophages is a cellular hallmark of tuberculosis (TB) disease, which involves the transformation of infected phagolysosomes from a site of killing into a nutrient-rich replicative niche. Here, we show that a terpenyl nucleoside shed from Mycobacterium tuberculosis, 1-tuberculosinyladenosine (1-TbAd), caused lysosomal maturation arrest and autophagy blockade, leading to lipid storage in M1 macrophages. Pure 1-TbAd, or infection with terpenyl nucleoside–producing M. tuberculosis, caused intralysosomal and peribacillary lipid storage patterns that matched both the molecules and subcellular locations known in foamy macrophages. Lipidomics showed that 1-TbAd induced storage of triacylglycerides and cholesterylesters and that 1-TbAd increased M. tuberculosis growth under conditions of restricted lipid access in macrophages. Furthermore, lipidomics identified 1-TbAd–induced lipid substrates that define Gaucher’s disease, Wolman’s disease, and other inborn lysosomal storage diseases. These data identify genetic and molecular causes of M. tuberculosis–induced lysosomal failure, leading to successful testing of an agonist of TRPML1 calcium channels that reverses lipid storage in cells. These data establish the host-directed cellular functions of an orphan effector molecule that promotes survival in macrophages, providing both an upstream cause and detailed picture of lysosome failure in foamy macrophages.
    Keywords Infectious disease ; Microbiology ; Medicine ; R
    Subject code 572
    Language English
    Publishing date 2023-03-01T00:00:00Z
    Publisher American Society for Clinical Investigation
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  9. Article ; Online: The late stage of COPI vesicle fission requires shorter forms of phosphatidic acid and diacylglycerol

    Seung-Yeol Park / Jia-Shu Yang / Zhen Li / Pan Deng / Xiaohong Zhu / David Young / Maria Ericsson / Ruben L. H. Andringa / Adriaan J. Minnaard / Chunmei Zhu / Fei Sun / D. Branch Moody / Andrew J. Morris / Jun Fan / Victor W. Hsu

    Nature Communications, Vol 10, Iss 1, Pp 1-

    2019  Volume 14

    Abstract: Phosphatidic acid and diacylglycerol are required for COPI vesicle fission. Here, the authors find that shorter forms of these lipids promote the late stage of COPI vesicle fission, further suggesting how lipid geometry contributes to membrane ... ...

    Abstract Phosphatidic acid and diacylglycerol are required for COPI vesicle fission. Here, the authors find that shorter forms of these lipids promote the late stage of COPI vesicle fission, further suggesting how lipid geometry contributes to membrane deformation in driving fission.
    Keywords Science ; Q
    Language English
    Publishing date 2019-07-01T00:00:00Z
    Publisher Nature Publishing Group
    Document type Article ; Online
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  10. Article ; Online: A T-cell receptor escape channel allows broad T-cell response to CD1b and membrane phospholipids

    Adam Shahine / Peter Reinink / Josephine F. Reijneveld / Stephanie Gras / Mira Holzheimer / Tan-Yun Cheng / Adriaan J. Minnaard / John D. Altman / Steffi Lenz / Jacques Prandi / Joanna Kubler-Kielb / D. Branch Moody / Jamie Rossjohn / Ildiko Van Rhijn

    Nature Communications, Vol 10, Iss 1, Pp 1-

    2019  Volume 12

    Abstract: CD1 proteins present lipid antigens to T cells via the T cell receptor. Here the authors describe T cell reactivity to human membrane lipid moieties and provide structural data to define a molecular mechanism of promiscuous recognition of self-derived ... ...

    Abstract CD1 proteins present lipid antigens to T cells via the T cell receptor. Here the authors describe T cell reactivity to human membrane lipid moieties and provide structural data to define a molecular mechanism of promiscuous recognition of self-derived phospholipids.
    Keywords Science ; Q
    Language English
    Publishing date 2019-01-01T00:00:00Z
    Publisher Nature Publishing Group
    Document type Article ; Online
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