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WELCOME TO THE 2011 - Harvard Initiative for Global Health ...

WELCOME TO THE 2011 - Harvard Initiative for Global Health ...

Department of Chemistry,

Department of Chemistry, Stony Brook University, Stony Brook, NY, USA, 11794. Department of Pharmacology, Stony Brook University, Stony Brook, NY, USA, 11794. The inherent drug resistance of Mycobacterium tuberculosis (Mtb) has been attributed to the low permeability of its cell wall, which includes many unique and extremely hydrophobic lipids. While several biosynthesis pathways have been elucidated, comparatively little is known about lipid transport through the periplasm and assembly in the outer membrane. My focus is on the elucidation of protein-lipid interactions important in lipid biosynthesis and transport. Our goals are (1) to use known lipid biosynthetic enzymes to generate chemical tools and biochemical standards and (2) to use these tools to explore lipid-associated processes. We are currently characterizing functionally similar acyltransferase enzymes for their substrate preferences and potential utility in the chemoenzymatic synthesis of the corresponding lipid analogues. Phthiocerol dimycocerosate (PDIM) is a wax ester that has been implicated in virulence. The acyltransferase PapA5 is associated with the acylation of phthiocerol with two mycocerosate fatty acids. Currently, phthiocerol analogues are being synthesized for PapA5 substrate preference studies. The analogues will then be used to create PDIM analogues. The substrate preferences of the putative PDIM binding protein, LppX for the PDIM analogues will be studied using a competitive fluorescence binding assay. In the future, labeling strategies for acyl chains will be examined to generate chemical probes that can be applied to discovering transport machinery for Mtb glycolipids. This work is supported by the Office for the Vice President for Research and the Research Foundation, State University New York. 19) A genetic approach to enhance innate host resistance to intracellular pathogens 1,4 Bidisha Bhattacharya, 2 Abigail Newby-Kew, 1 Jesse Goldshear, 3 Stewart Rudnicki, 3 Xie Tiao, and 1,4 Igor Kramnik 1 National Emerging Infectious Diseases Laboratory (NEIDL), Boston University, Boston, MA, USA, 02118; 2 High Throughoutput Screening Core, Boston University, Boston, MA, USA, 02118 3 Screening Facility ICCB-Longwood, NERCE, Harvard Medical School, Boston, MA, USA, 02115; 4 Pulmonary Center and Infectious Diseases section, Boston University School of Medicine, Boston, MA, USA 02118 We used forward genetic analysis in a mouse model to identify the genetic locus sst1 (supersusceptibility to tuberculosis 1) that mediates innate resistance to intracellular bacterial pathogens Mycobacterium tuberculosis, Listeria monocytogenes, Francisella tularensis LVS and Chlamydia pneumoniae in vivo. In all models the sst1 locus had dramatic effect on the dynamics of inflammation and tissue necrosis. Using positional cloning a novel candidate gene Ipr1 (intracellular pathogen resistance 1) within the sst1 locus has been identified. We found that Ipr1 is an interferon-inducible nuclear protein expressed in activated macrophages. Our data suggest that Ipr1 does not control effector mechanisms of anti-bacterial immunity, but plays an important role in macrophage stress response, adaptation and survival within inflammatory lesions. Using a Tet-On lentiviral system for inducible GFP-Ipr1 expression in macrophages, we observed posttranscriptional regulation of Ipr1 protein by interferons: the tet-induced GFP-Ipr1 protein is rapidly eliminated from the nuclei of non-activated macrophages, but it is accumulated in the nuclei of interferon-γ activated macrophages where it forms multiprotein complexes with nuclear proteins and associates with chromatin. The GFP-Ipr1 nuclear accumulation is IFN-γ dose dependent. Using nuclear level of GFP-Ipr1 protein as a biomarker of macrophage priming with interferons, a high throughput screening has been developed to identify compounds that synergize with, or inhibit, IFN-γ-mediated macrophage activation. This novel strategy is aimed at enhancing cell 25

sensitivity to interferons, prolonging activated state, preventing inflammatory lung damage, and, therefore, reducing transmission of M. tuberculosis. This work was supported by the National Institute of Health (NIH-HL59836) and the Pilot Screen Ignition Award from the Office of Technology and Development, Boston University 20) Tim3/Galectin-9 interactions regulate innate and adaptive immunity to Mycobacterium tuberculosis P.Jayaraman 1 , I. Sada-Ovalle 3 , A. Anderson 2 , V. Kuchroo 2 , and SM. Behar 1 1 Division of Rheumatology Immunology and Allergy, 2 Division of Molecular Immunology, Center for Neurologic Diseases, Brigham and Women’s Hospital and Harvard Medical School, Boston; 3 Research Unit, Immunochemistry Department, National Institute of Respiratory Diseases, México City, México. In vivo control of Mycobacterium tuberculosis (Mtb) reflects the balance between host-immunity and bacterial evasion strategies. Effector TH1 cells that mediate protective immunity by depriving the bacterium of its intracellular niche are regulated in many ways to prevent overexuberant inflammation. Although Tim3 is generally recognized to down regulate TH1 responses and mediate T cell exhaustion, we recently described that its interaction with Galectin-9 (Gal9) expressed by Mtb infected macrophages (Mφ) stimulates IL-1β secretion, which is essential for host resistance to Mtb. IL-1β signaling is both necessary for Tim3 mediated Mtb control and sufficient to directly kill Mtb in murine and human Mφ. The molecular mechanism by which IL-1β restricts bacterial growth is not known. We report that IL-1β kills Mtb through the recruitment of other antimicrobial effector molecules. IL-1β directly augments TNF signaling through increased TNF secretion and TNFR cell surface expression. Furthermore, Tim3/Gal9 and IL-1β activates the executioner caspase-3. Thus, Tim3/Gal9, via IL-1β and downstream TNF production lead to apoptosis and restriction of intracellular Mtb growth. We propose that Tim3/Gal9 interaction acts as a bidirectional molecular rheostat that activates pathways to clear intracellular pathogens in innate immune cells while fine-tuning termination of TH1 responses to prevent immunopathology. 21) Efferocytosis is responsible for apoptosis-mediated Mycobacterium tuberculosis control Constance J. Martin 1 , Matthew G. Booty 2 , Tracy R. Rosebrock 1 , Cláudio Nunes-Alves 3 , Danielle M. Desjardins 3 , Iris Keren 4 , Sarah M. Fortune 1 , Heinz G. Remold 3 and Samuel M. Behar 1,2,3 . 1 Harvard School of Public Health. Department of Immunology and Infectious Diseases. Boston, MA 02115. 2 Program in Immunology. Harvard Medical School Boston, MA 02115. 3 Department of Rheumatology, Immunology and Allergy. Brigham and Women’s Hospital and Harvard Medical School. Boston, MA 02115. 4 Antimicrobial Discovery Center, Northeastern University. Boston, MA. 02115. Mycobacterium tuberculosis persists within macrophages in an arrested phagosome and depends upon necrosis to elude immunity and disseminate. Conversely, apoptosis of an M. tuberculosis-infected macrophage restricts bacterial replication via a hitherto unknown mechanism. We report here that following apoptosis, M. tuberculosis-infected macrophages are rapidly engulfed by uninfected macrophages through the process of efferocytosis. Engulfment of M. tuberculosis sequestered within an apoptotic macrophage further compartmentalizes the bacterium and delivers it along with the apoptotic cell debris to the lysosomal compartment. M. tuberculosis is killed following efferocytosis, indicating that apoptosis itself is not intrinsically bactericidal and demonstrating for the first time efferocytosis as an innate immune mechanism of bacterial control. Furthermore, we confirm that efferocytosis is required for apoptosismediated control of M. tuberculosis in vivo. While efferocytosis is recognized as a constitutive 26

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