Doron Levin

Doron Levin

Israel
3K‏ עוקבים מעל 500 קשרים

הצטרפ/י כדי להציג פרופיל

על אודות

A molecular biologist and biochemist by training, with over nine years of industrial…

פעילות

הצטרפו עכשיו כדי לראות את כל פעילות

ניסיון

חינוך

פרסומים

  • Engineering Toxoplasma gondii secretion systems for intracellular delivery of multiple large therapeutic proteins to neurons.

    Nature Microbiology

    ראה פרסום

  • Mouse PVRIG Has CD8+ T Cell-Specific Coinhibitory Functions and Dampens Antitumor Immunity.

    Cancer Immunology Research

    A limitation to antitumor immunity is the dysfunction of T cells in the tumor microenvironment, in part due to upregulation of coinhibitory receptors such as PD-1. Here, we describe that poliovirus receptor–related immunoglobulin domain protein (PVRIG) acts as a coinhibitory receptor in mice. Murine PVRIG interacted weakly with poliovirus receptor (PVR) but bound poliovirus receptor–like 2 (PVRL2) strongly, making the latter its principal ligand. As in humans, murine NK and NKT cells…

    A limitation to antitumor immunity is the dysfunction of T cells in the tumor microenvironment, in part due to upregulation of coinhibitory receptors such as PD-1. Here, we describe that poliovirus receptor–related immunoglobulin domain protein (PVRIG) acts as a coinhibitory receptor in mice. Murine PVRIG interacted weakly with poliovirus receptor (PVR) but bound poliovirus receptor–like 2 (PVRL2) strongly, making the latter its principal ligand. As in humans, murine NK and NKT cells constitutively expressed PVRIG. However, when compared with humans, less PVRIG transcript and surface protein was detected in murine CD8+ T cells ex vivo. However, activated CD8+ T cells upregulated PVRIG expression. In the mouse tumor microenvironment, infiltrating CD8+ T cells expressed PVRIG whereas its ligand, PVRL2, was detected predominantly on myeloid cells and tumor cells, mirroring the expression pattern in human tumors. PVRIG-deficient mouse CD8+ T cells mounted a stronger antigen-specific effector response compared with wild-type CD8+ T cells during acute Listeria monocytogenes infection. Furthermore, enhanced CD8+ T-cell effector function inhibited tumor growth in PVRIG−/− mice compared with wild-type mice and PD-L1 blockade conferred a synergistic antitumor response in PVRIG−/− mice. Therapeutic intervention with antagonistic anti-PVRIG in combination with anti–PD-L1 reduced tumor growth. Taken together, our results suggest PVRIG is an inducible checkpoint receptor and that targeting PVRIG–PVRL2 interactions results in increased CD8+ T-cell function and reduced tumor growth.

    אַחֵר הכותבים
    • Benjamin Murter
    ראה פרסום

  • Fine Tuning of a Type 1 Interferon Antagonist

    PLOS one

    Type I interferons are multi-potent cytokines that serve as first line of defense against viruses and other pathogens, posses immunomudolatory functions and elicit a growth inhibitory response. In recent years it has been shown that interferons are also detrimental, for example in lupus, AIDS, tuberculosis and cognitive decline, highlighted the need to develop interferon antagonists. We have previously developed the antagonist IFN-1ant, with much reduced binding to the IFNAR1 receptor and…

    Type I interferons are multi-potent cytokines that serve as first line of defense against viruses and other pathogens, posses immunomudolatory functions and elicit a growth inhibitory response. In recent years it has been shown that interferons are also detrimental, for example in lupus, AIDS, tuberculosis and cognitive decline, highlighted the need to develop interferon antagonists. We have previously developed the antagonist IFN-1ant, with much reduced binding to the IFNAR1 receptor and enhanced binding to IFNAR2. Here, we further tune the IFN-1ant by producing three additional antagonists based on IFN-1ant but with altered activity profiles. We show that in all three cases the antiproliferative activity of interferons is blocked and the induction of gene transcription of immunomudolatory and antiproliferative associated genes are substantially decreased. Conversely, each of the new antagonists elicits a different degree of antiviral response, STAT phosphorylation and related gene induction. Two of the new antagonists promote decreased activity in relation to the original IFN-1ant, while one of them promotes increased activity. As we do not know the exact causes of the detrimental effects of IFNs, the four antagonists that were produced and analyzed provide the opportunity to investigate the extent of antagonistic and agonistic activity optimal for a given condition.

    אַחֵר הכותבים
    ראה פרסום

  • Type I interferon responses in rhesus macaques prevent SIV infection and slow disease progression

    Nature

    Inflammation in HIV infection is predictive of non-AIDSmorbidity
    and death1, higher set point plasma virus load2 and virus acquisition3;
    thus, therapeutic agents are in development to reduce its causes and
    consequences. However, inflammation may simultaneously confer
    both detrimental and beneficial effects. This dichotomy is particularly
    applicable to type I interferons (IFN-I) which, while contributing to
    innate control of infection4–10, also provide target cells for the…

    Inflammation in HIV infection is predictive of non-AIDSmorbidity
    and death1, higher set point plasma virus load2 and virus acquisition3;
    thus, therapeutic agents are in development to reduce its causes and
    consequences. However, inflammation may simultaneously confer
    both detrimental and beneficial effects. This dichotomy is particularly
    applicable to type I interferons (IFN-I) which, while contributing to
    innate control of infection4–10, also provide target cells for the virus
    during acute infection, impairCD4T-cell recovery, and are associated
    with disease progression6,7,11–19.Herewe manipulated IFN-I signalling
    in rhesus macaques (Macaca mulatta) during simian immunodeficiency
    virus (SIV) transmission and acute infection with two complementary
    in vivo interventions. We show that blockade of the IFN-I
    receptor caused reduced antiviral gene expression, increased SIV reservoir
    size and accelerated CD4 T-cell depletion with progression to
    AIDS despite decreased T-cell activation. In contrast, IFN-a2a administration
    initially upregulated expression of antiviral genes and prevented
    systemic infection. However, continued IFN-a2a treatment
    induced IFN-I desensitization and decreased antiviral gene expression,
    enabling infection with increased SIV reservoir size and accelerated
    CD4 T-cell loss. Thus, the timing of IFN-induced innate responses in
    acute SIV infection profoundly affects overall disease course and outweighs
    the detrimental consequences of increased immune activation.
    Yet, the clinical consequences of manipulation of IFN signalling are
    difficult to predict in vivo and therapeutic interventions in human
    studies should be approached with caution.

    אַחֵר הכותבים

  • Multifaceted Activities of Type I Interferon Are Revealed by a Receptor Antagonist

    Science signaling

    Type I interferons (IFNs), including various IFN-α isoforms and IFN-β, are a family of homologous, multifunctional cytokines. IFNs activate different cellular responses by binding to a common receptor that consists of two subunits, IFNAR1 and IFNAR2. In addition to stimulating antiviral responses, they also inhibit cell proliferation and modulate other immune responses. We characterized various IFNs, including a mutant IFN-α2 (IFN-1ant) that bound tightly to IFNAR2 but had markedly reduced…

    Type I interferons (IFNs), including various IFN-α isoforms and IFN-β, are a family of homologous, multifunctional cytokines. IFNs activate different cellular responses by binding to a common receptor that consists of two subunits, IFNAR1 and IFNAR2. In addition to stimulating antiviral responses, they also inhibit cell proliferation and modulate other immune responses. We characterized various IFNs, including a mutant IFN-α2 (IFN-1ant) that bound tightly to IFNAR2 but had markedly reduced binding to IFNAR1. Whereas IFN-1ant stimulated antiviral activity in a range of cell lines, it failed to elicit immunomodulatory and antiproliferative activities. The antiviral activities of the various IFNs tested depended on a set of IFN-sensitive genes (the "robust" genes) that were controlled by canonical IFN response elements and responded at low concentrations of IFNs. Conversely, these elements were not found in the promoters of genes required for the antiproliferative responses of IFNs (the "tunable" genes). The extent of expression of tunable genes was cell type–specific and correlated with the magnitude of the antiproliferative effects of the various IFNs. Although IFN-1ant induced the expression of robust genes similarly in five different cell lines, its antiviral activity was virus- and cell type–specific. Our findings suggest that IFN-1ant may be a therapeutic candidate for the treatment of specific viral infections without inducing the immunomodulatory and antiproliferative functions of wild-type IFN.

    אַחֵר הכותבים
    • William M. Schneider
    • Hans-Heinrich Hoffmann
    • Ganit Yarden
    • Ohad Manor
    • Nanaocha Sharma
    • Charles M. Rice
    • Gideon Schreiber

  • Chloroplast β chaperonins from A. thaliana function with endogenous cpn10 homologs in vitro

    Plant Molecular biology

    The involvement of type I chaperonins in bacterial and organellar protein folding has been well-documented. In E. coli and mitochondria, these ubiquitous and highly conserved proteins form chaperonin oligomers of identical 60 kDa subunits (cpn60), while in chloroplasts, two distinct cpn60 α and β subunit types co-exist together. The primary sequence of α and β subunits is ~50% identical, similar to their respective homologies to the bacterial GroEL. Moreover, the A. thaliana genome contains two…

    The involvement of type I chaperonins in bacterial and organellar protein folding has been well-documented. In E. coli and mitochondria, these ubiquitous and highly conserved proteins form chaperonin oligomers of identical 60 kDa subunits (cpn60), while in chloroplasts, two distinct cpn60 α and β subunit types co-exist together. The primary sequence of α and β subunits is ~50% identical, similar to their respective homologies to the bacterial GroEL. Moreover, the A. thaliana genome contains two α and four β genes. The functional significance of this variability in plant chaperonin proteins has not yet been elucidated. In order to gain insight into the functional variety of the chloroplast chaperonin family members, we reconstituted β homo-oligomers from A. thaliana following their expression in bacteria and subjected them to a structure-function analysis. Our results show for the first time, that A. thaliana β homo-oligomers can function in vitro with authentic chloroplast co-chaperonins (ch-cpn10 and ch-cpn20). We also show that oligomers made up of different β subunit types have unique properties and different preferences for co-chaperonin partners. We propose that chloroplasts may contain active β homo-oligomers in addition to hetero-oligomers, possibly reflecting a variety of cellular roles.

    אַחֵר הכותבים
    • Anna Vitlin... Doron Levin... Abdussalam Azem
    ראה פרסום

  • Structural Linkage between Ligand Discrimination and Receptor Activation by Type I Interferons

    Cell

    Type I Interferons (IFNs) are important cytokines for innate immunity against viruses and cancer. Sixteen human type I IFN variants signal through the same cell-surface receptors, IFNAR1 and IFNAR2, yet they can evoke markedly different physiological effects. The crystal structures of two human type I IFN ternary signaling complexes containing IFNα2 and IFNω reveal recognition modes and heterotrimeric architectures that are unique among the cytokine receptor superfamily but conserved between…

    Type I Interferons (IFNs) are important cytokines for innate immunity against viruses and cancer. Sixteen human type I IFN variants signal through the same cell-surface receptors, IFNAR1 and IFNAR2, yet they can evoke markedly different physiological effects. The crystal structures of two human type I IFN ternary signaling complexes containing IFNα2 and IFNω reveal recognition modes and heterotrimeric architectures that are unique among the cytokine receptor superfamily but conserved between different type I IFNs. Receptor-ligand cross-reactivity is enabled by conserved receptor-ligand “anchor points” interspersed among ligand-specific interactions that “tune” the relative IFN-binding affinities, in an apparent extracellular “ligand proofreading” mechanism that modulates biological activity. Functional differences between IFNs are linked to their respective receptor recognition chemistries, in concert with a ligand-induced conformational change in IFNAR1, that collectively control signal initiation and complex stability, ultimately regulating differential STAT phosphorylation profiles, receptor internalization rates, and downstream gene expression patterns.

    אַחֵר הכותבים
    • Christoph Thomas, Ignacio Moraga, Doron Levin...
    • Jacob Piehler, Gideon Schreiber, K. Christopher Garcia
    ראה פרסום

  • Stochastic receptor expression determines cell fate upon interferon treatment.

    Molecular and Cellular biology

    Type I interferons trigger diverse biological effects by binding a common receptor, composed of IFNAR1 and IFNAR2. Intriguingly, while the activation of an antiviral state is common to all cells, antiproliferative activity and apoptosis affect only part of the population, even when cells are stimulated with saturating interferon concentrations. Manipulating receptor expression by different small interfering RNA (siRNA) concentrations reduced the fraction of responsive cells independent of the…

    Type I interferons trigger diverse biological effects by binding a common receptor, composed of IFNAR1 and IFNAR2. Intriguingly, while the activation of an antiviral state is common to all cells, antiproliferative activity and apoptosis affect only part of the population, even when cells are stimulated with saturating interferon concentrations. Manipulating receptor expression by different small interfering RNA (siRNA) concentrations reduced the fraction of responsive cells independent of the interferon used, including a newly generated, extremely tight-binding variant. Reduced receptor numbers increased 50% effective concentrations (EC(50)s) for alpha interferon 2 (IFN-α2) but not for the tight-binding variant. A correlation between receptor numbers, STAT activation, and gene induction is observed. Our data suggest that for a given cell, the response is binary (+/-) and dependent on the stochastic expression levels of the receptors on an individual cell. A low number of receptors suffices for antiviral response and is thus a robust feature common to all cells. Conversely, a high number of receptors is required for antiproliferative activity, which allows for fine-tuning on a single-cell level.

    אַחֵר הכותבים
    ראה פרסום

כבוד ופרסים

  • BSc Scholarship for outstanding students.

    -

    2004-2006

  • Dean's honor list, Faculty of Life Sciences, Tel Aviv University.

    -

    2005-2007

  • Elad Grenadir Memorial Scholarship for outstanding students.

    -

    2006

  • Summa cum lauda

    Tel Aviv University

שפות

  • English

    מיומנות מקצועי מלאה

  • Hebrew

    מיומנות שפת אם או דו-לשונית

עוד פעילות על ידי Doron

הצג Doron את הפרופיל המלא

  • ראה את מי שאתה מכיר במשותף
  • הכירו
  • צור קשר Doron ישירות
הצטרפו נוף הפרופיל המלא

פרופילים דומים אחרים

גלה פוסטים נוספים

שמות אחרים Doron Levin ב Israel

17 Doron Levin שמות אחרים מופיעים Israel ב-לינקדאין

הצג/י אנשים אחרים בשם Doron Levin

הוסף כישורים חדשים עם קורסים אלה

הצג את כל הקורסים