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    Abraham Louis Brass MD, PhD

    TitleAssistant Professor
    InstitutionUniversity of Massachusetts Medical School
    DepartmentMicrobiology and Physiological Systems
    AddressUniversity of Massachusetts Medical School
    368 Plantation Street, AS8-2055
    Worcester MA 01605
    Phone508-856-4059
      Other Positions
      InstitutionUMMS - Graduate School of Biomedical Sciences
      DepartmentImmunology and Virology

      InstitutionUMMS - Graduate School of Biomedical Sciences
      DepartmentMolecular Genetics and Microbiology

        Biography 
        awards and honors
        Charles H. Hood Foundation2010 - 2012Child Health Research Award
        Burroughs Wellcome Fund2013 - 2018Investigators in the Pathogenesis of Infectious Disease
        Overview 
        Narrative

        Viruses exploit host factors to replicate. However, each of these interactions also represents a viral weakness that may be targeted to combat infection. Functional genomics represents a powerful methodology for uncovering such viral dependency factors. By combining the human genome sequencing project and the technology of RNAi, we can specifically deplete each human gene product, and subsequently test if loss of that factor impacts viral replication. Combined with proteomics, as well as conventional molecular genetic and biochemical approaches, functional genomics promises to greatly increase our knowledge of host-viral interactions, and further our goal of alleviating human suffering by defeating these pathogens.

        We are currently applying these strategies to studying the pathogenesis of human immunodeficiency virus (HIV-1), hepatitis C virus (HCV), and most recently influenza A virus, revealing not only key host components which are co-opted by invading viruses, but also native host genes (e.g., the IFITM family) which confer a baseline level of resistance to influenza, as well as other devastating viruses.

          

        http://www.bbc.co.uk/news/health-25034524

        http://www.the-scientist.com/?articles.view/articleNo/38414/title/Antifungal-Permits-Flu-/

        https://www.microbemagazine.org/images/New%20Folder/Feb2014/znw00214000048.pdf

        The IFITMs inhibit influenza A virus (IAV) replication in vitro and in vivo. In this study, we establish that amphotericin B (AmphoB), an antifungal heptaen, disrupts IFITM3-mediated restriction of IAV consequently improving IAV replication. Mechanistic studies determined that IFITM1 decreases membrane fluidity and may underlie the mechanism of IFITM-mediated restriction as well as its abolishment by AmphoB.  Mice treated with AmBisome, a clinical preparation of AmphoB, had an increased mortality rate when infected with IAV compared to controls. Therefore, patients receiving treatment with AmBisome may be immunocompromised and more vulnerable to IFITM3-restricted viruses.  

        Schematic representation of the screen. Arrayed pools of siRNAs were transfected into TZM-bl cells in a 384-well format. After 72 hours, HIV-IIIB virus was added, and 48 hours after infection, cultured supernatant was removed and added to fresh TZM-bl cells. In part one, 48 hours after infection, the siRNA transfected cells were fixed, permeabilized, stained, and imaged for HIV p24 protein and DNA. In part two, cells were cultured for 24 hours after the addition of supernatant, then analysed, exposed to a luminescent b-Gal substrate, and relative light units (RLU) recorded. From Fig. 1A, Brass et al. Science, 2008. 

         

        The results of the screen are shown with the siRNA SMARTpools ranked in order of average Z score, from lowest (decreased infection) to highest (increased infection). The position of known influenza A virus-host factors and several newly identified genes from the screen are indicated. From Fig. 1C, Brass et al. Cell, 2009.

         

        Immunofluorescence images showing the block to HIV infection with loss of TNPO3. Cells were treated as described in (B), with either the luciferase (Luc), negative control siRNA; or TNPO3, siRNA #8 targeting TNPO3. “Merge” denotes the combined image for nuclei (blue) and HIV p24 (green). From Fig. 3H, Brass et al. Science, 2008..

         

        A549 or U2OS cells stably overexpressing IFITM3 protein or vector alone were infected with influenza A H1N1 WSN/33. Twelve hours later, cells were fixed and stained for surface HA expression. Values represent the mean ± SD, n = 3 (green: HA, blue: nuclei; 43). From Fig. 4C, Brass et al. Cell, 2009.
         

        Localization of IFITM3 in A549 cells stably overexpressing IFITM3 protein, by confocal microscopy



        Rotation Projects
        no student rotations are available


        Bibliographic 
        selected publications
        List All   |   Timeline
        1. Desai TM, Marin M, Chin CR, Savidis G, Brass AL, Melikyan GB. IFITM3 Restricts Influenza A Virus Entry by Blocking the Formation of Fusion Pores following Virus-Endosome Hemifusion. PLoS Pathog. 2014 Apr; 10(4):e1004048.
          View in: PubMed
        2. Gaiha GD, Brass AL. Immunology. The fiery side of HIV-induced T cell death. Science. 2014 Jan 24; 343(6169):383-4.
          View in: PubMed
        3. Xiaofei E, Savidis G, Chin CR, Wang S, Lu S, Brass AL, Kowalik TF. A Novel DDB2-ATM Feedback Loop Regulates Human Cytomegalovirus Replication. J Virol. 2013 Dec 11.
          View in: PubMed
        4. Lin TY, Chin CR, Everitt AR, Clare S, Perreira JM, Savidis G, Aker AM, John SP, Sarlah D, Carreira EM, Elledge SJ, Kellam P, Brass AL. Amphotericin B Increases Influenza A Virus Infection by Preventing IFITM3-Mediated Restriction. Cell Rep. 2013 Nov 20.
          View in: PubMed
        5. Perreira JM, Chin CR, Feeley EM, Brass AL. IFITMs Restrict the Replication of Multiple Pathogenic Viruses. J Mol Biol. 2013 Sep 25.
          View in: PubMed
        6. Lin TY, Brass AL. Host genetic determinants of influenza pathogenicity. Curr Opin Virol. 2013 Oct; 3(5):531-6.
          View in: PubMed
        7. John SP, Chin CR, Perreira JM, Feeley EM, Aker AM, Savidis G, Smith SE, Elia AE, Everitt AR, Vora M, Pertel T, Elledge SJ, Kellam P, Brass AL. The CD225 Domain of IFITM3 Is Required for both IFITM Protein Association and Inhibition of Influenza A Virus and Dengue Virus Replication. J Virol. 2013 Jul; 87(14):7837-52.
          View in: PubMed
        8. Anafu AA, Bowen CH, Chin CR, Brass AL, Holm GH. Interferon-inducible Transmembrane Protein 3 (IFITM3) Restricts Reovirus Cell Entry. J Biol Chem. 2013 Jun 14; 288(24):17261-71.
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        9. Fusco DN, Brisac C, John SP, Huang YW, Chin CR, Xie T, Zhao H, Zhang L, Chevalier S, Wambua D, Lin W, Peng L, Chung RT, Brass AL. A Genetic Screen Identifies Interferon-a Effector Genes Required to Suppress Hepatitis C Virus Replication. Gastroenterology. 2013 Feb 22.
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        10. Waheed AA, Brass AL, Gummuluru S, Tachedjian G. Host-pathogen interactions of retroviruses. Mol Biol Int. 2012; 2012:648512.
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        11. Zhu J, Gaiha GD, John SP, Pertel T, Chin CR, Gao G, Qu H, Walker BD, Elledge SJ, Brass AL. Reactivation of Latent HIV-1 by Inhibition of BRD4. Cell Rep. 2012 Oct 25; 2(4):807-16.
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        12. Chin CR, Brass AL. A genome wide RNA interference screening method to identify host factors that modulate Influenza A virus replication. Methods. 2013 Feb; 59(2):217-24.
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        13. Cho JL, Roche MI, Sandall B, Brass AL, Seed B, Xavier RJ, Medoff BD. Enhanced tim3 activity improves survival after influenza infection. J Immunol. 2012 Sep 15; 189(6):2879-89.
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        14. Everitt AR, Clare S, Pertel T, John SP, Wash RS, Smith SE, Chin CR, Feeley EM, Sims JS, Adams DJ, Wise HM, Kane L, Goulding D, Digard P, Anttila V, Baillie JK, Walsh TS, Hume DA, Palotie A, Xue Y, Colonna V, Tyler-Smith C, Dunning J, Gordon SB. IFITM3 restricts the morbidity and mortality associated with influenza. Nature. 2012 Apr 26; 484(7395):519-23.
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        15. Valle-Casuso JC, Di Nunzio F, Yang Y, Reszka N, Lienlaf M, Arhel N, Perez P, Brass AL, Diaz-Griffero F. TNPO3 Is Required for HIV-1 Replication after Nuclear Import but prior to Integration and Binds the HIV-1 Core. J Virol. 2012 May; 86(10):5931-6.
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        16. Soghoian DZ, Jessen H, Flanders M, Sierra-Davidson K, Cutler S, Pertel T, Ranasinghe S, Lindqvist M, Davis I, Lane K, Rychert J, Rosenberg ES, Piechocka-Trocha A, Brass AL, Brenchley JM, Walker BD, Streeck H. HIV-Specific Cytolytic CD4 T Cell Responses During Acute HIV Infection Predict Disease Outcome. Sci Transl Med. 2012 Feb 29; 4(123):123ra25.
          View in: PubMed
        17. Feeley EM, Sims JS, John SP, Chin CR, Pertel T, Chen LM, Gaiha GD, Ryan BJ, Donis RO, Elledge SJ, Brass AL. IFITM3 inhibits influenza A virus infection by preventing cytosolic entry. PLoS Pathog. 2011 Oct; 7(10):e1002337.
          View in: PubMed
        18. Buzon MJ, Seiss K, Weiss R, Brass AL, Rosenberg ES, Pereyra F, Yu XG, Lichterfeld M. Inhibition of HIV-1 integration in ex vivo-infected CD4 T cells from elite controllers. J Virol. 2011 Sep; 85(18):9646-50.
          View in: PubMed
        19. Chen H, Li C, Huang J, Cung T, Seiss K, Beamon J, Carrington MF, Porter LC, Burke PS, Yang Y, Ryan BJ, Liu R, Weiss RH, Pereyra F, Cress WD, Brass AL, Rosenberg ES, Walker BD, Yu XG, Lichterfeld M. CD4+ T cells from elite controllers resist HIV-1 infection by selective upregulation of p21. J Clin Invest. 2011 Apr 1; 121(4):1549-60.
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        20. Huang IC, Bailey CC, Weyer JL, Radoshitzky SR, Becker MM, Chiang JJ, Brass AL, Ahmed AA, Chi X, Dong L, Longobardi LE, Boltz D, Kuhn JH, Elledge SJ, Bavari S, Denison MR, Choe H, Farzan M. Distinct patterns of IFITM-mediated restriction of filoviruses, SARS coronavirus, and influenza A virus. PLoS Pathog. 2011; 7(1):e1001258.
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        21. Singh R, Gaiha G, Werner L, McKim K, Mlisana K, Luban J, Walker BD, Karim SS, Brass AL, Ndung'u T. Association of TRIM22 with the Type 1 Interferon Response and Viral Control during Primary HIV-1 Infection. J Virol. 2011 Jan; 85(1):208-16.
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        22. Brass AL, Huang IC, Benita Y, John SP, Krishnan MN, Feeley EM, Ryan BJ, Weyer JL, van der Weyden L, Fikrig E, Adams DJ, Xavier RJ, Farzan M, Elledge SJ. The IFITM proteins mediate cellular resistance to influenza A H1N1 virus, West Nile virus, and dengue virus. Cell. 2009 Dec 24; 139(7):1243-54.
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        23. Li Q, Brass AL, Ng A, Hu Z, Xavier RJ, Liang TJ, Elledge SJ. A genome-wide genetic screen for host factors required for hepatitis C virus propagation. Proc Natl Acad Sci U S A. 2009 Sep 22; 106(38):16410-5.
          View in: PubMed
        24. Zhang L, Lee SY, Beznoussenko GV, Peters PJ, Yang JS, Gilbert HY, Brass AL, Elledge SJ, Isaacs SN, Moss B, Mironov A, Hsu VW. A role for the host coatomer and KDEL receptor in early vaccinia biogenesis. Proc Natl Acad Sci U S A. 2009 Jan 6; 106(1):163-8.
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        25. Krishnan MN, Ng A, Sukumaran B, Gilfoy FD, Uchil PD, Sultana H, Brass AL, Adametz R, Tsui M, Qian F, Montgomery RR, Lev S, Mason PW, Koski RA, Elledge SJ, Xavier RJ, Agaisse H, Fikrig E. RNA interference screen for human genes associated with West Nile virus infection. Nature. 2008 Sep 11; 455(7210):242-5.
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        26. Brass AL, Dykxhoorn DM, Benita Y, Yan N, Engelman A, Xavier RJ, Lieberman J, Elledge SJ. Identification of host proteins required for HIV infection through a functional genomic screen. Science. 2008 Feb 15; 319(5865):921-6.
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        27. Escalante CR, Brass AL, Pongubala JM, Shatova E, Shen L, Singh H, Aggarwal AK. Crystal structure of PU.1/IRF-4/DNA ternary complex. Mol Cell. 2002 Nov; 10(5):1097-105.
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        28. Escalante CR, Shen L, Escalante MC, Brass AL, Edwards TA, Singh H, Aggarwal AK. Crystallization and characterization of PU.1/IRF-4/DNA ternary complex. J Struct Biol. 2002 Jul; 139(1):55-9.
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        29. Brass AL, Zhu AQ, Singh H. Assembly requirements of PU.1-Pip (IRF-4) activator complexes: inhibiting function in vivo using fused dimers. EMBO J. 1999 Feb 15; 18(4):977-91.
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        30. Brass AL, Kehrli E, Eisenbeis CF, Storb U, Singh H. Pip, a lymphoid-restricted IRF, contains a regulatory domain that is important for autoinhibition and ternary complex formation with the Ets factor PU.1. Genes Dev. 1996 Sep 15; 10(18):2335-47.
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        31. Brass AL, Barnard J, Patai BL, Salvi D, Rukstalis DB. Androgen up-regulates epidermal growth factor receptor expression and binding affinity in PC3 cell lines expressing the human androgen receptor. Cancer Res. 1995 Jul 15; 55(14):3197-203.
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