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    Neal S Silverman PhD

    TitleProfessor
    InstitutionUniversity of Massachusetts Medical School
    DepartmentMedicine
    AddressUniversity of Massachusetts Medical School
    364 Plantation Street, LRB-313
    Worcester MA 01605
    Phone508-856-5826
      Other Positions
      InstitutionUMMS - School of Medicine
      DepartmentMicrobiology and Physiological Systems

      InstitutionUMMS - Graduate School of Biomedical Sciences
      DepartmentImmunology and Virology

      InstitutionUMMS - Graduate School of Biomedical Sciences
      DepartmentInterdisciplinary Graduate Program

      InstitutionUMMS - Graduate School of Biomedical Sciences
      DepartmentMD/PhD Program

      InstitutionUMMS - Graduate School of Biomedical Sciences
      DepartmentMolecular Genetics and Microbiology

      InstitutionUMMS - Graduate School of Biomedical Sciences
      DepartmentTranslational Science

      InstitutionUMMS - Programs, Centers and Institutes
      DepartmentBioinformatics and Integrative Biology

      InstitutionUMMS - Programs, Centers and Institutes
      DepartmentCenter for AIDS Research

        Biography 
        awards and honors
        1989 - 1989B.A., UC Berkeley, Molecular Biology
        1996 - 1996Ph.D., MIT, Biology
        1999Helen Hay Whitney Fellow
        Harvard University2001Postdoctoral Fellow, Department of Molecular and Cellular Biology
        2006 - 2006GSBS Faculty Achievement Award for Outstanding Contributions in the Classroom Settings
        2006 - 2006Presidential Early Career Award for Scientists and Engineers (PECASE).
        2007Ellison Foundation Young Investigator in Global Pathogenesis
        2007 - 2007GSBS Faculty Achievement Award for outstanding contributions to curriculum development
        2010 - 2010Dean’s Award for outstanding contribution to graduate education
        2012Burroughs Welcome Fund, Investigator in Pathogenesis of Infectious Disease
        Overview 
        Narrative

        Immune Signaling Pathways

        Dr. Neal SilvermanThe main goal of our lab is to decipher the molecular mechanisms responsible for transmitting a signal from the site of infection to the nucleus of an immune responsive cell. We are interested in how pathogens are distinguished, how related signaling pathways maintain specificity, and how various signals are integrated to produce the proper response. Research will focus on the immune response of the experimentally powerful fruit fly, Drosophila melanogaster. We are particularly interested in the mechanisms used in Drosophila that allow distinct pathogenic challenges to lead to specific immune responses by activating different signaling pathways and transcription factors. The immune signaling pathways in Drosophila have much in common with the pathways required for the activation of the mammalian innate immune response. In fact, the Toll-like receptor (TLR) family, which was discovered in Drosophila, plays a central role in pathogen recognition in both mammals and insects. A deeper understanding of these pathways in insects will undoubtedly lead to further advances in related mammalian fields.

        The Drosophila antibacterial signaling pathway
        The Drosophila antibacterial
        signaling pathway

        In flies, infection causes the rapid production of a host of powerful antimicrobial peptides that are produced in the fat body (the insect liver) and ciruculate throughout the body. Pathogens are known to activate two separate and specific immune response signaling pathways, an antibacterial and an antifungal pathway, each of which culminates in the activation of different Drosophila NF-kB transcription factors. Fungal infection leads to the activation of Toll, which initiates a signal transduction cascade leading to the proteasome-mediated degradation of Cactus (the fly IkB), the nuclear translocation of two Drosophila NF-kB transcription factors, Dif and Dorsal, and the rapid expression of antifungal peptide genes. The Toll signaling pathway is also essential for the dorsoventral patterning of the developing embryo. The third Drosophila NF-kB protein, Relish, is required for antibacterial immunity. Relish is initially synthesized as a bipartite protein with an N-terminal NF-kB-like domain and C-terminal IkB-like domain, which inhibits its own nuclear translocation. Upon infection Relish is cleaved, freeing the NF-kB module to translocate to the nucleus where it activates antibacterial peptide gene expression.

        Our lab is focused upon understanding the molecular mechanisms responsible for the activation of these two NF-kB pathways during the insect immune response. The antibacterial pathway, which is controlled by Relish, requires the Drosophila IkB kinase complex (IKK), a high molecular weight complex which contains a catalytic subunit, DmIKKb, and regulatory subunit, DmIKKg. Upon infection, the Drosophila IKK complex is activated and is required for the cleavage (and activation) of Relish. We are interested to know what lies upstream of the Drosophila IKK complex, what receptors are used to recognize pathogens and how does activation of these receptors, in turn, lead to the activation of the IKK complex. The mechanism of DmIKK-stimulated Relish cleavage is also a major focus in the laboratory.

        The <i>Drosophila</i > Toll/antifungal signaling 
pathway
        The Drosophila Toll/antifungal
        signaling pathway

        The antifungal pathway, which relies on the classic Toll signaling pathway, is also a focus of our research. Although we know a great deal about this signaling pathway, many important questions remain. In particular, we are interested in mechanisms of signal-induced Cactus degradation. Like mammalian IkBs, Cactus is phosphorylated upon signaling and this signaling leads to its proteasome mediated degradation. However, unlike IkB, Cactus degradation does not require the IKK complex, and the identity of the Cactus kinase is currently unknown.

        Our goal is to uncover the molecular mechanism used by the innate immune system to recognize dangerous microbes and to rapidly mount a potent and specific response against them. Using Drosophila, with its powerful genetic, molecular, and biochemical tools, will enable us to gain a thorough understanding of the signal transduction pathways used by eukaryotes to fend-off their adversaries. This research has potential medical benefits beyond its primary goal of basic scientific understanding. A deeper understanding of the insect immune response will enable the design of new methods to combat the spread of infectious microbes by insects. Moreover, the similarities between the insect immune response and mammalian innate immunity will open-up new and exciting avenues of research into the mechanisms which control our more complicated immune response.

        Also Vist: The Silverman Lab



        Rotation Projects

        Rotation Projects

        Intro:

        Like us, insects recognize pathogenic microorganisms andrespond with potent antimicrobial defenses.  Insects have only a primitiveimmune system which relies solely on germline encoded receptors to recognizevarious microbial derived substances.  Mammals have similar system, known asthe innate immune response, that plays a critical role in recognizing dangerouspathogens and activating the more complicated adaptive immune responseinvolving antigen presentations and T- and B-cell receptors.  Insect andmammalian innate immunity have much in common.  For example, they both use theNF-kB /Rel family of transcriptionfactors to rapidly activate immune inducible gene expression.  Drosophila hasthree NF-kB homologs, all of which areinvolved in immunity.  One Drosophila NF-kB,known as Relish, is activated by proteolytic cleavage in response to infectionwith gram-negative bacteria.  The other two NF-kB homologs, Dorsal and Dif, are activated during a fungal (or gram postivebacterial) infection when their inhibitor, known as Cactus (IkB) is degraded.  The focus of the lab is tounderstand the underlying molecular mechanisms responsible for activation ofspecific NF-kB transcription factors inresponse to different pathogens.

        1. Goal:  To examine the role of all seven Drosophila caspase proteases in the activation of immunity.  Relish is activated by caspase-mediated proteolysis, but the protease that cleaves Relish is not yet identified. This experiment will use RNAi to inhibit caspase gene function in an immune responsive Drosophila cell line, followed by analysis of the immune-inducible gene expression.  This project is designed to identify which caspase proteases are required for Relish activation.  Further experiments will be designed to demonstrate the direct cleavage of Relish by caspase proteases.


        2. Goal:  Genome wide analysis of the insect immune response.  In this project we will utilize Drosophila cDNA microarrays to study the changes in gene expression induced by immunostimulatory molecules.  In particular, we will analyze the activity of various microbial derived products to illicit specific immune responses. Also, we will examine if the role of different signaling pathways in the immune response, especially the JNK and NF-kB signaling pathways.


        3. Goal:  To genetically characterize the function of the second Drosophila IKK homolog, IKKe.  The function of human and Drosophila IKKe remains controversial.  Drosophila IKKe mutants do not survive to adulthood.  This project will focus on studying the role of Drosophila IKKe in the developing embryo, by studying its expression pattern and by making germliine clones.  In the long term, we hope to determine the role, if any, of DmIKKe in the activation of NF-kB family transcription factors in Drosophila.


        4. Goal:  To use Drosophila genetics to understand the pathogenesis of the plague.  In this project, we will establish transgenic flies that express  YopJ, a protein from the plague pathogen Yersinia pestis.  In mammals, YopJ blocks important signaling pathways, such as NF-kB, and thus prevents immune activation.  Although, YopJ has been proposed to be a ubiquitin-like protein protease (ULP), the molecular mechanisms by which YopJ functions are unclear.  We will demonstrate in flies that YopJ blocks immune activation of NF-kB.  Further genetic experiments will be designed to test the possibility that YopJ acts as a ULP.  Ultimately, forward genetic screens will be performed to identify genes required for YopJ function.


        Bibliographic 
        selected publications
        List All   |   Timeline
        1. Kim CH, Paik D, Rus F, Silverman N. The Caspase-8 Homolog Dredd Cleaves Imd and Relish but Is Not Inhibited by p35. J Biol Chem. 2014 Jul 18; 289(29):20092-101.
          View in: PubMed
        2. Gupta R, Ghosh S, Monks B, DeOliveira RB, Tzeng TC, Kalantari P, Nandy A, Bhattacharjee B, Chan J, Ferreira F, Rathinam V, Sharma S, Lien E, Silverman N, Fitzgerald K, Firon A, Trieu-Cuot P, Henneke P, Golenbock DT. RNA and ß-Hemolysin of Group B Streptococcus Induce Interleukin-1ß (IL-1ß) by Activating NLRP3 Inflammasomes in Mouse Macrophages. J Biol Chem. 2014 May 16; 289(20):13701-5.
          View in: PubMed
        3. Marinotti O, Cerqueira GC, de Almeida LG, Ferro MI, Loreto EL, Zaha A, Teixeira SM, Wespiser AR, Almeida E Silva A, Schlindwein AD, Pacheco AC, Silva AL, Graveley BR, Walenz BP, Lima Bde A, Ribeiro CA, Nunes-Silva CG, de Carvalho CR, Soares CM, de Menezes CB, Matiolli C, Caffrey D, Araújo DA, de Oliveira DM, Golenbock D, Grisard EC, Fantinatti-Garboggini F, de Carvalho FM, Barcellos FG, Prosdocimi F, May G, Azevedo Junior GM, Guimarães GM, Goldman GH, Padilha IQ, Batista Jda S, Ferro JA, Ribeiro JM, Fietto JL, Dabbas KM, Cerdeira L, Agnez-Lima LF, Brocchi M, de Carvalho MO, Teixeira Mde M, Diniz Maia Mde M, Goldman MH, Cruz Schneider MP, Felipe MS, Hungria M, Nicolás MF, Pereira M, Montes MA, Cantão ME, Vincentz M, Rafael MS, Silverman N, Stoco PH, Souza RC, Vicentini R, Gazzinelli RT, Neves Rde O, Silva R, Astolfi-Filho S, Maciel TE, Urményi TP, Tadei WP, Camargo EP, de Vasconcelos AT. The genome of Anopheles darlingi, the main neotropical malaria vector. Nucleic Acids Res. 2013 Aug; 41(15):7387-400.
          View in: PubMed
        4. Kleino A, Silverman N. The Drosophila IMD pathway in the activation of the humoral immune response. Dev Comp Immunol. 2014 Jan; 42(1):25-35.
          View in: PubMed
        5. Rus F, Flatt T, Tong M, Aggarwal K, Okuda K, Kleino A, Yates E, Tatar M, Silverman N. Ecdysone triggered PGRP-LC expression controls Drosophila innate immunity. EMBO J. 2013 May 29; 32(11):1626-38.
          View in: PubMed
        6. Bossaller L, Chiang PI, Schmidt-Lauber C, Ganesan S, Kaiser WJ, Rathinam VA, Mocarski ES, Subramanian D, Green DR, Silverman N, Fitzgerald KA, Marshak-Rothstein A, Latz E. Cutting edge: FAS (CD95) mediates noncanonical IL-1ß and IL-18 maturation via caspase-8 in an RIP3-independent manner. J Immunol. 2012 Dec 15; 189(12):5508-12.
          View in: PubMed
        7. Paquette N, Conlon J, Sweet C, Rus F, Wilson L, Pereira A, Rosadini CV, Goutagny N, Weber AN, Lane WS, Shaffer SA, Maniatis S, Fitzgerald KA, Stuart L, Silverman N. Serine/threonine acetylation of TGFß-activated kinase (TAK1) by Yersinia pestis YopJ inhibits innate immune signaling. Proc Natl Acad Sci U S A. 2012 Jul 31; 109(31):12710-5.
          View in: PubMed
        8. Kleino A, Silverman N. UnZIPping mechanisms of effector-triggered immunity in animals. Cell Host Microbe. 2012 Apr 19; 11(4):320-2.
          View in: PubMed
        9. Rus F, Morlock K, Silverman N, Pham N, Kotwal GJ, Marshall WL. Characterization of poxvirus-encoded proteins that regulate innate immune signaling pathways. Methods Mol Biol. 2012; 890:273-88.
          View in: PubMed
        10. Ganesan S, Aggarwal K, Paquette N, Silverman N. NF-?B/Rel proteins and the humoral immune responses of Drosophila melanogaster. Curr Top Microbiol Immunol. 2011; 349:25-60.
          View in: PubMed
        11. Paquette N, Broemer M, Aggarwal K, Chen L, Husson M, Ertürk-Hasdemir D, Reichhart JM, Meier P, Silverman N. Caspase-mediated cleavage, IAP binding, and ubiquitination: linking three mechanisms crucial for Drosophila NF-kappaB signaling. Mol Cell. 2010 Jan 29; 37(2):172-82.
          View in: PubMed
        12. Ertürk-Hasdemir D, Broemer M, Leulier F, Lane WS, Paquette N, Hwang D, Kim CH, Stöven S, Meier P, Silverman N. Two roles for the Drosophila IKK complex in the activation of Relish and the induction of antimicrobial peptide genes. Proc Natl Acad Sci U S A. 2009 Jun 16; 106(24):9779-84.
          View in: PubMed
        13. Aggarwal K, Rus F, Vriesema-Magnuson C, Ertürk-Hasdemir D, Paquette N, Silverman N. Rudra interrupts receptor signaling complexes to negatively regulate the IMD pathway. PLoS Pathog. 2008; 4(8):e1000120.
          View in: PubMed
        14. Aggarwal K, Silverman N. Positive and negative regulation of the Drosophila immune response. BMB Rep. 2008 Apr 30; 41(4):267-77.
          View in: PubMed
        15. Silverman N, Paquette N. Immunology. The right resident bugs. Science. 2008 Feb 8; 319(5864):734-5.
          View in: PubMed
        16. Aggrawal K, Silverman N. Peptidoglycan recognition in Drosophila. Biochem Soc Trans. 2007 Dec; 35(Pt 6):1496-500.
          View in: PubMed
        17. Sweet CR, Conlon J, Golenbock DT, Goguen J, Silverman N. YopJ targets TRAF proteins to inhibit TLR-mediated NF-kappaB, MAPK and IRF3 signal transduction. Cell Microbiol. 2007 Nov; 9(11):2700-15.
          View in: PubMed
        18. Kaneko T, Yano T, Aggarwal K, Lim JH, Ueda K, Oshima Y, Peach C, Erturk-Hasdemir D, Goldman WE, Oh BH, Kurata S, Silverman N. PGRP-LC and PGRP-LE have essential yet distinct functions in the drosophila immune response to monomeric DAP-type peptidoglycan. Nat Immunol. 2006 Jul; 7(7):715-23.
          View in: PubMed
        19. Ertürk-Hasdemir D, Silverman N. Eater: a big bite into phagocytosis. Cell. 2005 Oct 21; 123(2):190-2.
          View in: PubMed
        20. Puliyanda DP, Silverman NS, Lehman D, Vo A, Bunnapradist S, Radha RK, Toyoda M, Jordan SC. Successful use of oral ganciclovir for the treatment of intrauterine cytomegalovirus infection in a renal allograft recipient. Transpl Infect Dis. 2005 Jun; 7(2):71-4.
          View in: PubMed
        21. Kaneko T, Silverman N. Bacterial recognition and signalling by the Drosophila IMD pathway. Cell Microbiol. 2005 Apr; 7(4):461-9.
          View in: PubMed
        22. Kaneko T, Golenbock D, Silverman N. Peptidoglycan recognition by the Drosophila Imd pathway. J Endotoxin Res. 2005; 11(6):383-9.
          View in: PubMed
        23. Silverman N, Zhou R, Erlich RL, Hunter M, Bernstein E, Schneider D, Maniatis T. Immune activation of NF-kappaB and JNK requires Drosophila TAK1. J Biol Chem. 2003 Dec 5; 278(49):48928-34.
          View in: PubMed
        24. Silverman N. Flies kNOw how to signal. Dev Cell. 2003 Jan; 4(1):5-6.
          View in: PubMed
        25. Silverman NS, Greif A. Influenza vaccination during pregnancy. Patients' and physicians' attitudes. J Reprod Med. 2001 Nov; 46(11):989-94.
          View in: PubMed
        26. Silverman NS, Morgan M, Nichols WS. Candida lusitaniae as an unusual cause of recurrent vaginitis and its successful treatment with intravaginal boric acid. Infect Dis Obstet Gynecol. 2001; 9(4):245-7.
          View in: PubMed
        27. Silverman NS, Morgan M, Nichols WS. Antibiotic resistance patterns of group B streptococcus in antenatal genital cultures. J Reprod Med. 2000 Dec; 45(12):979-82.
          View in: PubMed
        28. Macones GA, Ewing S, Silverman NS. Strategies for prevention of varicella pneumonia: a cost-effectiveness analysis. Infect Dis Obstet Gynecol. 1996; 4(2):71-6.
          View in: PubMed
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