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    Egil Lien PhD

    TitleAssociate Professor
    InstitutionUniversity of Massachusetts Medical School
    DepartmentMedicine
    AddressUniversity of Massachusetts Medical School
    364 Plantation Street, LRB
    Worcester MA 01605
    Phone508-856-5825
      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
      DepartmentMD/PhD Program

      InstitutionUMMS - Graduate School of Biomedical Sciences
      DepartmentMolecular Genetics and Microbiology

        Overview 
        Narrative

        Research Interests:

        Pathogen activation and evasion of innate immune signaling - Inflammasomes and Toll-like Receptors.

        Over the last several years, we have gained a lot of information on how the body defends itself against pathogenic microbes by activation of the innate immune system. This part of the immune system provides the immediate defense against invading bacteria, virus or fungi, and is also able to fine-tune and optimize the subsequent more specialized adaptive immune response.

        My laboratory is primarily focused on understanding the innate immune recognition of pathogens by Toll-like receptors (TLRs) and inflammasomes. Lipopolysaccharide (LPS) from Gram-negative bacteria (also called endotoxin) is particularly interesting, it is a saccharide containing acyl chains (“fatty sugar”). LPS is a main component of the Gram-negative outer membrane, and one of the most potent activators of immune cells. LPS activation of host cells is a double-edged sword: An early sensing of LPS is important for clearance of an initial Gram-negative infection, but high amounts of LPS in circulation during overwhelming bacteremia and sepsis can lead to Gram-negative endotoxic shock and death. Thus, a well timed, balanced and measured host response to LPS is critical in determining outcome of an infection. LPS activates cells via TLR4 and MD-2, but recognition of other microbial components, such as those mediated by inflammasomes, also participates in an optimal host response. Inflammasomes formed in response to microbial compounds typically involve complex formation with NOD-like receptors (NLRs) such as NLRP3, NLRP12 or NLRC4, often an adapter called Asc and inflammatory caspases such as caspase-1. Activation leads to the generation of active caspase and subsequent cleavage of pro-IL-1b and pro-IL-18 into mature IL-1b/IL-18, key cytokines in many inflammatory responses. A number of pathogens may attempt to minimize signaling via TLRs and NLRs, as this may be beneficial from a pathogen point of view. A greater understanding of microbial activation and evasion of innate immunity can lead to new therapies and vaccines against infectious diseases.

        One of the model systems we utilize involves bacteria of the genus Yersiniae, such as Yersinia pestis, the causative agents of plague, and the other human-pathogenic Yersinia, Y. pseudotuberculosis and Y. enterocolitica. Y. pestis, a master of immune evasion, normally produces tetra-acylated LPS with low ability to trigger TLR4 signaling. However, the activation potential can be restored upon the forced generation of a hexa-acylated LPS similar to that found in Y. pseudotuberculosis, and this markedly attenuates Y. pestis in vivo, suggesting a role for evasion of TLR4 signaling in the evolution of high virulence in plague. IL-1b and in particular IL-18 appear to be effective mediators of antibacterial defenses against Y. pestis, and NLR containing inflammasomes participate in optimal IL-18 and IL-1b production. We are also interested in innate immune responses to other pathogens such as Salmonella, Klebsiella, E. coli and cytomegalovirus, and in understanding mechanisms of adjuvant action for Yersinia, HIV-1 and malaria vaccines. Another topic we study is inflammation involved in the development of diabetes and obesity.

        Biography:

        Norwegian Institute of Technology (NTH), M.Sc. 1992

        Norwegian University of Science and Technology (NTNU); Ph.D. 1998

        Boston University/Boston Medical Center; Postdoc 1997-99

        NTNU; Postdoc 1999-2001

        UMass Medical School; Assistant Professor of Medicine, Department of Medicine, Division of Infectious Diseases and Immunology, 2002-2007

        UMass Medical School; Associate Professor of Medicine and Microbiology and Physiological Systems 2007-present

        NTNU; Associate Professor II, 2008-2011

        NTNU; Professor II, 2011-present



        Bibliographic 
        selected publications
        List All   |   Timeline
        1. Buglione-Corbett R, Pouliot K, Marty-Roix R, West K, Wang S, Lien E, Lu S. Serum cytokine profiles associated with specific adjuvants used in a DNA prime-protein boost vaccination strategy. PLoS One. 2013; 8(9):e74820.
          View in: PubMed
        2. Marty-Roix R, Lien E. (De-) oiling inflammasomes. Immunity. 2013 Jun 27; 38(6):1088-90.
          View in: PubMed
        3. Sandanger O, Ranheim T, Vinge LE, Bliksøen M, Alfsnes K, Finsen AV, Dahl CP, Askevold ET, Florholmen G, Christensen G, Fitzgerald KA, Lien E, Valen G, Espevik T, Aukrust P, Yndestad A. The NLRP3 inflammasome is up-regulated in cardiac fibroblasts and mediates myocardial ischaemia-reperfusion injury. Cardiovasc Res. 2013 Jul 1; 99(1):164-74.
          View in: PubMed
        4. Vladimer GI, Marty-Roix R, Ghosh S, Weng D, Lien E. Inflammasomes and host defenses against bacterial infections. Curr Opin Microbiol. 2013 Feb; 16(1):23-31.
          View in: PubMed
        5. Vladimer GI, Weng D, Paquette SW, Vanaja SK, Rathinam VA, Aune MH, Conlon JE, Burbage JJ, Proulx MK, Liu Q, Reed G, Mecsas JC, Iwakura Y, Bertin J, Goguen JD, Fitzgerald KA, Lien E. The NLRP12 Inflammasome Recognizes Yersinia pestis. Immunity. 2012 Jul 27; 37(1):96-107.
          View in: PubMed
        6. Johnsen IB, Nguyen TT, Bergstrøm B, Lien E, Anthonsen MW. Toll-like receptor 3-elicited MAPK activation induces stabilization of interferon-ß mRNA. Cytokine. 2012 Mar; 57(3):337-46.
          View in: PubMed
        7. Husebye H, Aune MH, Stenvik J, Samstad E, Skjeldal F, Halaas O, Nilsen NJ, Stenmark H, Latz E, Lien E, Mollnes TE, Bakke O, Espevik T. The Rab11a GTPase controls Toll-like receptor 4-induced activation of interferon regulatory factor-3 on phagosomes. Immunity. 2010 Oct 29; 33(4):583-96.
          View in: PubMed
        8. Melo MB, Kasperkovitz P, Cerny A, Könen-Waisman S, Kurt-Jones EA, Lien E, Beutler B, Howard JC, Golenbock DT, Gazzinelli RT. UNC93B1 mediates host resistance to infection with Toxoplasma gondii. PLoS Pathog. 2010; 6(8).
          View in: PubMed
        9. Dickinson GS, Piccone H, Sun G, Lien E, Gatto L, Alugupalli KR. Toll-like receptor 2 deficiency results in impaired antibody responses and septic shock during Borrelia hermsii infection. Infect Immun. 2010 Nov; 78(11):4579-88.
          View in: PubMed
        10. Duewell P, Kono H, Rayner KJ, Sirois CM, Vladimer G, Bauernfeind FG, Abela GS, Franchi L, Nuñez G, Schnurr M, Espevik T, Lien E, Fitzgerald KA, Rock KL, Moore KJ, Wright SD, Hornung V, Latz E. NLRP3 inflammasomes are required for atherogenesis and activated by cholesterol crystals. Nature. 2010 Apr 29; 464(7293):1357-61.
          View in: PubMed
        11. He X, Mekasha S, Mavrogiorgos N, Fitzgerald KA, Lien E, Ingalls RR. Inflammation and fibrosis during Chlamydia pneumoniae infection is regulated by IL-1 and the NLRP3/ASC inflammasome. J Immunol. 2010 May 15; 184(10):5743-54.
          View in: PubMed
        12. Zhao H, Leu SW, Shi L, Dedaj R, Zhao G, Garg HG, Shen L, Lien E, Fitzgerald KA, Shiedlin A, Shen H, Quinn DA, Hales CA. TLR4 is a negative regulator in noninfectious lung inflammation. J Immunol. 2010 May 1; 184(9):5308-14.
          View in: PubMed
        13. Nguyen TT, Johnsen IB, Knetter CF, Drabløs F, Fitzgerald KA, Lien E, Anthonsen MW. Differential gene expression downstream of Toll-like receptors (TLRs): role of c-Src and activating transcription factor 3 (ATF3). J Biol Chem. 2010 May 28; 285(22):17011-9.
          View in: PubMed
        14. Meng J, Lien E, Golenbock DT. MD-2-mediated ionic interactions between lipid A and TLR4 are essential for receptor activation. J Biol Chem. 2010 Mar 19; 285(12):8695-702.
          View in: PubMed
        15. Szaba FM, Kummer LW, Wilhelm LB, Lin JS, Parent MA, Montminy-Paquette SW, Lien E, Johnson LL, Smiley ST. D27-pLpxL, an avirulent strain of Yersinia pestis, primes T cells that protect against pneumonic plague. Infect Immun. 2009 Oct; 77(10):4295-304.
          View in: PubMed
        16. Kenzel S, Santos-Sierra S, Deshmukh SD, Moeller I, Ergin B, Fitzgerald KA, Lien E, Akira S, Golenbock DT, Henneke P. Role of p38 and early growth response factor 1 in the macrophage response to group B streptococcus. Infect Immun. 2009 Jun; 77(6):2474-81.
          View in: PubMed
        17. Lien E, Zipris D. The role of Toll-like receptor pathways in the mechanism of type 1 diabetes. Curr Mol Med. 2009 Feb; 9(1):52-68.
          View in: PubMed
        18. Damås JK, Davì G, Jensenius M, Santilli F, Otterdal K, Ueland T, Flo TH, Lien E, Espevik T, Frøland SS, Vitale G, Raoult D, Aukrust P. Relative chemokine and adhesion molecule expression in Mediterranean spotted fever and African tick bite fever. J Infect. 2009 Jan; 58(1):68-75.
          View in: PubMed
        19. Robinson RT, Khader SA, Locksley RM, Lien E, Smiley ST, Cooper AM. Yersinia pestis evades TLR4-dependent induction of IL-12(p40)2 by dendritic cells and subsequent cell migration. J Immunol. 2008 Oct 15; 181(8):5560-7.
          View in: PubMed
        20. Bartholomeu DC, Ropert C, Melo MB, Parroche P, Junqueira CF, Teixeira SM, Sirois C, Kasperkovitz P, Knetter CF, Lien E, Latz E, Golenbock DT, Gazzinelli RT. Recruitment and endo-lysosomal activation of TLR9 in dendritic cells infected with Trypanosoma cruzi. J Immunol. 2008 Jul 15; 181(2):1333-44.
          View in: PubMed
        21. Nilsen NJ, Deininger S, Nonstad U, Skjeldal F, Husebye H, Rodionov D, von Aulock S, Hartung T, Lien E, Bakke O, Espevik T. Cellular trafficking of lipoteichoic acid and Toll-like receptor 2 in relation to signaling: role of CD14 and CD36. J Leukoc Biol. 2008 Jul; 84(1):280-91.
          View in: PubMed
        22. Jain V, Halle A, Halmen KA, Lien E, Charrel-Dennis M, Ram S, Golenbock DT, Visintin A. Phagocytosis and intracellular killing of MD-2 opsonized gram-negative bacteria depend on TLR4 signaling. Blood. 2008 May 1; 111(9):4637-45.
          View in: PubMed
        23. Pouliot K, Pan N, Wang S, Lu S, Lien E, Goguen JD. Evaluation of the role of LcrV-Toll-like receptor 2-mediated immunomodulation in the virulence of Yersinia pestis. Infect Immun. 2007 Jul; 75(7):3571-80.
          View in: PubMed
        24. Alugupalli KR, Akira S, Lien E, Leong JM. MyD88- and Bruton's tyrosine kinase-mediated signals are essential for T cell-independent pathogen-specific IgM responses. J Immunol. 2007 Mar 15; 178(6):3740-9.
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        25. Zipris D, Lien E, Nair A, Xie JX, Greiner DL, Mordes JP, Rossini AA. TLR9-signaling pathways are involved in Kilham rat virus-induced autoimmune diabetes in the biobreeding diabetes-resistant rat. J Immunol. 2007 Jan 15; 178(2):693-701.
          View in: PubMed
        26. Montminy SW, Khan N, McGrath S, Walkowicz MJ, Sharp F, Conlon JE, Fukase K, Kusumoto S, Sweet C, Miyake K, Akira S, Cotter RJ, Goguen JD, Lien E. Virulence factors of Yersinia pestis are overcome by a strong lipopolysaccharide response. Nat Immunol. 2006 Oct; 7(10):1066-73.
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        27. Visintin A, Halmen KA, Khan N, Monks BG, Golenbock DT, Lien E. MD-2 expression is not required for cell surface targeting of Toll-like receptor 4 (TLR4). J Leukoc Biol. 2006 Dec; 80(6):1584-92.
          View in: PubMed
        28. Johnsen IB, Nguyen TT, Ringdal M, Tryggestad AM, Bakke O, Lien E, Espevik T, Anthonsen MW. Toll-like receptor 3 associates with c-Src tyrosine kinase on endosomes to initiate antiviral signaling. EMBO J. 2006 Jul 26; 25(14):3335-46.
          View in: PubMed
        29. Lehnardt S, Henneke P, Lien E, Kasper DL, Volpe JJ, Bechmann I, Nitsch R, Weber JR, Golenbock DT, Vartanian T. A mechanism for neurodegeneration induced by group B streptococci through activation of the TLR2/MyD88 pathway in microglia. J Immunol. 2006 Jul 1; 177(1):583-92.
          View in: PubMed
        30. Ngampasutadol J, Ram S, Blom AM, Jarva H, Jerse AE, Lien E, Goguen J, Gulati S, Rice PA. Human C4b-binding protein selectively interacts with Neisseria gonorrhoeae and results in species-specific infection. Proc Natl Acad Sci U S A. 2005 Nov 22; 102(47):17142-7.
          View in: PubMed
        31. Zipris D, Lien E, Xie JX, Greiner DL, Mordes JP, Rossini AA. TLR activation synergizes with Kilham rat virus infection to induce diabetes in BBDR rats. J Immunol. 2005 Jan 1; 174(1):131-42.
          View in: PubMed
        32. Heggelund L, Flo T, Berg K, Lien E, Mollnes TE, Ueland T, Aukrust P, Espevik T, Frøland SS. Soluble toll-like receptor 2 in HIV infection: association with disease progression. AIDS. 2004 Dec 3; 18(18):2437-9.
          View in: PubMed
        33. Heggelund L, Müller F, Lien E, Yndestad A, Ueland T, Kristiansen KI, Espevik T, Aukrust P, Frøland SS. Increased expression of toll-like receptor 2 on monocytes in HIV infection: possible roles in inflammation and viral replication. Clin Infect Dis. 2004 Jul 15; 39(2):264-9.
          View in: PubMed
        34. Nilsen N, Nonstad U, Khan N, Knetter CF, Akira S, Sundan A, Espevik T, Lien E. Lipopolysaccharide and double-stranded RNA up-regulate toll-like receptor 2 independently of myeloid differentiation factor 88. J Biol Chem. 2004 Sep 17; 279(38):39727-35.
          View in: PubMed
        35. Gibson FC, Hong C, Chou HH, Yumoto H, Chen J, Lien E, Wong J, Genco CA. Innate immune recognition of invasive bacteria accelerates atherosclerosis in apolipoprotein E-deficient mice. Circulation. 2004 Jun 8; 109(22):2801-6.
          View in: PubMed
        36. Latz E, Schoenemeyer A, Visintin A, Fitzgerald KA, Monks BG, Knetter CF, Lien E, Nilsen NJ, Espevik T, Golenbock DT. TLR9 signals after translocating from the ER to CpG DNA in the lysosome. Nat Immunol. 2004 Feb; 5(2):190-8.
          View in: PubMed
        37. Lien E, Golenbock DT. Adjuvants and their signaling pathways: beyond TLRs. Nat Immunol. 2003 Dec; 4(12):1162-4.
          View in: PubMed
        38. Kandimalla ER, Bhagat L, Zhu FG, Yu D, Cong YP, Wang D, Tang JX, Tang JY, Knetter CF, Lien E, Agrawal S. A dinucleotide motif in oligonucleotides shows potent immunomodulatory activity and overrides species-specific recognition observed with CpG motif. Proc Natl Acad Sci U S A. 2003 Nov 25; 100(24):14303-8.
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        39. Paterson HM, Murphy TJ, Purcell EJ, Shelley O, Kriynovich SJ, Lien E, Mannick JA, Lederer JA. Injury primes the innate immune system for enhanced Toll-like receptor reactivity. J Immunol. 2003 Aug 1; 171(3):1473-83.
          View in: PubMed
        40. Heine H, Lien E. Toll-like receptors and their function in innate and adaptive immunity. Int Arch Allergy Immunol. 2003 Mar; 130(3):180-92.
          View in: PubMed
        41. Espevik T, Latz E, Lien E, Monks B, Golenbock DT. Cell distributions and functions of Toll-like receptor 4 studied by fluorescent gene constructs. Scand J Infect Dis. 2003; 35(9):660-4.
          View in: PubMed
        42. Latz E, Visintin A, Lien E, Fitzgerald KA, Espevik T, Golenbock DT. The LPS receptor generates inflammatory signals from the cell surface. J Endotoxin Res. 2003; 9(6):375-80.
          View in: PubMed
        43. Henneke P, Takeuchi O, Malley R, Lien E, Ingalls RR, Freeman MW, Mayadas T, Nizet V, Akira S, Kasper DL, Golenbock DT. Cellular activation, phagocytosis, and bactericidal activity against group B streptococcus involve parallel myeloid differentiation factor 88-dependent and independent signaling pathways. J Immunol. 2002 Oct 1; 169(7):3970-7.
          View in: PubMed
        44. Latz E, Visintin A, Lien E, Fitzgerald KA, Monks BG, Kurt-Jones EA, Golenbock DT, Espevik T. Lipopolysaccharide rapidly traffics to and from the Golgi apparatus with the toll-like receptor 4-MD-2-CD14 complex in a process that is distinct from the initiation of signal transduction. J Biol Chem. 2002 Dec 6; 277(49):47834-43.
          View in: PubMed
        45. Bieback K, Lien E, Klagge IM, Avota E, Schneider-Schaulies J, Duprex WP, Wagner H, Kirschning CJ, Ter Meulen V, Schneider-Schaulies S. Hemagglutinin protein of wild-type measles virus activates toll-like receptor 2 signaling. J Virol. 2002 Sep; 76(17):8729-36.
          View in: PubMed
        46. Flo TH, Ryan L, Latz E, Takeuchi O, Monks BG, Lien E, Halaas Ø, Akira S, Skjåk-Braek G, Golenbock DT, Espevik T. Involvement of toll-like receptor (TLR) 2 and TLR4 in cell activation by mannuronic acid polymers. J Biol Chem. 2002 Sep 20; 277(38):35489-95.
          View in: PubMed
        47. Fichorova RN, Cronin AO, Lien E, Anderson DJ, Ingalls RR. Response to Neisseria gonorrhoeae by cervicovaginal epithelial cells occurs in the absence of toll-like receptor 4-mediated signaling. J Immunol. 2002 Mar 1; 168(5):2424-32.
          View in: PubMed
        48. Dybdahl B, Wahba A, Lien E, Flo TH, Waage A, Qureshi N, Sellevold OF, Espevik T, Sundan A. Inflammatory response after open heart surgery: release of heat-shock protein 70 and signaling through toll-like receptor-4. Circulation. 2002 Feb 12; 105(6):685-90.
          View in: PubMed
        49. Lien E, Ingalls RR. Toll-like receptors. Crit Care Med. 2002 Jan; 30(1 Suppl):S1-11.
          View in: PubMed
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