Deborah J. Lenschow, M.D., Ph.D.

Associate Professor
Internal Medicine

Immunology Program
Molecular Microbiology and Microbial Pathogenesis Program

  • 314-362-8637

  • 314-362-8639

  • 314-454-1091

  • 8045

  • CSRB 6617

  • DLenschow@WUSTL.EDU

  • host-pathogen interactions, immunology, innate immunity, interferons, pathogenesis, virology, autoimmune disease, lupus

  • Antiviral mechanisms of type I interferons and the role of interferons and viruses in autoimmune diseases

Research Abstract:

We are interested in understanding the mechanism by which type I interferons function, and how these cytokines impact upon the host response to viral infection and in the development of autoimmune diseases including systemic lupus erythematosis (SLE). Type I interferons regulate a wide array of biological effects. These include the induction of an antiviral state, regulation of apoptosis, inhibition of cell growth, and modulation of both the innate and adaptive immune responses. Interferons mediate these activities through the induction of hundred of gene products known as interferon stimulated genes. While several of these genes, such as PKR and RNAseL, have previously been defined as important antiviral molecules, many of these genes have no known function ascribed to them. Utilizing an in vivo screen, we identified interferon stimulated gene 15 (ISG15) as a novel antiviral molecule. ISG15 is an ubiquitin-like molecule with two biological activities. It forms conjugates with intracellular proteins, with over 150 host proteins having been identified as ISG15 targets. It can also be released from cells to function as an immunostimulatory cytokine. Mice deficient in ISG15 exhibit increased susceptibility to multiple viruses including influenza A and B viruses, herpes simplex virus, and Sindbis virus. Ongoing work in our lab is aimed at elucidating the mechanism by which ISG15 exerts its antiviral activity, using a number of different viral model systems. We are pursuing this question by exploring the function of the innate immune system in the absence of ISG15; determining the fate of both host and viral proteins conjugated to ISG15; and investigating the cytokine activity of ISG15. We are also currently studying the impact of different IFN subtypes on disease. Finally, we are pursuing studies to identify additional IFN induced effector molecules and exploring their roles in antiviral responses and in the development of autoimmune diseases, such as SLE.

Selected Publications:

Campbell J and Lenschow DJ. Invited Review: Immunoregulatory properties of ISG15. (2013) Journal of Interferon and Cytokine Research. In press.

S Shoji-Kawata, Sumpter Jr. R, Leveno M, Zou Z, Kinch L, Wilkins A, Sun Q, Pallauf L, MacDuff D, Huerta C, Virgin HW, Helms B, Eerland R, Tooze SA, Xavier R, Lenschow DJ, Yamamoto A, King D, Lichtarge O, Grishin NV, Spector S, Kaloyanova DV, and Levine B. (2013). A GAPR-1-interacting autophagy-inducing peptide with therapeutic potential. Nature, 494:201-206.

Swiecki M, Wang Y, Gilfillan S, Lenschow DJ, and Colonna M. (2012). Cutting Edge: Paradoxical roles of BST-2/Tetherin in host antiviral responses. Journal of Immunology. 188(6):2488-92.

Joubert PE, Werneke S, de la Calle C, Guivel-Benhassine F, Giodini A, Peduto L, Levine B, Schwartz O, Lenschow DJ, and Albert, MA. (2012). Chikungunya virus-induced autophagy delays apoptosis via the induction of ER stress and generation of reactive oxygen species. Journal of Experimental Medicine, 209:1029-1047.

Werneke S, Schilte C, Rohatgi A, Monte KJ, Michault A, Arenzana-Seisdedos F, Fontanet A, Albert MA, and Lenschow DJ. (2011). ISG15 is critical in the control of Chikungunya virus infection independent of UbE1L mediated conjugation. PLoS Pathogens, 10:e1002322.

Lai C, Struckhoff JJ, Schneider J, Martinez-Sobrido L, Wolff T, Garca-Sastre A, Zhang DE, and Lenschow DJ. Mice lacking the ISG15 E1 enzyme, Ube1L, demonstrate increased susceptibility to both mouse adapted and non-adapted influenza virus infection. Journal of Virology 2009 83: 1147-1151.

Lenschow DJ, Lai C, Frias-Staheli N, Giannakopoulos NV, Lutz A, Wolff T, Osiak A, Levine B, Schmidt RE, Garcia-Sastre A, Leib DA, Pekosz A, Knobeloch KP, Horak I, and Virgin HW. ISG15 functions as a critical antiviral molecule against influenza, herpes and Sindbis viruses. Proc Natl Acad Sci USA 2007 104: 1371-1376.

Frias-Staheli N, Giannakopoulos NV, Kikkert M, Taylor SL, Bridgen A, Paragas JJ, Richt JA, Rowland RR, Schmaljohn CS, Lenschow DJ, Snijder EJ, Garcia-Sastre A, and Virgin HW. Ovarian Tumor (OTU)-domain containing viral proteases evade ubiquitin- and ISG15- dependent innate immune responses. Cell Host and Microbe 2007 2:404-416.

Giannakopoulos NV, Luo J, Papov V, Zou W, LenschowDJ, Jacobs BS, Borden EC, Li J, Virgin HW, Zhang D. Proteomic identification of ISGylated proteins in mouse and human cells. Biochem and Biophysical Res Comm 2005 336: 496-506.

Lenschow DJ, Giannakopoulos N, Gunn LJ, Johnston C, O’Guin AK, Schmidt RE, Levine B, and Virgin HW. Identification of ISG15 as an antiviral molecule during Sindbis virus infection in vivo. J Virology 2005 79: 13974-13983.

Last Updated: 8/7/2013 2:40:20 PM

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