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

John S. Daniels Professor
Internal Medicine
Rheumatology

Immunology Program
Molecular Microbiology and Microbial Pathogenesis Program

  • 314-362-8637

  • 314-362-8639

  • 314-454-1091

  • CSRB 6617

  • DLenschow@WUSTL.EDU

  • https://sites.wustl.edu/lenschowlab

  • 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 studying the host pathogenesis of viruses such as chikungunya and influenza virus with an emphasis on innate immunity. These viruses cause significant mortality and morbidity which demands that we gain a better understanding of their pathogenesis to inform treatment options. Specifically, we focus on how soluble mediators such as type I interferons contribute to host protection, disease tolerance, and/or susceptibility during viral infection. Type I interferons mediate their effects by signaling on target cells to induce downstream outcomes via the induction of hundreds of interferon stimulated genes (ISGs). Recently, we have described how the members of the type I interferons and their ISGs mediate a variety of different effects depending on their timing, location, and disease state of the host. To study these phenomena, we use a variety of tools such as animal models, in vitro cell culture systems, pharmacological agents, genetic deletion mutants, monoclonal antibody technology, and more.

Type I Interferons - IFNs are a family of multifunctional cytokines that consists of 14 IFN-α subtypes (IFN-α) and single forms of IFN-β, IFN-ε, IFN-κ, and IFN-ω in mice. Their broad, pleiotropic properties include upregulating cell-intrinsic antiviral defense mechanisms, modulating proinflammatory cytokine production, and augmenting innate and adaptive cellular immune responses. Despite signaling through a single, shared receptor, the IFN subtypes have distinct properties, presumably due to different binding affinities and receptor dissociation rates for the individual IFN subtypes. Our lab and others have demonstrated that IFNs are essential to control alphavirus infection, including chikungunya virus (CHIKV). Despite their essential role in limiting CHIKV infection, little is known about the contributions of individual IFN subtypes to protection. To explore this question, we are using genetic deletion mutants and monoclonal antibody blockade to determine the differential functions of IFN-α and IFN-β during acute CHIKV infection.

Chikungunya virus- Chikungunya virus (CHIKV) is an arthritogenic alphavirus that acutely causes fever as well as severe joint and muscle pain. Chronic musculoskeletal pain persists in a substantial fraction of patients for months to years after the initial infection, yet we still have a poor understanding of what promotes chronic disease. While replicating virus has not been detected in joint-associated tissues of patients with persistent arthritis nor in various animal models at convalescent time points, viral RNA is detected months after acute infection. To study chronic CHIKV, we developed a system to visualize and isolate cells that survive CHIKV infection. Using this novel approach, we are currently investigating the nature of the viral RNA that persists, the transcriptional profiles of the cells that survive CHIKV infection, and the contribution of these cells to chronic CHIKV pathogenesis.

Interferon Stimulated Gene 15- The host response to viral infection is complex and must balance inhibiting replication with limiting damage to the host. A key mediator of the host response to viral infection are type I interferons and the hundreds of interferon stimulated genes they induce. Among these, the ubiquitin-like protein ISG15, functions as an antiviral protein, limiting replication of many viruses. Our studies have demonstrated that ISG15 can also regulate the host response and recovery from viral infection, independent of any effects on viral replication, a process known as disease tolerance. During respiratory viral infection we have detected increased epithelial damage in both cells and mice lacking ISG15. Ongoing efforts to understand these disease tolerance mechanisms have revealed that ISG15 can interact with cellular machinery known as the necrosome to regulate a type of programmed cell death known as necroptosis. Understanding the mechanism by which ISG15 protects the host from viral infection, both through inhibition of viral replication and by limiting the damage induced to the host may lead to the development of therapies that target this pathway and can be used for the treatment of acute viral infections.

Selected Publications:

1. Young AR*, Locke MC*, Cook LE, Hiller BE, Zhang R, Hedberg ML, Monte KJ, Veis DJ, Diamond MS, Lenschow DJ. Dermal and muscle fibroblasts and skeletal myofibers survive chikungunya virus infection and harbor persistent RNA. PLoS Pathog. In Press. * Co-authors

2. Perng YC, Lenschow DJ. ISG15 in antiviral immunity and beyond. Nat Rev Microbiol. 2018 Jul;16(7):423-439.

3. Steed AL, Christophi GP, Kaiko GE, Sun L, Goodwin VM, Jain U, Esaulova E, Artyomov MN, Morales DJ, Holtzman MJ, Boon ACM, Lenschow DJ, Stappenbeck TS. The microbial metabolite desaminotyrosine protects from influenza through type I interferon. Science. 2017 Aug 4;357(6350):498-502.

4. Kimmey JM, Campbell JA, Weiss LA, Monte KJ, Lenschow DJ, Stallings CL. The impact of ISGylation during Mycobacterium tuberculosis infection in mice. Microbes Infect. 2017 Apr - May;19(4-5):249-258.

5. Miner JJ*, Cook LE*, Hong JP, Smith AM, Richner JM, Shirmak RM, Young AR, Monte K, Poddar S, Crowe JE Jr, Lenschow DJ+, Diamond MS+. Therapy with CTLA4-Ig and an antiviral monoclonal antibody controls chikungunya virus arthritis. Sci Transl Med. 2017 Feb 1;9(375). pii: eaah3438. Highlight in 2017 Science Translational Medicine. * co-authors, + co-corresponding authors.

6. Speer SD, Li Z, Buta S, Payelle-Brogard B, Qian L, Vigant F, Rubino E, Gardner TJ, Wedeking T, Hermann M, Duehr J, Sanal O, Tezcan I, Mansouri N, Tabarsi P, Mansouri D, Francois-Newton V, Daussy CF, Rodriguez MR, Lenschow DJ, Freiberg AN, Tortorella D, Piehler J, Lee B, García-Sastre A, Pellegrini S, Bogunovic D. ISG15 deficiency and increased viral resistance in humans but not mice. Nat Commun. 2016 May 19;7:11496.

7. Miner JJ, Aw-Yeang HX, Fox JM, Taffner S, Malkova ON, Oh ST, Kim AHJ, Diamond MS, Lenschow DJ, Yokoyama WM. Chikungunya viral arthritis in the United States: a mimic of seronegative rheumatoid arthritis. Arthritis Rheumatol. 2015 May;67(5):1214-1220.

8. Ketscher L, Hannß R, Morales DJ, Basters A, Guerra S, Goldmann T, Hausmann A, Prinz M, Naumann R, Pekosz A, Utermöhlen O, Lenschow DJ, Knobeloch KP. Selective inactivation of USP18 isopeptidase activity in vivo enhances ISG15 conjugation and viral resistance. Proc Natl Acad Sci U S A. 2015 Feb 3;112(5):1577-82.

9. Morales DJ, Monte K, Sun L, Struckhoff JJ, Agapov E, Holtzman MJ, Stappenbeck TS, Lenschow DJ. Novel mode of ISG15-mediated protection against influenza A virus and Sendai virus in mice. J Virol. 2015 Jan;89(1):337-49. doi: 10.1128/JVI.02110-14.

10. Rodriguez MR, Monte K, Thackray LB, Lenschow DJ. ISG15 functions as an interferon-mediated antiviral effector early in the murine norovirus life cycle. J Virol. 2014 Aug; 88(16):9277-86.

11. Rohatgi A, Corbo JC, Monte K, Higgs S, Vanlandingham DL, Kardon G, Lenschow DJ. Infection of myofibers contributes to increased pathogenicity during infection with an epidemic strain of chikungunya virus. J Virol. 2014 Mar;88(5):2414-25.

12. Joubert PE, Werneke SW, de la Calle C, Guivel-Benhassine F, Giodini A, Peduto L, Levine B, Schwartz O, Lenschow DJ, Albert ML. Chikungunya virus-induced autophagy delays caspase-dependent cell death. J Exp Med. 2012 May 7;209(5):1029-47.

13. Werneke SW, Schilte C, Rohatgi A, Monte KJ, Michault A, Arenzana-Seisdedos F, Vanlandingham DL, Higgs S, Fontanet A, Albert ML, Lenschow DJ. ISG15 is critical in the control of Chikungunya virus infection independent of UbE1L mediated conjugation. PLoS Pathog. 2011 Oct;7(10):e1002322.

Last Updated: 8/15/2019 2:06:28 PM

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