Deborah Lenschow, MD
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 hundreds 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 Chikungunya 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.
If you are a Chikungunya patient and would like to participate in a study, please visit our registry webiste:
- Rohatgi A, Monte KK, Kardon G, Corbo JC, Higgs S, and Lenschow DJ. 2014. Infection of myofibers contributes to the increased pathogenicity during neonatal infection with an epidemic strain of Chikungunya virus. Journal of Virology, 88(5):2414-2425.
- Rodriguez M, Monte K., Thackray L, and Lenschow DJ. 2014. ISG15 functions as an interferon-mediated antiviral effector early in the murine norovirus life cycle. Journal of Virology, In press.