Michael Gale, Jr. , PhD
Associate Professor, Immunology
Adjunct Associate Professor, Microbiology

Department of Immunology
University of Washington
Office H 466 HSC, Box 357650
1959 NE Pacific Street
Seattle, WA 98195-7650
Tel: 206.685-7953
Fax: 206.543-1013
Email: mgale@u.washington.edu

Gale Lab

Dr. Michael Gale, Jr. received his training at Seattle Biomedical Research Institute and the University of Washington School of Medicine. He served on the faculty of the University of Texas Southwestern Medical Center until joining the University of Washington in 2007.

Research in the Gale laboratory is focused on understanding innate immunity to virus infection, and the intracellular immune processes and virus-host interactions that govern viral replication and infection outcome. In addition to studying West Nile virus, influenza virus, and human immunodeficiency virus, the laboratory
is a component of the Hepatitis C virus Cooperative Research Centers supported by the NIH.

Virus infection of mammalian cells triggers an intracellular immune response, termed the “innate immune response” that functions to suppress replication and spread of the virus. During infection specific motifs within viral products are recognized as pathogen associated molecular patterns (PAMPs) by cellular factors called pathogen recognition receptors (PRRs). Studies in the Gale laboratory have defined the retinoic acid-inducible gene I (RIG-I) as the major PRR that triggers immunity against hepatitis C virus. Accumulating evidence now indicates that immunity against RNA viruses is largely triggered through the PRR actions of RIG-I and/or a related protein called MDA5. RIG-I and MDA5 are cytosolic RNA helicase and are expressed at a low levels in most cells. During virus infection RIG-I or MDA5 binds to RNA PAMP motifs of viral genome or replication product RNA generated by specific viruses. RIG-I binding of viral RNA triggers its downstream signaling to induce the activation of latent transcription factors and the eventual production of alpha/beta interferons and expression of interferon-stimulated genes. These processes induce the innate immune response that serves to limit virus replication and spread. Many viruses direct actions of immune evasion through regulation of innate immune signaling and function. Our studies have linked the course of virus infection to regulation of innate immune processes, and have identified novel interactions as therapeutic targets for the intervention of infection.

Hepatitis C virus. Hepatitis C virus mediates chronic infection in 2% of the world population, and is a major etiology of liver disease; infection is treated through injection of alpha interferon. Our studies are currently focused on defining the processes by which hepatitis C virus suppresses innate immunity and interferon actions to persist in the infected cell. We have identified the viral interface with the RIG-I pathway and specific interferon –stimulated genes as major determinants hepatitis C virus infection outcome. Current studies are focused on defining the molecular mechanisms by which the RIG-I pathway, interferon signaling, and therapeutic interferon actions are governed during hepatitis C virus infection.

West Nile virus. West Nile virus has emerged across the Western hemisphere and North America. Our studies utilize in vitro and gene knockout mouse models to determine how West Nile virus modulates the actions of alpha/beta interferons during infection.

Human Immunodeficiency virus (HIV). AIDS is a global public health problem directly linked to immune regulation and immune cell depletion by HIV. Our studies are centered on defining the processes of innate immune governance in T cells and their control by HIV.

Influenza virus. Influenza virus remains a constant health threat through seasonal outbreaks and the emergence of new strains, including H5N1 influenza viruses or “bird flu”. We Aim to determine the viral processes that regulate the RIG-I pathway, antiviral immunity, and pathogenesis of H5N1 influenza virus infection.

Innate immune signaling and the actions of alpha/beta interferons. The Gale laboratory is engaged in ongoing studies to define the molecular mechanisms of innate immune signaling actions of RIG-I, MDA5, and other PRR pathways that regulate immunity against RNA virus infection. These studies include a specific focus to define the interferon-stimulate genes and their actions in innate immune programs in vivo within gene knockout mouse models.

Students training in the Gale Lab: Andrea Kaup Erickson, David Owen, Olivia Perwitasari

Selected publications:

Saito, T., Hirai, R.,Loo, Y.-M., Owen, D., Johnson, C.L., Sinha, S.C., Akira, S., Fujita, T., and Gale. M., Jr. (2007) Regulation of innate antiviral defenses through a shared repressor domain in RIG-I and LGP2. Proc. Natl. Acad. Sci, U.S.A., 104:582-587.

Johnson, C.L., Owen, D. and Gale, M., Jr. (2007) Functional and therapeutic analysis of hepatitis C virus NS3/4A protease control of antiviral immune defense. J Biol. Chem. 282:10792-10803.

Malathi, K., Dong, B., Gale, M., Jr., Silverman, R. (2007) Small self-RNA generated by RNase L amplifies antiviral innate immunity. Nature 448: 816-819.

Daffis, S., Samuel, M.S., Keller, B., Taniguchi, T., Gale, M., Jr., and Diamond, M.S. (2007) Cell-specific IRF-3 responses protect against West Nile virus infection by IFN-dependent and independent mechanisms. PLoS Pathogens 3:1005-1015

Loo, Y.-M., Owen, D.M., Li, K., Erickson, A. K., Johnson, C., Fish, P. M., Carney, D. S., Wang, T., Ishida, H., Yoneyama, M., Fujita, T., Saito, T., Lee, W. M., Hagedorn, C., Lau, T.-Y.D., Weinman, S. A., Lemons S. M., Gale, M. Jr. (2006) Viral and therapeutic control of IPS-1 function during hepatitis C virus infection. Proc Natl Acad Sci USA, 103:6001-6006.

Keller, B., Fredericksen, B., Samuel, M., Mock, R., Mason, P., Diamond, M., Gale, M. Jr. (2006) Resistance to ß interferon defines replication fitness and virulence of West Nile virus. J. Virol. 80:9424-34.

Fredericksen, B., Gale M. Jr. (2006) West Nile virus evades activation of interferon regulatory 3 through RIG-I-dependent and independent pathways without antagonizing host defense signaling. J. Virol. 80:2913-2923.

Gale M. Jr. and Foy, E. (2005) Evasion of intracellular host defense by hepatitis C virus. Nature 436: 939-945.

Wang, C., Gale, M. Jr., Huang, H., Brown, M., Goldstein, J., and Ye, J. (2005) Identification of FBL2 as a geranylgeranylated cellular protein required for hepatitis C virus RNA replication. Mol. Cell 18: 425-434.

Foy, E., Li, K., Sumpter, R., Loo, Y.-M., Johnson, C., Wang, C., Fish, P., Yoneyama, M., Fujita, T., Lemon, S. and Gale, M. J. Jr. (2005) Suppression of intracellular immune defense by hepatic C virus occurs through viral protease-dependent disruption of RIG-I signaling. Proc. Natl. Acad. Sci. U.S.A. 102:2986-2991.

Sumpter, R., Loo, Y.-M., Foy, E., Li, K., Yoneyama, M., Fujita, T., Lemon, S. and Gale, M. J. Jr (2005) Regulating intracellular antiviral defense and permissiveness to hepatitis C virus RNA replication through a cellular RNA helicase, RIG-I. J. Virol. 79: 2689-2699.

Sumpter, R., Wang, C. Loo, Y.-M., and Gale, M. J. Jr (2004) Viral evolution and interferon resistance of hepatitis C virus in a cell culture model. J. Virol. 78: 11591-11604.

Foy, E., C. Wang, R. Sumpter, M. Ikeda, K. L. S. M. Li, and Gale, M. J. Jr. (2003). Regulation of interferon regulatory factor-3 by the hepatitis C virus serine protease. Science, 300:1145-1148.

Keller, B., Johnson C., Erickson A., and Gale, M., Jr. Innate immune evasion by hepatitis C virus and West Nile virus. (2007) Cytokine Growth Factor Rev. 2007 epub Aug 14 Saito, T., and Gale, M., Jr. (2007) Principles of intracellular viral recognition. Curr Opin Immunol. 19:17-23.

posted 9/3/07