Research Summary

During viral infection, the symptoms experienced are either a direct result of the virus infecting and damaging cells and tissue or a consequence of the activated inflammatory host immune response that was generated to pursue and remove the virus. Typically, it is a combination of both. As the virus is eliminated, the immune response subsides and recovery from disease is observed as symptoms subside. Furthermore, many viruses have been associated and identified as the triggers of more complex diseases. These diseases involve chronic autoimmunity, immunosuppression, haemorrhagic fever and meningitis. In these instances, chronic disease develops as a result of improper control and regulation of the viral-induced immune response. Understanding the involvement and regulation of the immune system in response to viral infection is central to the discovery of mechanisms designed at prevention and treatment of viral-induced complex disorders.

Our laboratory is interested in identifying, characterizing and determining the mechanisms of viral-induced immune disease in a variety of complex chronic disorders. These include, but are not limited to autoimmune diseases like diabetes, autoimmune myocarditis and multiple sclerosis, immunosuppression induced by viruses such as HIV and Measles, haemorrhagic fevers as observed following Dengue fever virus infection, and meningitis induced by viruses like West Nile Virus.

Specifically, the primary goal of our program is to interconnect the changes effecting the ability of the immune system to respond to infection with its ability to develop immune dysfunction leading to disease. Ongoing studies are aimed at describing and controlling the mechanisms of viral-induced autoimmune disease in at least two different mouse models. Both insulin-dependent Diabetes Mellitus and autoimmune myocarditis can be induced in mice and man by a common pathogen of childhood, coxsackievirus. Dependent on the strain of virus and the strain of mice, different outcomes of acute coxsackieviral infection can lead to the induction of chronic autoimmune diabetes, heart disease or no disease. Our laboratory has taken advantage of this model to study the specific components that regulate disease induction.

Bio

B.Sc., University of California, Davis, (1982)
Ph.D., University of Minnesota, (1991)
Postdoctoral fellow, The Scripps Research Institute, (1991-1997)

Publications
  1. Richer, M.J., Poffenberger, M. and Horwitz, M.S. Early Inflammatory responses direct chronic autoimmunity development in the heart following coxsackievirus infection. Future Virology, 2(3) 1-9, May, 2007.
  2. Richer, M.J., Fang, D., Shanina, I. and Horwitz, M.S. Toll-like Receptor 4-induced cytokine production circumvents protection conferred by TGF-β in coxsackievirus mediated autoimmune myocarditis. Clinical Immunology, 121(3):339-49 in Press-online, September 11th, 2006.
  3. Horwitz, M.S., Knudsen, M., Ilic, A., Fine, C., and Sarvetnick, N. TGF-β inhibits Coxsackievirus-mediated autoimmune myocarditis. Viral Immunology, 19(4):722-33, 2006. (cover photo)
  4. Horwitz, M.S., Ilic, A., Fine, C., and Sarvetnick, N. Antigen specific peripheral tolerance to cardiac myosin does not prevent CB3-mediated autoimmune myocarditis. Journal of Autoimmunity, online July 11th, 2005.
  5. Horwitz, M.S., Ilic, A., Fine, C., Balasa, B. and Sarvetnick, N. Coxsackievirus-mediated diabetes: Induction requires antigen presenting cells and is accompanied by phagocytosis of beta cells. Clinical Immunology, 110(2):134-44, 2004.
  6. Robey, I.F., Peterson, M., Horwitz, M.S. , Kono, D.H., Stratmann, T. Theofilopoulos, A.N., Sarvetnick, N., Teyton, L. and Feeney, A.J. Terminal Deoxynucleotidyl Transferase Deficiency Decreases Autoimmune Disease in Diabetes-prone NOD Mice and Lupus-prone MRL-Faslpr Mice. Journal of Immunology, 172(7) 4624-29,2004.
  7. Horwitz, M.S., Ilic, A., Fine, C., Rodriguez, E. and Sarvetnick, N. Coxsackievirus-mediated hyperglycemia is enhanced by re-infection and this occurs independent of T cells. Virology, 314: 510-520, 2003.
  8. Horwitz, M.S., Ilic, A., Fine, C., Rodriguez, E. and Sarvetnick, N. Presented antigen from damaged pancreatic beta cells activates autoreactive T cells in virus-mediated autoimmune diabetes. Journal of Clinical Investigations, 109: 79-87, 2002.
  9. Horwitz, M.S., Fine, C., Ilic, A. and Sarvetnick, N. Requirements for Viral-mediated Autoimmune Diabetes: beta cell damage and immune infiltration. Journal of Autoimmunity. 16(3): 211-218, 2001.
  10. Flodstrom, M., Horwitz, M.S., Balakrishna, D., Maday, A., Rodriguez, E. and Sarvetnick, N. A critical role for inducible nitric oxide synthase in viral clearance and host survival following coxsackievirus B4 infection. Virology.281(2): 205-215, 2001.
  11. Horwitz, M.S., Ilic, A., Fine, C., and Sarvetnick, N. Antigen specific peripheral tolerance to cardiac myosin does not prevent CB3-mediated autoimmune myocarditis. Journal of Autoimmunity, in Press-online July 11th, 2005.
  12. Horwitz, M.S., La Cava, A., Fine, C., Rodriguez, E., Ilic, A. and Sarvetnick, N. Pancreatic expression of interferon-gamma protects mice from lethal coxsackievirus B3 infection and subsequent myocarditis. Nature Medicine 6(6): 693-7, 2000. (Cover photo and News and Views, pp.631 )
  13. Horwitz, M.S., Krahl, T., Lee, J., and Sarvetnick, N. Protection from lethal Coxsackie virus-induced pancreatitis by local expression of interferon-gamma. J. Virology 73(3): 1756-66, 1999.
  14. Horwitz, M.S., Evans, C.F., Klier, F.G., and Oldstone, M.B.A. Detailed in vivo analysis of interferon-gamma induced MHC expression in the CNS: Astrocytes fail to express MHC class I and II molecules. Laboratory Investigations. 79(2): 235-242, 1999. (Cover photo and Inside L. I., pp.81)
  15. Horwitz, M.S., Bradley, L.M., Harbertson, J., Krahl, T., Lee, J., and Sarvetnick, N. Diabetes induced by Coxsackie virus: Initiation by bystander damage and not molecular mimicry. Nature Medicine, 4(7): 781-785, 1998. (News & Views, pp. 770-1).
  16. Horwitz, M.S., Evans, C.F., Rodriguez, M., and Oldstone, M.B.A. Primary Demyelination in Transgenic Mice Expressing Interferon-Gamma. Nature Medicine, 3(9):1037-1041, 1997.
  17. Borrow, P., Lewicki, H., Wei, X., Horwitz, M.S. Peffer, N., Myers, H., Nelson, J., Gairin, J., Hahn, B., Oldstone, M.B.A., and Shaw, G. Antiviral pressure exerted by HIV-1-specific CTL during primary infection demonstrated by rapid selection of CTL escape virus. Nature Medicine, 3(2)205-211, 1997.
  18. Horwitz, M.S., *Evans, C.F., Hobbs, M.V., and Oldstone., M.B.A. Viral infection of transgenic mice expressing a viral protein in Oligodendrocytes lends to chronic central nervous system autoimmune disease. J. Exp. Med., 184:2371-2384, 1996.
  19. Horwitz, M.S., Yanagi, Y., and Oldstone, M.B.A. T cell receptors from virus-specific cytotoxic T lymphocytes recognizing a single immunodominant nine amino acid viral epitope show marked diversity. J. Virol. 68:352-357, 1994.
  20. Horwitz, M.S., Boyce-Jacino, M.T., and Faras, A.J. Novel human endogenous sequences related to human immunodeficiency virus type I. J. Virol. 66:2170-2179, 1992.
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