MOLECULAR BIOLOGY AND PATHOGENESIS OF MOUSE ADENOVIRUS

Summary

Principal Investigator: KATHERINE SPINDLER
Abstract: Mouse adenovirus type 1 (MAV-1) causes disease in the newborn or adult mouse by infecting endothelial cells and cells of the monocyte/macrophage lineage throughout the animal. Depending on the dose, virus strain, or host mouse strain, the outcome of infection can be inapparent infection, persistent infection, or death. The wealth ofmurine immunological reagents and inbred mouse strains, including immunodeficient mice, coupled with an easily manipulated virus causing several disease phenotypes, make MAV-1 an ideal model for studying viral pathogenesis in the natural host. This project will provide an understanding of (a) the role of the immune system in both control of viral infection and in producing viral disease, (b) the basis for infection by MAV-1 of two specific cell types, endothelial cells and macrophages, and (c) the contributions of early viral gene products to infection of cells in culture and mice. There are three specific aims: 1. Identify early immune response components affecting mouse susceptibility to infection. The role of B lymphocytes, natural killer cells, and monocytes/macrophages will be investigated using immunodeficient mice and depletions of specific cell types. 2. Determine whether MAV-1 infection induces gene expression changes that can alter effector function of endothelial and macrophage cells. Cellular genes, including interferon response, eytokine, and major histocompatibility complex gene class II genes will be characterized with respect to expression changes in target endothelial and macrophage cells by wild-type and early region 1A and 3 (E1A and E3) mutant viruses. The results of assays of in vitro and in vivo gene expression will be integrated to define host response pathways and strategies used by the virus to evade them. 3. Determine mechanisms by which viral early region genes contribute to MAV-1 infection. A biochemical assay will be used to identify host proteins that interact with MAV-1 E 1A and E3, and these results will be incorporated into models developed in Aim 2. Viruses with mutations in E1A, E1B, and E3 will be used to infect immunodeficient mice to test specific hypotheses about early adenoviral gene function in vivo. These studies will further our knowledge of adenovirus biology, host immune mechanisms and viral immune evasion.
Funding Period: 1987-07-01 - 2007-11-30
more information: NIH RePORT

Top Publications

  1. pmc E1A-CR3 interaction-dependent and -independent functions of mSur2 in viral replication of early region 1A mutants of mouse adenovirus type 1
    Lei Fang
    Department of Microbiology and Immunology, University of Michigan Medical School, 1150 W Medical Center Dr, 6723 Medical Science Bldg II, Ann Arbor, MI 48109 0620, USA
    J Virol 79:3267-76. 2005
  2. pmc Acute respiratory infection with mouse adenovirus type 1
    Jason B Weinberg
    University of Michigan Health System, Division of Pediatric Infectious Diseases, Department of Pediatrics, Ann Arbor, 48109 0244, USA
    Virology 340:245-54. 2005
  3. pmc Identification of quantitative trait loci for susceptibility to mouse adenovirus type 1
    Amanda R Welton
    Department of Microbiology and Immunology, University of Michigan Medical School, Ann Arbor, 48109 0620, USA
    J Virol 79:11517-22. 2005
  4. pmc Contributions of E1A to mouse adenovirus type 1 pathogenesis following intranasal inoculation
    Jason B Weinberg
    University of Michigan Health System, Division of Pediatric Infectious Diseases, L2225 Women s 0244, 1500 East Medical Center Drive, Ann Arbor, MI 48109 0244, USA
    Virology 357:54-67. 2007
  5. pmc Mouse adenovirus type 1 infection of natural killer cell-deficient mice
    Amanda R Welton
    Department of Microbiology and Immunology, University of Michigan, Ann Arbor, Michigan 48109, USA
    Virology 373:163-70. 2008
  6. pmc Usage of integrin and heparan sulfate as receptors for mouse adenovirus type 1
    Sharmila Raman
    Department of Microbiology and Immunology, University of Michigan, Michigan 48109 5620, USA
    J Virol 83:2831-8. 2009
  7. pmc Novel immunocompetent murine tumor model for evaluation of conditionally replication-competent (oncolytic) murine adenoviral vectors
    Michael Robinson
    Cell Genesys, Inc, 500 Forbes Blvd, South San Francisco, CA 94080, USA
    J Virol 83:3450-62. 2009
  8. pmc Mouse adenovirus type 1 infection of macrophages
    Shanna L Ashley
    Department of Microbiology and Immunology, University of Michigan, Ann Arbor, MI 48109, USA
    Virology 390:307-14. 2009
  9. pmc Mouse adenovirus type 1-induced breakdown of the blood-brain barrier
    Lisa E Gralinski
    Department of Microbiology and Immunology, University of Michigan, Ann Arbor, 48109 5620, USA
    J Virol 83:9398-410. 2009

Scientific Experts

  • JASON BRICE WEINBERG
  • Michael Robinson
  • Katherine R Spindler
  • Amanda R Welton
  • Shanna L Ashley
  • Lisa E Gralinski
  • Sharmila Raman
  • Lei Fang
  • Shandee D Dixon
  • Kirsten M Harwood
  • Nico Van Rooijen
  • Tien Huei Hsu
  • Carla Sturkie
  • Anne U Jackson
  • Elissa J Chesler
  • Gwen N Hirsch

Detail Information

Publications9

  1. pmc E1A-CR3 interaction-dependent and -independent functions of mSur2 in viral replication of early region 1A mutants of mouse adenovirus type 1
    Lei Fang
    Department of Microbiology and Immunology, University of Michigan Medical School, 1150 W Medical Center Dr, 6723 Medical Science Bldg II, Ann Arbor, MI 48109 0620, USA
    J Virol 79:3267-76. 2005
    ..This result supports the hypothesis that the MAV-1 E1A-mSur2 interaction is important in MAV-1 replication in mice...
  2. pmc Acute respiratory infection with mouse adenovirus type 1
    Jason B Weinberg
    University of Michigan Health System, Division of Pediatric Infectious Diseases, Department of Pediatrics, Ann Arbor, 48109 0244, USA
    Virology 340:245-54. 2005
    ..MAV-1 infection of mice has the potential to serve as a model for inflammatory changes seen in human adenovirus respiratory disease...
  3. pmc Identification of quantitative trait loci for susceptibility to mouse adenovirus type 1
    Amanda R Welton
    Department of Microbiology and Immunology, University of Michigan Medical School, Ann Arbor, 48109 0620, USA
    J Virol 79:11517-22. 2005
    ..Identification of the major QTL is the first step in characterizing host genes involved in susceptibility to MAV-1...
  4. pmc Contributions of E1A to mouse adenovirus type 1 pathogenesis following intranasal inoculation
    Jason B Weinberg
    University of Michigan Health System, Division of Pediatric Infectious Diseases, L2225 Women s 0244, 1500 East Medical Center Drive, Ann Arbor, MI 48109 0244, USA
    Virology 357:54-67. 2007
    ..n. inoculation. However, E1A is not essential for the induction of inflammatory responses in the lung or for viral dissemination out of the lung...
  5. pmc Mouse adenovirus type 1 infection of natural killer cell-deficient mice
    Amanda R Welton
    Department of Microbiology and Immunology, University of Michigan, Ann Arbor, Michigan 48109, USA
    Virology 373:163-70. 2008
    ..We conclude that NK cells are not required to control virus replication in the brains of MAV-1-infected mice...
  6. pmc Usage of integrin and heparan sulfate as receptors for mouse adenovirus type 1
    Sharmila Raman
    Department of Microbiology and Immunology, University of Michigan, Michigan 48109 5620, USA
    J Virol 83:2831-8. 2009
    ....
  7. pmc Novel immunocompetent murine tumor model for evaluation of conditionally replication-competent (oncolytic) murine adenoviral vectors
    Michael Robinson
    Cell Genesys, Inc, 500 Forbes Blvd, South San Francisco, CA 94080, USA
    J Virol 83:3450-62. 2009
    ....
  8. pmc Mouse adenovirus type 1 infection of macrophages
    Shanna L Ashley
    Department of Microbiology and Immunology, University of Michigan, Ann Arbor, MI 48109, USA
    Virology 390:307-14. 2009
    ..Thus macrophages serve both as targets of infection and as effectors of the host response...
  9. pmc Mouse adenovirus type 1-induced breakdown of the blood-brain barrier
    Lisa E Gralinski
    Department of Microbiology and Immunology, University of Michigan, Ann Arbor, 48109 5620, USA
    J Virol 83:9398-410. 2009
    ..Furthermore, while the MAV-1-induced pathogenesis and inflammation were dependent on E3, MAV-1-induced breakdown of the blood-brain barrier and alteration of endothelial cell function were not dependent on E3 or CCL2...