Cloning a major gene for mouse adenovirus susceptibility

Summary

Principal Investigator: KATHERINE SPINDLER
Abstract: Adenoviruses cause 5-10% of respiratory illness in children and are associated with acute pneumonia in children in developing countries, where they are a major cause of illness and death. 5-15% of pediatric bone marrow transplant patients develop adenovirus infections;morbidity ranges from 50-80%. However, little is known about adenovirus pathogenesis, especially contributions of host factors to disease susceptibility. Identification of such host factors will enable better design of antiviral and immune suppressive therapy and adenovirus-based gene therapy. Mouse adenovirus type 1 (MAV-1) provides an excellent model for studying susceptibility to infectious disease, because it can be studied in the natural host and there are inbred strains with different susceptibilities to MAV-1. The objective of this proposal is to define and characterize the host gene(s) underlying a major quantitative trait locus (QTL) for MAV-1 susceptibility in inbred mice. The central hypothesis is that the major QTL on Chromosome 15 for MAV-1 susceptibility in SJL/J mice contains an immune system gene that is polymorphic in susceptible and resistant mice. Genetic mapping will be combined with candidate gene approaches in two specific aims. (1) The major QTL for susceptibility will be fine mapped using several complementary approaches. A high density of polymorphic markers will be used to genotype recombinant progeny backcross, intercross, and third-generation cross mice (recombinant progeny testing). An interval-specific congenic strain will be constructed in which the interval from susceptible SJL/J mice will be introgressed into the resistant BALB/cJ background. Additional inbred mouse strains will be tested to determine whether they share a genetic basis for susceptibility with the major QTL in SJL/J mice. If so they will be used for fine mapping, haplotype analysis, and candidate gene identification. (2) A list of 20-30 candidate genes for the Chromosome 15 QTL will be compared for sequence and gene expression differences between susceptible and resistant strains. A candidate gene will be identified and tested genetically by replacing it in a resistant strain with the susceptible allele. The project is expected to identify a previously undescribed intractiorT^ieT^eerrK6sfiTrTrmrne res immune evasion, thus increasing our understanding of viral infections and mechanisms of host response to pathogens. ~
Funding Period: ----------------2006 - ---------------2011-
more information: NIH RePORT

Top Publications

  1. pmc Host genetic variation in susceptibility to Punta Toro virus
    Shanna L Ashley
    Department of Microbiology and Immunology, University of Michigan, Ann Arbor, MI 48109, USA
    Virus Res 157:71-5. 2011
  2. pmc Viral disruption of the blood-brain barrier
    Katherine R Spindler
    Department of Microbiology and Immunology, University of Michigan Medical School, Ann Arbor, MI 48109 5620, USA
    Trends Microbiol 20:282-90. 2012
  3. pmc The major locus for mouse adenovirus susceptibility maps to genes of the hematopoietic cell surface-expressed LY6 family
    Katherine R Spindler
    Department of Microbiology and Immunology, University of Michigan, Ann Arbor, MI 48109, USA
    J Immunol 184:3055-62. 2010
  4. pmc Polymorphisms in Ly6 genes in Msq1 encoding susceptibility to mouse adenovirus type 1
    Matthew T Stier
    Department of Microbiology and Immunology, University of Michigan Medical School, Ann Arbor, MI, 48109 5620, USA
    Mamm Genome 23:250-8. 2012

Scientific Experts

  • KATHERINE SPINDLER
  • Matthew T Stier
  • Shanna L Ashley
  • Stefanie M Ameres
  • Sonja R Gerrard
  • Oded Foreman
  • Jason B Weinberg
  • Kathryn A Eaton

Detail Information

Publications5

  1. pmc Host genetic variation in susceptibility to Punta Toro virus
    Shanna L Ashley
    Department of Microbiology and Immunology, University of Michigan, Ann Arbor, MI 48109, USA
    Virus Res 157:71-5. 2011
    ..These findings will enable an unbiased genetic approach to identify host genes mediating susceptibility to PTV...
  2. pmc Viral disruption of the blood-brain barrier
    Katherine R Spindler
    Department of Microbiology and Immunology, University of Michigan Medical School, Ann Arbor, MI 48109 5620, USA
    Trends Microbiol 20:282-90. 2012
    ..Viral proteins acting in BBB disruption are described for HIV-1, currently the most studied encephalitic virus; other viruses are also discussed...
  3. pmc The major locus for mouse adenovirus susceptibility maps to genes of the hematopoietic cell surface-expressed LY6 family
    Katherine R Spindler
    Department of Microbiology and Immunology, University of Michigan, Ann Arbor, MI 48109, USA
    J Immunol 184:3055-62. 2010
    ..The results indicate that a major host factor in mouse adenovirus type 1 susceptibility is likely to be a member of the Ly6 gene family...
  4. pmc Polymorphisms in Ly6 genes in Msq1 encoding susceptibility to mouse adenovirus type 1
    Matthew T Stier
    Department of Microbiology and Immunology, University of Michigan Medical School, Ann Arbor, MI, 48109 5620, USA
    Mamm Genome 23:250-8. 2012
    ..Collectively, these genetic variations have implications for the structure, function, and/or expression of Ly6 and Ly6-related genes that may contribute to the observed strain-specific differences in susceptibility to MAV-1...