Faculty

Molecular pathogenesis and host susceptibility genetics of virus infections

    My laboratory is studying the molecular genetics of virus-host cell interactions in two animal viruses, mouse adenovirus type 1 (MAV 1), and Punta Toro virus. Human adenoviruses cause 5-10% of respiratory illness in children and are associated with acute pneumonia in children in developing countries. Also, adenovirus infections are a serious complication of pediatric bone marrow transplants. MAV-1 affords us the opportunity to address adenovirus–host interactions in the natural host as well as in cell culture. By understanding how viral and cellular gene functions are regulated during infection, we can gain insight into disease processes.

     MAV-1 causes acute and persistent viral infections in susceptible mice via infection of cells of the monocyte/macrophage lineage and endothelial cells. We are using a molecular genetic approach to identify and characterize specific viral genes involved in pathogenesis of MAV-1. We have constructed mutant viruses in viral E1A and E3 genes, and these have reduced virulence in mice, indicating that E1A and E3 are key players in virus-host interactions.

     Current experiments are directed at understanding the molecular mechanisms by which these genes contribute to disease. We are investigating the host immune system contributions to MAV-1 disease using immunodeficient mice. We have identified an important role for early immune IgM production by B cells. We are addressing contributions of innate and adaptive immunity to viral disease.

     We are also studying virus-host interactions by investigating the contributions of host genetics to adenovirus disease. We have identified some inbred strains of mice that are far more susceptible to MAV-1 disease than other strains. We are performing a rigorous genetic analysis (positional cloning) of the basis for mouse susceptibility to MAV-1 infection. We have evidence for at least two quantitative trait loci (QTLs) for susceptibility to MAV-1, including a major one on mouse Chromosome 15. We anticipate that identifying the genes associated with these QTLs will identify new mechanisms in virus-host interactions.

     Punta Toro virus (PTV) is a negative strand RNA virus that causes severe infections in mice; it is a model for disease caused by the related highly pathogenic Rift Valley fever virus in humans.  We are studying virus-host interactions using PTV initially by identifying inbred mouse strains susceptible and resistant to the virus. We are carrying out a genetic analysis to identify determine whether susceptibility is a quantitative trait and to begin positional cloning of QTLs involved in susceptibility.

Selected Publications:

     Welton, A.R., L.E. Gralinski, and K.R. Spindler. 2008. Mouse adenovirus infection of natural killer cell-deficient mice. Virology 373:163-170.

     Weinberg, J.B., D.R. Jensen, L.E. Gralinski, A.R. Lake, G.S. Stempfle, and K.R. Spindler. 2007. Contributions of E1A to mouse adenovirus pathogenesis following intranasal inoculation. Virology 357:54-67.

     Weinberg, J.B., G.S. Stempfle, J.E. Wilkinson, J.G. Younger, and K.R. Spindler. 2005. Acute respiratory infection with mouse adenovirus type 1. Virology 340:245-254.

     Welton, A.R., E.J. Chesler, C. Sturkie, A.U. Jackson, G.N. Hirsch, and K.R. Spindler. 2005. Identification of quantitative trait loci for susceptibility to mouse adenovirus type 1. J. Virol. 79:11517-11522.

     Fang, L., and K.R. Spindler. 2005. E1A-CR3 Interaction-dependent and -independent functions of mSur2 in viral replication of early region 1A mutants of mouse adenovirus type 1. J. Virol. 79:3267-3276.

     Fang, L., J.L. Stevens, A.J. Berk, and K.R. Spindler. 2004. Requirement of Sur2 for Efficient replication of mouse adenovirus type 1. J. Virol. 78:12888-12900.
    
     Moore , M.L., E.L. McKissic, C.C. Brown, J.E. Wilkinson, and K.R. Spindler. 2004. Fatal disseminated mouse adenovirus type 1 infection in mice lacking B cells or Bruton's tyrosine kinase. J. Virol. 78:5584-5590.

     Moore , M.L., C.C. Brown, and K.R. Spindler. 2003. T cells cause acute immunopathology and are required for long-term survival in mouse adenovirus type 1-induced encephalomyelitis. J. Virol. 77: 10060-10070.

     Spindler, K.R., L. Fang, M.L. Moore, C.C. Brown, G.N. Hirsch, and A.K. Kajon. 2001. SJL/J mice are highly susceptible to infection by mouse adenovirus type 1. J. Virol. 75: 12039-12046.