Host-pathogen Genetics Using Listeria and Drosophila

Summary

Principal Investigator: NANCY ELIZABETH FREITAG
Abstract: Listeria monocytogenes is a facultative intracellular bacterial pathogen that is an important agent of serious human food-borne infections. L. monocytogenes has served for decades as an outstanding model system for elucidating cellular and molecular interactions that take place during host infection. This proposal seeks to combine the power of bacterial genetics with the use of a genetically tractable model host system to isolate host mutants with altered resistance to L. monocytogenes infection. The fruit fly Drosophila melanogaster has been intensely studied as a model genetic system for decades, and it offers several advantages as a model host including the striking conservation of its innate immune recognition pathways with those of vertebrate animals. Studies have demonstrated the conservation of pathogenic mechanisms used by infectious agents within flies and vertebrates, and the feasibility of screening thousands of flies to isolate mutants with altered responses to infection provides a powerful means of identifying host factors that contribute to host survival. Recent work has demonstrated that D. melanogaster serves as a suitable host for L. monocytogenes infection, thus this proposal seeks to exploit the use of these genetically tractable organisms to functionally identify critical factors of both pathogen and host that contribute to the establishment of microbe infection. In Aim 1, experiments will examine the cellular course of L. monocytogenes infection within insect tissue culture cells, larvae, and adult flies. These studies will provide a foundation for the functional analysis of pathogen and host gene products identified for their potential roles in influencing the outcome of microbial infection. Aim 2 will functionally characterize L. monocytogenes mutants that are attenuated for virulence in flies. Bacterial gene products required for insect infection will be analyzed for potential roles in mammalian infection. Aim 3 will isolate and identify Drosophila mutants with altered susceptibility to Listeria infection. These studies will help identify the host factors that contribute to immune responses directed against intracellular pathogens. The ultimate goal of the experiments described will be the functional characterization of bacterial factors that support survival within the host, and the elucidation of host mechanisms that serve to counter bacterial survival strategies.
Funding Period: 2004-07-01 - 2009-06-30
more information: NIH RePORT

Top Publications

  1. ncbi From hot dogs to host cells: how the bacterial pathogen Listeria monocytogenes regulates virulence gene expression
    Nancy E Freitag
    University of Washington, Seattle Biomedical Research Institute and the Department of Pathobiology, WA 98109 5219, USA
    Future Microbiol 1:89-101. 2006
  2. pmc How the bacterial pathogen Listeria monocytogenes mediates the switch from environmental Dr. Jekyll to pathogenic Mr. Hyde
    Michael J Gray
    Department of Food Science, Cornell University, Ithaca, NY 14853, USA
    Infect Immun 74:2505-12. 2006
  3. ncbi Interactions between circadian rhythm and immunity in Drosophila melanogaster
    Mimi M Shirasu-Hiza
    Curr Biol 17:R353-5. 2007
  4. pmc Identification of novel Listeria monocytogenes secreted virulence factors following mutational activation of the central virulence regulator, PrfA
    Gary C Port
    Molecular and Cellular Biology Program, University of Washington, Seattle, Washington, USA
    Infect Immun 75:5886-97. 2007
  5. ncbi Stimulation of enhanced CD8 T cell responses following immunization with a hyper-antigen secreting intracytosolic bacterial pathogen
    Megan J Smithey
    Veterans Affairs Medical Center, Portland, OR 97239, USA
    J Immunol 180:3406-16. 2008
  6. ncbi Two ways to survive infection: what resistance and tolerance can teach us about treating infectious diseases
    David S Schneider
    Department of Microbiology and Immunology, Stanford University, Stanford, California 94305, USA
    Nat Rev Immunol 8:889-95. 2008
  7. pmc Identification of Drosophila mutants altering defense of and endurance to Listeria monocytogenes infection
    Janelle S Ayres
    Department of Microbiology and Immunology, University of Illinois, Chicago, Illinois 60612, USA
    Genetics 178:1807-15. 2008

Detail Information

Publications7

  1. ncbi From hot dogs to host cells: how the bacterial pathogen Listeria monocytogenes regulates virulence gene expression
    Nancy E Freitag
    University of Washington, Seattle Biomedical Research Institute and the Department of Pathobiology, WA 98109 5219, USA
    Future Microbiol 1:89-101. 2006
    ..Once within the host cytosol, multiple changes in bacterial metabolism and gene expression help to complete the transformation of L. monocytogenes from soil dweller to intracellular pathogen...
  2. pmc How the bacterial pathogen Listeria monocytogenes mediates the switch from environmental Dr. Jekyll to pathogenic Mr. Hyde
    Michael J Gray
    Department of Food Science, Cornell University, Ithaca, NY 14853, USA
    Infect Immun 74:2505-12. 2006
  3. ncbi Interactions between circadian rhythm and immunity in Drosophila melanogaster
    Mimi M Shirasu-Hiza
    Curr Biol 17:R353-5. 2007
  4. pmc Identification of novel Listeria monocytogenes secreted virulence factors following mutational activation of the central virulence regulator, PrfA
    Gary C Port
    Molecular and Cellular Biology Program, University of Washington, Seattle, Washington, USA
    Infect Immun 75:5886-97. 2007
    ..monocytogenes virulence. The use of mutationally activated prfA alleles therefore provides a useful approach towards identifying gene products that contribute to L. monocytogenes pathogenesis...
  5. ncbi Stimulation of enhanced CD8 T cell responses following immunization with a hyper-antigen secreting intracytosolic bacterial pathogen
    Megan J Smithey
    Veterans Affairs Medical Center, Portland, OR 97239, USA
    J Immunol 180:3406-16. 2008
    ....
  6. ncbi Two ways to survive infection: what resistance and tolerance can teach us about treating infectious diseases
    David S Schneider
    Department of Microbiology and Immunology, Stanford University, Stanford, California 94305, USA
    Nat Rev Immunol 8:889-95. 2008
    ..An increased understanding of tolerance to pathogen infection could lead to more efficient treatments for infectious diseases and a better description of host-pathogen interactions...
  7. pmc Identification of Drosophila mutants altering defense of and endurance to Listeria monocytogenes infection
    Janelle S Ayres
    Department of Microbiology and Immunology, University of Illinois, Chicago, Illinois 60612, USA
    Genetics 178:1807-15. 2008
    ..By using a whole-animal model and screening for host survival, we revealed genes involved in physiologies different from those that were found in previous screens, which all had defects in defensive immune signaling...