TLR5 and Pulmonary Innate Immunity

Summary

Principal Investigator: THOMAS HAWN
Affiliation: University of Washington
Country: USA
Abstract: Although Toll-like receptors (TLRs) are critical mediators of the immune response to pathogens, the influence of polymorphisms in this gene family on susceptibility to infection in humans is poorly understood. We previously demonstrated that TLRS recognizes flagellin, a potent inflammatory stimulus present in the flagellar structure of many bacteria. We have also shown that approximately 10% of individuals have a TLRS stop codon polymorphism (TLR5-392STOP) that inhibits flagellin signaling in a dominant fashion and is associated with susceptibility to pneumonia caused by Legionella pneumophila, a flagellated bacterium. While these observations indicate that TLRS influences susceptibility to human infection, a number of critical issues are not understood, including the mechanism, scope, and nature of TLRS's influence on the immune response during the course of an in vivo infection. Our hypothesis is that alteration of TLRS, via polymorphisms in humans or targeted TLRS gene deletion in mice, will change the host response to flagellated bacteria at molecular, cellular, and in vivo levels. We aim to: 1) determine the novel molecular mechanism of TLR5-392STOP's dominant inhibition of flagellin signaling in humans, 2) use mouse knockout strains to understand the influence of TLRS on the in vivo immune response to infection with Legionella pneumophila, and 3) use murine transgenic and bone marrow chimera studies to examine which cells regulate TLRS-mediated immune responses to Legionella. The TLR5-392STOP mutation provides a unique opportunity to study the in vitro and in vivo effects of human TLRS deficiency and, along with TLRS-/- mice, will enable us to address critical questions in innate immunity of receptor redundancy, regulation, and specificity. The immunogenetic models derived from these studies will illuminate the molecular basis of why individuals have different susceptibility to flagellated bacterial infections and hopefully culminate in novel insights for future therapies.
Funding Period: 2005-03-01 - 2010-02-28
more information: NIH RePORT

Top Publications

  1. ncbi Myeloid differentiation primary response gene (88)- and toll-like receptor 2-deficient mice are susceptible to infection with aerosolized Legionella pneumophila
    Thomas R Hawn
    Department of Medicine, University of Washington School of Medicine, Seattle, WA 98195, USA
    J Infect Dis 193:1693-702. 2006
  2. ncbi Cutting edge: Tlr5-/- mice are more susceptible to Escherichia coli urinary tract infection
    Erica Andersen-Nissen
    Institute for Systems Biology, Seattle, WA 98103, USA
    J Immunol 178:4717-20. 2007
  3. ncbi Altered inflammatory responses in TLR5-deficient mice infected with Legionella pneumophila
    Thomas R Hawn
    Department of Medicine, University of Washington School of Medicine, Seattle, WA 98195, USA
    J Immunol 179:6981-7. 2007
  4. ncbi Toll-like receptor signaling in airborne Burkholderia thailandensis infection
    T Eoin West
    Division of Pulmonary and Critical Care Medicine, Department of Medicine, University of Washington School of Medicine, Seattle, Washington 98104, USA
    Infect Immun 77:5612-22. 2009
  5. ncbi Role of Toll-like receptor 5 in the innate immune response to acute P. aeruginosa pneumonia
    Amy E Morris
    Harborview Medical Center, Seattle, WA 98104, USA
    Am J Physiol Lung Cell Mol Physiol 297:L1112-9. 2009

Scientific Experts

  • THOMAS HAWN
  • T Eoin West
  • Amy E Morris
  • Erica Andersen-Nissen
  • H Denny Liggitt
  • Shawn J Skerrett
  • Kelly D Smith
  • Satoshi Uematsu
  • Alex Nachman
  • Aaron E Lampano
  • Alan Aderem
  • Shizuo Akira

Detail Information

Publications6

  1. ncbi Myeloid differentiation primary response gene (88)- and toll-like receptor 2-deficient mice are susceptible to infection with aerosolized Legionella pneumophila
    Thomas R Hawn
    Department of Medicine, University of Washington School of Medicine, Seattle, WA 98195, USA
    J Infect Dis 193:1693-702. 2006
    ..Although pathogens are typically recognized by multiple TLRs, the specific roles of individual TLRs in mediating host protection during in vivo infection are not well understood...
  2. ncbi Cutting edge: Tlr5-/- mice are more susceptible to Escherichia coli urinary tract infection
    Erica Andersen-Nissen
    Institute for Systems Biology, Seattle, WA 98103, USA
    J Immunol 178:4717-20. 2007
    ..Together, these data represent the first evidence that TLR5 regulates the innate immune response in the urinary tract and is essential for an effective murine in vivo immune response to an extracellular pathogen...
  3. ncbi Altered inflammatory responses in TLR5-deficient mice infected with Legionella pneumophila
    Thomas R Hawn
    Department of Medicine, University of Washington School of Medicine, Seattle, WA 98195, USA
    J Immunol 179:6981-7. 2007
    ..Thus, TLR5 mediates recognition of Lp in AMs and performs a distinct role during the in vivo pulmonary immune response through regulation of early PMN recruitment and subsequent later development of pneumonia...
  4. ncbi Toll-like receptor signaling in airborne Burkholderia thailandensis infection
    T Eoin West
    Division of Pulmonary and Critical Care Medicine, Department of Medicine, University of Washington School of Medicine, Seattle, Washington 98104, USA
    Infect Immun 77:5612-22. 2009
    ..TLR signaling in B. thailandensis infection is substantially comparable to signaling induced by virulent B. pseudomallei. These studies provide additional insights into the host-pathogen interaction in pneumonic Burkholderia infection...
  5. ncbi Role of Toll-like receptor 5 in the innate immune response to acute P. aeruginosa pneumonia
    Amy E Morris
    Harborview Medical Center, Seattle, WA 98104, USA
    Am J Physiol Lung Cell Mol Physiol 297:L1112-9. 2009
    ..aeruginosa and contributes to antibacterial resistance in a manner that is partially inoculum dependent. These data are the first to demonstrate a unique role for TLR5 in the innate immune response to P. aeruginosa lung infection...