Synergy between TLR2 and IL-22R in airway epithelial cells during MRSA challenge

Summary

Principal Investigator: Jeremy P McAleer
Abstract: DESCRIPTION (provided by applicant): The gram-positive organism Staphylococcus aureus colonizes the nasal passages in 20-50 percent of people, and community-acquired pneumonia caused by methicillin-resistant S. aureus (MRSA) is increasing. This suggests a need to develop vaccination and/or treatment strategies. Toll-like receptor 2 (TLR2) recognizes peptidoglycan and initiates natural immunity to S. aureus. Dendritic cells respond to TLR ligands by producing many factors including IL-1b and IL-23. These cytokines condition T cells to produce IL-17 and IL-22 during a process called Th17 differentiation. Interleukin-17 and IL- 22 were recently shown to control lung S. aureus infection (Kudva, Scheller, et al;J Immunol, in press). It is not known which cell type(s) must express TLR2 for efficient production of IL-1b and IL-23 in vivo, or for clearance of MRSA. Since airway epithelial cells (AECs) express TLRs and are the first point of contact with lung pathogens, they could play a role in initiating inflammation. Interleukin-22 has multiple effects on epithelial cells including proliferation, survival, and induction of antimicrobial proteins. Intestinal epithelial cells respond to IL-22 by producing regenerating islet-derived 3 (Reg3) family genes, which can directly inhibit the growth of MRSA (preliminary data). In the lung, the IL-22 receptor (IL-22R1) is restricted to AECs, and exposure to MRSA increased Reg3 expression (preliminary data). These data led to the hypothesis that TLR2 signaling in AECs initiates Th17 cell recruitment to the lung during MRSA infection, and also synergizes with IL-22R to mediate host defense through the induction of Reg3 antimicrobial lectins. This hypothesis will be tested with the following aims: Specific Aim 1: Determine the roles of TLR2 and IL-22R1 expression in AECs during lung infection with S. aureus USA300. TLR2 expression in radio-resistant cells such as AECs will be studied using bone marrow chimeras between C57BL/6 and TLR2-/- mice. The role of IL-22R1 in AECs will be determined by crossing epithelial-specific-Cre mice with IL22R1-floxed mice. These experiments will establish the complementary roles of TLR2 and IL-22R1 signaling in AECs during MRSA infection. Specific Aim 2: Determine the role of Reg3 family lectins as possible effectors downstream of IL-22R. In vitro experiments will determine if TLR ligands and IL-22 synergize to induce Reg3 in tracheal epithelial cells. In vivo experiments will examine the role of Th17-derived cytokines in Reg3 expression. Reg3g-/- mice will be used to clarify its role in controlling MRSA infection.
Funding Period: 2011-09-01 - 2014-08-31
more information: NIH RePORT

Top Publications

  1. pmc Innate Stat3-mediated induction of the antimicrobial protein Reg3γ is required for host defense against MRSA pneumonia
    Sun Mi Choi
    Department of Genetics, Louisiana State University Health Sciences Center, New Orleans, LA 70112, USA
    J Exp Med 210:551-61. 2013

Research Grants

  1. Influenza A Inhibits TH17 Host Defense Against Bacterial Pneumonia
    John F Alcorn; Fiscal Year: 2013
  2. BEHAVIORAL GENOMICS OF ALCOHOL NEUROADAPTATION
    John C Crabbe; Fiscal Year: 2013
  3. IL-22 in Thymic Regeneration
    Marcel R m van den Brink; Fiscal Year: 2013
  4. Th17 Cytokines and Lung Immunity
    Jay K Kolls; Fiscal Year: 2013
  5. A TOLERANCE APPROACH TO XENOTRANSPLANTATION
    David H Sachs; Fiscal Year: 2013
  6. Rocky Mountain Regional Center of Excellence or Biodefense and Emerging Infectiou
    John T Belisle; Fiscal Year: 2013
  7. Northeast Biodefense Center
    W Ian Lipkin; Fiscal Year: 2013
  8. Investigating the role of interleukin-22 in thymus function
    Jarrod Dudakov; Fiscal Year: 2013
  9. Improving Cardiac Function After Myocardial Infarction
    Steven R Houser; Fiscal Year: 2013
  10. Gene Networks controlling macrophage-adipocyte interactions in insulin
    Christopher K Glass; Fiscal Year: 2013

Detail Information

Publications1

  1. pmc Innate Stat3-mediated induction of the antimicrobial protein Reg3γ is required for host defense against MRSA pneumonia
    Sun Mi Choi
    Department of Genetics, Louisiana State University Health Sciences Center, New Orleans, LA 70112, USA
    J Exp Med 210:551-61. 2013
    ..These findings reveal an antibacterial function for lung epithelium through Stat3-mediated induction of Reg3γ...

Research Grants30

  1. Influenza A Inhibits TH17 Host Defense Against Bacterial Pneumonia
    John F Alcorn; Fiscal Year: 2013
    ..These data may be directly applicable to the hospital setting and may reveal novel therapeutic strategies that would decrease morbidity and mortality, and improve patient outcome. ..
  2. BEHAVIORAL GENOMICS OF ALCOHOL NEUROADAPTATION
    John C Crabbe; Fiscal Year: 2013
    ..An Education and Outreach component trains pre- and post-doctoral students in alcohol research, disseminates research findings to the public, and engages in a range of activities with elementary-to-high school students. ..
  3. IL-22 in Thymic Regeneration
    Marcel R m van den Brink; Fiscal Year: 2013
    ....
  4. Th17 Cytokines and Lung Immunity
    Jay K Kolls; Fiscal Year: 2013
    ..We have identified a novel T-cell population that plays a critical role in defense against pneumonia. This application will explore how these cells are generated and how they control host defense in the lung. ..
  5. A TOLERANCE APPROACH TO XENOTRANSPLANTATION
    David H Sachs; Fiscal Year: 2013
    ..abstract_text> ..
  6. Rocky Mountain Regional Center of Excellence or Biodefense and Emerging Infectiou
    John T Belisle; Fiscal Year: 2013
    ..abstract_text> ..
  7. Northeast Biodefense Center
    W Ian Lipkin; Fiscal Year: 2013
    ..As a Center based in a School of Public Health and a State Department of Health, the NBC has a firm commitment to and practical understanding of Emergency Preparedness. ..
  8. Investigating the role of interleukin-22 in thymus function
    Jarrod Dudakov; Fiscal Year: 2013
    ....
  9. Improving Cardiac Function After Myocardial Infarction
    Steven R Houser; Fiscal Year: 2013
    ..A gene vector core will generate AAV6 vectors with novel therapeutics for testing in the pig Ml model. An administrative core will ensure data sharing and effective use of all resources. ..
  10. Gene Networks controlling macrophage-adipocyte interactions in insulin
    Christopher K Glass; Fiscal Year: 2013
    ..abstract_text> ..