Pulmonary defense against aspergillus fumigatus

Summary

Principal Investigator: Chad Steele
Abstract: DESCRIPTION (provided by applicant): Invasive pulmonary aspergillosis caused by the mold Aspergillus fumigatus has emerged as one of the most severe invasive fungal infections, not only in an expanding population of immunosuppressed patients, but also in individuals who are not considered classically immunocompromised. Innate immunity against A. fumigatus involves an initial wave of inflammatory reaction by alveolar macrophages followed by the seek-and- destroy mission of neutrophils. We have previously shown that the beta-glucan receptor Dectin-1 mediates alveolar macrophage (AM) inflammatory responses to A. fumigatus in vitro (Steele et al. PLoS Pathog 1:e42 Dec. 2005) and since the last review of this proposal (February 2009), we have now reported that mice deficient in Dectin-1 display an inherent susceptibility to A. fumigatus lung infection (Werner et al. J Immunol 182: 4938-4946, April 2009). A recent, intriguing finding was the observation that "innate IL-17" was a central component of resistance to A. fumigatus: (1) Dectin-1 KO mice had a defect in lung IL-17 production shortly after A. fumigatus challenge and (2) WT mice administered IL-17 neutralizing antibodies became susceptible to A. fumigatus infection. We now show by intracellular cytokine staining that the predominant cellular sources of IL-17 in the lungs after A. fumigatus challenge are surprisingly not lymphoid in origin, but rather myeloid CD11b+ and CD11c+ cell populations, which produce IL-17 in a Dectin-1 dependent manner. In other data, we show that IL-6 and TGF-[unreadable], which are essential for the induction of Th17 cells, are not produced at lower levels in the lungs of Dectin-1 KO mice exposed to A. fumigatus, suggesting that other mechanisms/mediators are responsible for Dectin-1 dependent IL-17 production. In turn, new data indicate that production of the Th17/IL- 17 induction cytokine IL-21 and the Th17/IL-17 maintenance cytokine IL-23 are attenuated in Dectin-1 KO mice after A. fumigatus challenge, as are the chemokines CXCL12/SDF-1 and CCL2/MCP-1. These results suggest that Dectin-1 may control IL-17 levels in the lungs after A. fumigatus exposure via production of IL-17- associated induction cytokines or production of chemokines essential for the recruitment of IL-17-producing cells to the lungs. Finally, the Th17/IL-17 associated cytokine IL-22 was found to be highly dependent in Dectin-1 for its expression in the lungs. Therefore, we hypothesize that optimal IL-17-mediated defense against A. fumigatus is dependent on the beta glucan receptor Dectin-1. The following Specific Aims will test our hypothesis: (1) To identify the Dectin-1 dependent cellular source of IL-17 in the lungs after A. fumigatus exposure, (2) To identify the mechanism(s) responsible for Dectin-1 dependent, cell-specific production of IL-17 after A. fumigatus lung exposure and (3) To determine whether mediators associated with IL-17 induction (IL-21/IL-23), recruitment (SDF-1/MCP-1) and signaling (IL-22) pathways modulate lung host defense against A. fumigatus.
Funding Period: 2010-05-01 - 2014-04-30
more information: NIH RePORT

Top Publications

  1. pmc Vitamin D3 attenuates Th2 responses to Aspergillus fumigatus mounted by CD4+ T cells from cystic fibrosis patients with allergic bronchopulmonary aspergillosis
    James L Kreindler
    Children s Hospital of Pittsburgh, Pittsburgh, Pennsylvania, USA
    J Clin Invest 120:3242-54. 2010
  2. ncbi IL-33 and M2a alveolar macrophages promote lung defense against the atypical fungal pathogen Pneumocystis murina
    Michael P Nelson
    Department of Medicine, University of Alabama at Birmingham, Birmingham, AL 35294, USA
    J Immunol 186:2372-81. 2011
  3. pmc Aspergillus terreus accessory conidia are multinucleated, hyperpolarizing structures that display differential dectin staining and can induce heightened inflammatory responses in a pulmonary model of aspergillosis
    Eszter Deak
    Mycotic Diseases Branch, Centers for Disease Control and Prevention, Atlanta, GA, USA
    Virulence 2:200-7. 2011
  4. pmc Neutrophils produce interleukin 17A (IL-17A) in a dectin-1- and IL-23-dependent manner during invasive fungal infection
    Jessica L Werner
    Department of Medicine, School of Medicine, University of Alabama at Birmingham, Birmingham, AL 35294, USA
    Infect Immun 79:3966-77. 2011
  5. pmc Dectin-1-dependent interleukin-22 contributes to early innate lung defense against Aspergillus fumigatus
    Melissa A Gessner
    Department of Medicine, University of Alabama at Birmingham, Birmingham, Alabama, USA
    Infect Immun 80:410-7. 2012
  6. ncbi Immunology of fungal infections: lessons learned from animal models
    Chad Steele
    Department of Medicine, University of Alabama at Birmingham, Birmingham, AL 35294, United States
    Curr Opin Microbiol 15:413-9. 2012
  7. pmc Experimental Pneumocystis lung infection promotes M2a alveolar macrophage-derived MMP12 production
    Michael P Nelson
    Dept of Medicine, Univ of Alabama at Birmingham, Birmingham, AL 35294, USA
    Am J Physiol Lung Cell Mol Physiol 303:L469-75. 2012
  8. pmc The β-glucan receptor dectin-1 promotes lung immunopathology during fungal allergy via IL-22
    Lauren M Lilly
    Department of Medicine, University of Alabama at Birmingham, Birmingham, AL 35294, USA
    J Immunol 189:3653-60. 2012
  9. pmc Eosinophil deficiency compromises lung defense against Aspergillus fumigatus
    Lauren M Lilly
    Department of Medicine, University of Alabama at Birmingham, Birmingham, Alabama, USA
    Infect Immun 82:1315-25. 2014

Detail Information

Publications9

  1. pmc Vitamin D3 attenuates Th2 responses to Aspergillus fumigatus mounted by CD4+ T cells from cystic fibrosis patients with allergic bronchopulmonary aspergillosis
    James L Kreindler
    Children s Hospital of Pittsburgh, Pittsburgh, Pennsylvania, USA
    J Clin Invest 120:3242-54. 2010
    ..These data provide rationale for a therapeutic trial of vitamin D to prevent or treat ABPA in patients with CF...
  2. ncbi IL-33 and M2a alveolar macrophages promote lung defense against the atypical fungal pathogen Pneumocystis murina
    Michael P Nelson
    Department of Medicine, University of Alabama at Birmingham, Birmingham, AL 35294, USA
    J Immunol 186:2372-81. 2011
    ..Collectively, these results indicate that M2a AMs are potent effector cells against P. murina. Furthermore, enhancing M2a polarization may be an adjunctive therapy for the treatment of Pneumocystis...
  3. pmc Aspergillus terreus accessory conidia are multinucleated, hyperpolarizing structures that display differential dectin staining and can induce heightened inflammatory responses in a pulmonary model of aspergillosis
    Eszter Deak
    Mycotic Diseases Branch, Centers for Disease Control and Prevention, Atlanta, GA, USA
    Virulence 2:200-7. 2011
    ..We present evidence that A. terreus AC are phenotypically distinct from PC and can be potent activators of the innate immune mechanism thus possibly playing a role in this organism's pathogenesis...
  4. pmc Neutrophils produce interleukin 17A (IL-17A) in a dectin-1- and IL-23-dependent manner during invasive fungal infection
    Jessica L Werner
    Department of Medicine, School of Medicine, University of Alabama at Birmingham, Birmingham, AL 35294, USA
    Infect Immun 79:3966-77. 2011
    ..In summary, Dectin-1-dependent IL-17A production in the lungs during invasive fungal infection is mediated in part by CD11b(+) Ly-6G(+) neutrophils in an IL-23-dependent manner...
  5. pmc Dectin-1-dependent interleukin-22 contributes to early innate lung defense against Aspergillus fumigatus
    Melissa A Gessner
    Department of Medicine, University of Alabama at Birmingham, Birmingham, Alabama, USA
    Infect Immun 80:410-7. 2012
    ..Collectively, our results indicate that early innate lung defense against A. fumigatus is mediated by Dectin-1-dependent IL-22 production...
  6. ncbi Immunology of fungal infections: lessons learned from animal models
    Chad Steele
    Department of Medicine, University of Alabama at Birmingham, Birmingham, AL 35294, United States
    Curr Opin Microbiol 15:413-9. 2012
    ..This review focuses on recent advances in our understanding of immune responses to fungal infections gained using animal models...
  7. pmc Experimental Pneumocystis lung infection promotes M2a alveolar macrophage-derived MMP12 production
    Michael P Nelson
    Dept of Medicine, Univ of Alabama at Birmingham, Birmingham, AL 35294, USA
    Am J Physiol Lung Cell Mol Physiol 303:L469-75. 2012
    ..murina. Collectively, our data indicate that MMP12 induction is a component of the P. murina-induced M2 response and thus provides insight into the link between Pneumocystis colonization/infection and exacerbations in COPD...
  8. pmc The β-glucan receptor dectin-1 promotes lung immunopathology during fungal allergy via IL-22
    Lauren M Lilly
    Department of Medicine, University of Alabama at Birmingham, Birmingham, AL 35294, USA
    J Immunol 189:3653-60. 2012
    ..Collectively, these results indicate that the β-glucan receptor Dectin-1 contributes to lung inflammation and immunopathology associated with persistent fungal exposure via the production of IL-22...
  9. pmc Eosinophil deficiency compromises lung defense against Aspergillus fumigatus
    Lauren M Lilly
    Department of Medicine, University of Alabama at Birmingham, Birmingham, Alabama, USA
    Infect Immun 82:1315-25. 2014
    ..fumigtaus in vitro, which does not require cell contact and can be recapitulated by eosinophil whole-cell lysates. Collectively, our data support a role for eosinophils in the lung response after A. fumigatus exposure...

Research Grants30

  1. 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. ..
  2. Chemokine-Cytokine Nexus in Fungal Immunity
    George S Deepe; Fiscal Year: 2013
    ..Our work will demonstrate how important it is for appropriate signaling through a surface receptor for a particular chemokine in order that the host can survive. ..
  3. Oxidation in Inflammation and Cardiovascular Disease
    Stanley L Hazen; Fiscal Year: 2013
    ..It may also lead to important insights for atherosclerosis risk assessment, diagnosis and therapy. ..
  4. Regulation of monocyte recruitment and function by the IL-23/IL-17 axis
    Rance E Berg; Fiscal Year: 2013
    ..The data obtained from these studies may lead to therapeutic options aimed at regulating monocyte function during infectious and other disease states. ..
  5. Endothelial Injury and Repair: CardioPulmonary Vascular Biology COBRE
    SHARON IRENE SMITH ROUNDS; Fiscal Year: 2013
    ..abstract_text> ..
  6. Signaling in Inflammation, Stress, and Tumorigenesis
    GEORGE ROBERT STARK; Fiscal Year: 2013
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  7. Digitalis-Induced Signaling by Cardiac Na+/K+-ATPase
    Amir Askari; Fiscal Year: 2013
    ..abstract_text> ..
  8. Molecular Analyses and Interventions for Biodefense and Emerging Pathogens
    Olaf Schneewind; Fiscal Year: 2013
    ..Research and training at the GLRCE is governed by a mechanism involving ongoing review of scientific excellence and translational goals, inter-institutional advisory boards and external scientific advisory bodies. ..
  9. Mental Stress Ischemia: Prognosis and Genetic Influences
    Arshed A Quyyumi; Fiscal Year: 2013
    ....