Immune recognition of Pseudomonas aeruginosa mediated by the IPAF/NLRC4 inflammasome

Pseudomonas aeruginosa is a Gram-negative bacterium that causes opportunistic infections in immunocompromised individuals. P. aeruginosa employs a type III secretion system to inject effector molecules into the cytoplasm of the host cell. This interaction with the host cell leads to inflammatory responses that eventually result in cell death. We show that infection of macrophages with P. aeruginosa results in activation of caspase-1 in an IPAF-dependent, but flagellin-independent, manner. Macrophages deficient in IPAF or caspase-1 were markedly resistant to P. aeruginosa–induced cell death and release of the proinflammatory cytokine interleukin (IL)-1β. A subset of P. aeruginosa isolates express the effector molecule exoenzyme U (ExoU), which we demonstrate is capable of inhibiting caspase-1–driven proinflammatory cytokine production. This study shows a key role for IPAF and capase-1 in innate immune responses to the pathogen P. aeruginosa, and also demonstrates that virulent ExoU-expressing strains of P. aeruginosa can circumvent this innate immune response.

[1]  D. Golan,et al.  Resistance to Pseudomonas aeruginosa Chronic Lung Infection Requires Cystic Fibrosis Transmembrane Conductance Regulator-Modulated Interleukin-1 (IL-1) Release and Signaling through the IL-1 Receptor , 2007, Infection and Immunity.

[2]  S. Mariathasan,et al.  Inflammasome adaptors and sensors: intracellular regulators of infection and inflammation , 2007, Nature Reviews Immunology.

[3]  D. Philpott,et al.  Nod-like proteins in immunity, inflammation and disease , 2006, Nature Immunology.

[4]  T. Murray,et al.  FlhF Is Required for Swimming and Swarming in Pseudomonas aeruginosa , 2006, Journal of bacteriology.

[5]  J. Tschopp,et al.  Caspase-1 Activation of Lipid Metabolic Pathways in Response to Bacterial Pore-Forming Toxins Promotes Cell Survival , 2006, Cell.

[6]  J. Bertin,et al.  Role of the caspase-1 inflammasome in Salmonella typhimurium pathogenesis , 2006, The Journal of experimental medicine.

[7]  J. Bertin,et al.  Cytosolic flagellin requires Ipaf for activation of caspase-1 and interleukin 1β in salmonella-infected macrophages , 2006, Nature Immunology.

[8]  Alan Aderem,et al.  Cytoplasmic flagellin activates caspase-1 and secretion of interleukin 1β via Ipaf , 2006, Nature Immunology.

[9]  K. Bieging,et al.  A C-Terminal Domain Targets the Pseudomonas aeruginosa Cytotoxin ExoU to the Plasma Membrane of Host Cells , 2006, Infection and Immunity.

[10]  M. Swanson,et al.  Cytosolic recognition of flagellin by mouse macrophages restricts Legionella pneumophila infection , 2006, The Journal of experimental medicine.

[11]  V. Dixit,et al.  Cryopyrin activates the inflammasome in response to toxins and ATP , 2006, Nature.

[12]  S. Akira,et al.  Bacterial RNA and small antiviral compounds activate caspase-1 through cryopyrin/Nalp3 , 2006, Nature.

[13]  F. Martinon,et al.  Gout-associated uric acid crystals activate the NALP3 inflammasome , 2006, Nature.

[14]  J. Bertin,et al.  Critical role for NALP3/CIAS1/Cryopyrin in innate and adaptive immunity through its regulation of caspase-1. , 2006, Immunity.

[15]  W. Dietrich,et al.  Flagellin-Deficient Legionella Mutants Evade Caspase-1- and Naip5-Mediated Macrophage Immunity , 2006, PLoS pathogens.

[16]  W. Dietrich,et al.  The Birc1e cytosolic pattern-recognition receptor contributes to the detection and control of Legionella pneumophila infection , 2006, Nature Immunology.

[17]  V. Dixit,et al.  Innate immunity against Francisella tularensis is dependent on the ASC/caspase-1 axis , 2005, The Journal of experimental medicine.

[18]  M. Chamaillard,et al.  NOD-LRR proteins: role in host-microbial interactions and inflammatory disease. , 2005, Annual review of biochemistry.

[19]  J. Mekalanos,et al.  Role of the Type III Secreted Exoenzymes S, T, and Y in Systemic Spread of Pseudomonas aeruginosa PAO1 In Vivo , 2005, Infection and Immunity.

[20]  S. Lory,et al.  Activities of Pseudomonas aeruginosa Effectors Secreted by the Type III Secretion System In Vitro and during Infection , 2005, Infection and Immunity.

[21]  A. Hauser,et al.  Functional Regions of the Pseudomonas aeruginosa Cytotoxin ExoU , 2005, Infection and Immunity.

[22]  J. Ting,et al.  CATERPILLER: a novel gene family important in immunity, cell death, and diseases. , 2005, Annual review of immunology.

[23]  Sheng Yang He,et al.  Type III protein secretion mechanism in mammalian and plant pathogens. , 2004, Biochimica et biophysica acta.

[24]  D. Frank,et al.  ExoU is a potent intracellular phospholipase , 2004, Molecular microbiology.

[25]  V. Dixit,et al.  Differential activation of the inflammasome by caspase-1 adaptors ASC and Ipaf , 2004, Nature.

[26]  L. Hazlett,et al.  Regulation of Pseudomonas aeruginosa corneal infection in IL-1ß converting enzyme (ICE, caspase-1) deficient mice , 2004, Current eye research.

[27]  J. Sun,et al.  Pseudomonas aeruginosa ExoS and ExoT. , 2004, Reviews of physiology, biochemistry and pharmacology.

[28]  J. Rello,et al.  Secretion of the toxin ExoU is a marker for highly virulent Pseudomonas aeruginosa isolates obtained from patients with hospital-acquired pneumonia. , 2003, The Journal of infectious diseases.

[29]  E. Dennis,et al.  In Vivo Phospholipase Activity of the Pseudomonas aeruginosa Cytotoxin ExoU and Protection of Mammalian Cells with Phospholipase A2 Inhibitors* , 2003, Journal of Biological Chemistry.

[30]  Jack E. Dixon,et al.  Cleavage of Arabidopsis PBS1 by a Bacterial Type III Effector , 2003, Science.

[31]  M. Lei,et al.  The mechanism of action of the Pseudomonas aeruginosa‐encoded type III cytotoxin, ExoU , 2003, The EMBO journal.

[32]  C. Belka,et al.  Apoptotic Response of Chang Cells to Infection with Pseudomonas aeruginosa Strains PAK and PAO-I: Molecular Ordering of the Apoptosis Signaling Cascade and Role of Type IV Pili , 2003, Infection and Immunity.

[33]  R. Kolesnick,et al.  Host defense against Pseudomonas aeruginosa requires ceramide-rich membrane rafts , 2003, Nature Medicine.

[34]  J. Rello,et al.  Type III protein secretion is associated with poor clinical outcomes in patients with ventilator-associated pneumonia caused by Pseudomonas aeruginosa. , 2002, Critical Care Medicine.

[35]  T. van der Poll,et al.  Role of interleukin-1 in the pulmonary immune response during Pseudomonas aeruginosa pneumonia. , 2002, American journal of physiology. Lung cellular and molecular physiology.

[36]  R. Savel,et al.  Type III protein secretion is associated with death in lower respiratory and systemic Pseudomonas aeruginosa infections. , 2001, The Journal of infectious diseases.

[37]  Y. Usson,et al.  Pore‐forming activity of type III system‐secreted proteins leads to oncosis of Pseudomonas aeruginosa‐infected macrophages , 2001, Molecular microbiology.

[38]  J. Engel,et al.  The Arginine Finger Domain of ExoT Contributes to Actin Cytoskeleton Disruption and Inhibition of Internalization ofPseudomonas aeruginosa by Epithelial Cells and Macrophages , 2000, Infection and Immunity.

[39]  F. Lang,et al.  CD95/CD95 ligand interactions on epithelial cells in host defense to Pseudomonas aeruginosa. , 2000, Science.

[40]  J. Engel,et al.  Pseudomonas aeruginosa Induces Type-III-Secretion-Mediated Apoptosis of Macrophages and Epithelial Cells , 1999, Infection and Immunity.

[41]  J. Engel,et al.  Pili Binding to Asialo-GM1 on Epithelial Cells Can Mediate Cytotoxicity or Bacterial Internalization byPseudomonas aeruginosa , 1999, Infection and Immunity.

[42]  J. Coburn,et al.  Macrophages and Epithelial Cells Respond Differently to the Pseudomonas aeruginosa Type III Secretion System , 1999, Infection and Immunity.

[43]  S Falkow,et al.  The Salmonella invasin SipB induces macrophage apoptosis by binding to caspase-1. , 1999, Proceedings of the National Academy of Sciences of the United States of America.

[44]  Junying Yuan,et al.  Shigella-induced Apoptosis Is Dependent on Caspase-1 Which Binds to IpaB* , 1998, The Journal of Biological Chemistry.

[45]  C. Dinarello.  Interleukin‐1β, Interleukin‐18, and the Interleukin‐1β Converting Enzyme a , 1998 .

[46]  M Soltani,et al.  Functional conservation of the effector protein translocators PopB/YopB and PopD/YopD of Pseudomonas aeruginosa and Yersinia pseudotuberculosis , 1998, Molecular microbiology.

[47]  H. Schweizer,et al.  A broad-host-range Flp-FRT recombination system for site-specific excision of chromosomally-located DNA sequences: application for isolation of unmarked Pseudomonas aeruginosa mutants. , 1998, Gene.

[48]  J. Engel,et al.  Defects in Type III Secretion Correlate with Internalization of Pseudomonas aeruginosa by Epithelial Cells , 1998, Infection and Immunity.

[49]  Lei Zhu,et al.  ExoU expression by Pseudomonas aeruginosa correlates with acute cytotoxicity and epithelial injury , 1997, Molecular microbiology.

[50]  J. Engel,et al.  Identification of Pseudomonas aeruginosa genes required for epithelial cell injury , 1997, Molecular microbiology.

[51]  A. Zychlinsky,et al.  A bacterial invasin induces macrophage apoptosis by binding directly to ICE. , 1996, The EMBO journal.

[52]  H. Schweizer,et al.  An improved system for gene replacement and xylE fusion analysis in Pseudomonas aeruginosa. , 1995, Gene.

[53]  P. Liu,et al.  The roles of various fractions of Pseudomonas aeruginosa in its pathogenesis. 3. Identity of the lethal toxins produced in vitro and in vivo. , 1966, The Journal of infectious diseases.