This information is current as aeruginosa Pseudomonas but Not Klebsiella pneumoniae Antibacterial Defense in the Lung against Protein ( TIRAP ) Is a Critical Mediator of Toll / IL-1 R Domain-Containing Adaptor

Bacterial pneumonia is a leading cause of mortality and is associated with extensive neutrophil accumulation. Major pathogens associated with this disease include nonflagellated Klebsiella pneumoniae (Kp) and flagellated Pseudomonas aeruginosa (Pa). TLRs are essential for innate immune defense. TIRAP (Toll/IL-1R domain-containing adaptor protein) is an adaptor in TLR1, TLR2, TLR4, and TLR6 signaling, whereas MyD88 is an adaptor for all TLRs. However, the importance of TIRAP in pulmonary defense against Kp or Pa has not been examined. To demonstrate the role of TIRAP, TIRAP-deficient and wild-type littermates were intratracheally inoculated with Kp or Pa. We found that TIRAP (cid:1) / (cid:1) mice had substantial mortality, higher bacterial burden in the lungs, and enhanced dissemination following Kp challenge. Furthermore, Kp-induced neutrophil sequestration, histopathology, and MIP-2, TNF- (cid:2) , IL-6, and LIX (lipopolysaccharide-induced CXC chemokine) production were attenuated in the lungs of TIRAP (cid:1) / (cid:1) mice. In contrast, TIRAP is not required for Pa-induced mortality, pulmonary bacterial burden, bacterial dissemination, neutrophil accumulation, or histopathology, yet it is necessary for MIP-2, TNF- (cid:2) , and IL-6 production, but not LIX production. However, both Kp- and Pa-induced neutrophil influxes are MyD88 dependent. To determine the mechanisms associated with Pa-induced neutrophil accumulation, we inoculated mice with a flagellin C mutant of Pa (Pa (cid:3) fliC ) or purified flagellin, a TLR5 agonist. Pa (cid:3) fliC -induced neutrophil sequestration and LIX expression are dependent on TIRAP, whereas flagellin-induced neutrophil influx and LIX expression are independent of TIRAP. These novel findings illustrate a pathogen-specific role for TIRAP in pulmonary defense and suggest that TLR5 plays an essential role for Pa-induced neutrophil influx via LIX production. The Journal of Immunology, 2006, 177: 538–547.

[1]  S. Akira,et al.  Pathogen Recognition and Innate Immunity , 2006, Cell.

[2]  J. Mizgerd.  Lung Infection—A Public Health Priority , 2006, PLoS medicine.

[3]  S. Akira,et al.  Toll-IL-1 Receptor Domain-Containing Adaptor Protein Is Critical for Early Lung Immune Responses against Escherichia coli Lipopolysaccharide and Viable Escherichia coli1 , 2005, The Journal of Immunology.

[4]  Matthew R. Jones,et al.  Lung NF-κB Activation and Neutrophil Recruitment Require IL-1 and TNF Receptor Signaling during Pneumococcal Pneumonia1 , 2005, The Journal of Immunology.

[5]  Paul B. Mann,et al.  The Complex Mechanism of Antibody-Mediated Clearance of Bordetella from the Lungs Requires TLR41 , 2005, The Journal of Immunology.

[6]  J. Weiser,et al.  Host and Bacterial Factors Contributing to the Clearance of Colonization by Streptococcus pneumoniae in a Murine Model , 2005, Infection and Immunity.

[7]  S. Akira,et al.  The MyD88-Dependent, but Not the MyD88-Independent, Pathway of TLR4 Signaling Is Important in Clearing Nontypeable Haemophilus influenzae from the Mouse Lung1 , 2005, The Journal of Immunology.

[8]  J. Shellito,et al.  Divergent roles of IL-23 and IL-12 in host defense against Klebsiella pneumoniae , 2005, The Journal of experimental medicine.

[9]  R. Ramphal,et al.  TLRs 2 and 4 Are Not Involved in Hypersusceptibility to Acute Pseudomonas aeruginosa Lung Infections1 , 2005, The Journal of Immunology.

[10]  J. Nick,et al.  Inhibition of c-Jun N-terminal kinase limits lipopolysaccharide-induced pulmonary neutrophil influx. , 2005, American journal of respiratory and critical care medicine.

[11]  S. Akira,et al.  Induction of CXCL5 during inflammation in the rodent lung involves activation of alveolar epithelium. , 2005, American journal of respiratory cell and molecular biology.

[12]  M. Freeman,et al.  Distinct Roles of Pattern Recognition Receptors CD14 and Toll-Like Receptor 4 in Acute Lung Injury , 2005, Infection and Immunity.

[13]  J. Musial,et al.  Integrins in pulmonary inflammatory diseases. , 2005, Current pharmaceutical design.

[14]  J. Shellito,et al.  Central Role of Toll-Like Receptor 4 Signaling and Host Defense in Experimental Pneumonia Caused by Gram-Negative Bacteria , 2005, Infection and Immunity.

[15]  S. Young,et al.  Transcriptional Profiling of Lipopolysaccharide-Induced Acute Lung Injury , 2004, Infection and Immunity.

[16]  Yongde Peng,et al.  The Development of Early Host Response to Pseudomonas aeruginosa Lung Infection Is Critically Dependent on Myeloid Differentiation Factor 88 in Mice* , 2004, Journal of Biological Chemistry.

[17]  T. Standiford,et al.  STAT4 Is a Critical Mediator of Early Innate Immune Responses against Pulmonary Klebsiella Infection1 , 2004, The Journal of Immunology.

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

[19]  Samuel I. Miller,et al.  Respiratory epithelial cells regulate lung inflammation in response to inhaled endotoxin. , 2004, American journal of physiology. Lung cellular and molecular physiology.

[20]  J. Butler,et al.  Roles for early response cytokines during Escherichia coli pneumonia revealed by mice with combined deficiencies of all signaling receptors for TNF and IL-1. , 2004, American journal of physiology. Lung cellular and molecular physiology.

[21]  H. D. Liggitt,et al.  Cutting Edge: Myeloid Differentiation Factor 88 Is Essential for Pulmonary Host Defense against Pseudomonas aeruginosa but Not Staphylococcus aureus1 , 2004, The Journal of Immunology.

[22]  S. Akira,et al.  TIR domain-containing adaptors define the specificity of TLR signaling. , 2004, Molecular immunology.

[23]  Richard J. Laws,et al.  A Common Dominant TLR5 Stop Codon Polymorphism Abolishes Flagellin Signaling and Is Associated with Susceptibility to Legionnaires' Disease , 2003, The Journal of experimental medicine.

[24]  S. Akira,et al.  TRAM is specifically involved in the Toll-like receptor 4–mediated MyD88-independent signaling pathway , 2003, Nature Immunology.

[25]  S. Akira,et al.  Role of Adaptor TRIF in the MyD88-Independent Toll-Like Receptor Signaling Pathway , 2003, Science.

[26]  T. van der Poll,et al.  Anti-tumor necrosis factor antibody impairs the therapeutic effect of ceftriaxone in murine pneumococcal pneumonia. , 2003, The Journal of infectious diseases.

[27]  S. Akira,et al.  Toll receptors and pathogen resistance , 2003, Cellular microbiology.

[28]  M. Lipsitch,et al.  Recognition of pneumolysin by Toll-like receptor 4 confers resistance to pneumococcal infection , 2003, Proceedings of the National Academy of Sciences of the United States of America.

[29]  S. Akira,et al.  Essential role for TIRAP in activation of the signalling cascade shared by TLR2 and TLR4 , 2002, Nature.

[30]  D. Hassett,et al.  Static growth of mucoid Pseudomonas aeruginosa selects for non-mucoid variants that have acquired flagellum-dependent motility. , 2002, Microbiology.

[31]  P. Kubes,et al.  Lipopolysaccharide-Induced Leukocyte-Endothelial Cell Interactions: A Role for CD14 Versus Toll-Like Receptor 4 Within Microvessels1 , 2002, The Journal of Immunology.

[32]  J. Mizgerd.  Molecular mechanisms of neutrophil recruitment elicited by bacteria in the lungs. , 2002, Seminars in immunology.

[33]  G. Fantuzzi,et al.  Pulmonary Inflammation Induced by Pseudomonas aeruginosa Lipopolysaccharide, Phospholipase C, and Exotoxin A: Role of Interferon Regulatory Factor 1 , 2002, Infection and Immunity.

[34]  A. Miniño,et al.  Deaths: preliminary data for 2000. , 2001, National vital statistics reports : from the Centers for Disease Control and Prevention, National Center for Health Statistics, National Vital Statistics System.

[35]  S. Akira,et al.  The innate immune response to bacterial flagellin is mediated by Toll-like receptor 5 , 2001, Nature.

[36]  T. Standiford,et al.  Chemokine-Dependent Neutrophil Recruitment in a Murine Model of Legionella Pneumonia: Potential Role of Neutrophils as Immunoregulatory Cells , 2001, Infection and Immunity.

[37]  J. Mizgerd,et al.  Early Response Cytokines and Innate Immunity: Essential Roles for TNF Receptor 1 and Type I IL-1 Receptor During Escherichia coli Pneumonia in Mice1 , 2001, The Journal of Immunology.

[38]  T. Standiford,et al.  Impaired Pulmonary Host Defense in Mice Lacking Expression of the CXC Chemokine Lungkine1 , 2001, The Journal of Immunology.

[39]  C. Moser,et al.  Toll-Like Receptor 4 Mediates Innate Immune Responses to Haemophilus influenzae Infection in Mouse Lung , 2001 .

[40]  T. Standiford,et al.  CXC Chemokine Receptor CXCR2 Is Essential for Protective Innate Host Response in Murine Pseudomonas aeruginosaPneumonia , 2000, Infection and Immunity.

[41]  G. Bagby,et al.  Innate immunity and pulmonary host defense , 2000, Immunological reviews.

[42]  S. Akira,et al.  Unresponsiveness of MyD88-deficient mice to endotoxin. , 1999, Immunity.

[43]  A. Fein.  Pneumonia in the elderly: overview of diagnostic and therapeutic approaches. , 1999, Clinical infectious diseases : an official publication of the Infectious Diseases Society of America.

[44]  Sheldon P Stone,et al.  Community-acquired pneumonia , 1998, The Lancet.

[45]  C. Janeway,et al.  MyD88 is an adaptor protein in the hToll/IL-1 receptor family signaling pathways. , 1998, Molecular cell.

[46]  S. Akira,et al.  Targeted disruption of the MyD88 gene results in loss of IL-1- and IL-18-mediated function. , 1998, Immunity.

[47]  J. Nick,et al.  Common and distinct intracellular signaling pathways in human neutrophils utilized by platelet activating factor and FMLP. , 1997, The Journal of clinical investigation.

[48]  L. F. Kolakowski,et al.  Expression and biologic characterization of the murine chemokine KC. , 1995, Journal of immunology.

[49]  D. Riches,et al.  Early pulmonary inflammation in infants with cystic fibrosis. , 1995, American journal of respiratory and critical care medicine.

[50]  J. Paulauskis,et al.  Functional characterization of the rat chemokine KC and its importance in neutrophil recruitment in a rat model of pulmonary inflammation. , 1995, Journal of immunology.

[51]  J. Dorca,et al.  Risk factors for nosocomial Legionella pneumophila pneumonia. , 1994, American journal of respiratory and critical care medicine.

[52]  E. Elson,et al.  Mechanics of stimulated neutrophils: cell stiffening induces retention in capillaries. , 1989, Science.

[53]  A. Cerami,et al.  Identification and characterization of macrophage inflammatory protein 2. , 1989, Proceedings of the National Academy of Sciences of the United States of America.

[54]  R. Myerowitz,et al.  The pathology of the Legionella pneumonias. A review of 74 cases and the literature. , 1981, Human pathology.

[55]  T. M. Brown,et al.  The pathology of Legionnaires' disease. Fourteen fatal cases from the 1977 outbreak in Vermont. , 1978, Archives of pathology & laboratory medicine.