Type I Interferon Responses to Airway Pathogens



The type I interferons (IFNs) have been studied extensively in the context of viral infections, and have now been recognized as influencing the outcome of bacterial infections. The innate immune system possesses numerous receptors, including TLRs, RIG-like and cytosolic receptors to recognize specific molecular patterns of invading pathogens, be they viral or bacterial. Several of these receptors result in the activation of the type I signaling pathway via intracellular recognition of products such as: DNA, RNA, LPS, and peptidoglycan. Type I IFN signaling leads to the activation of inteferons alpha and beta that via the IFNAR receptor and JAK/STAT signaling influence the transcription of hundreds of genes. The receptors that lead to type I IFN signaling can be found on numerous cell types in the airways: epithelial cells, macrophages, and dendritic cells, which all respond to pathogens in unique ways to produce type I IFNs. The effect of type I IFNs on the infection outcome is variable. Type I IFNs can lead to protective as well as sensitizing effects depending upon the bacterial pathogen and the site of infection. Type I IFNs are able to exert their effects through both direct activation of antimicrobial gene products as well as immunomodulation of cell activation and chemotaxis. Bacterial pathogens, both intracellular and extracellular are able to activate the type I IFN response in the airway. Their ability to activate this pathway and the host outcome will be discussed.


Airway Epithelial Cell Cystic Fibrosis Transmembrane Regulator Cytosolic Receptor Chlamydia Muridarum Host Outcome 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


  1. Ablasser A, Bauernfeind F, Hartmann G, Latz E, Fitzgerald KA, Hornung V (2009) ­RIG-I-dependent sensing of poly(dA:dT) through the induction of an RNA polymerase III-transcribed RNA intermediate. Nat Immunol 10:1065–1072PubMedCrossRefGoogle Scholar
  2. Alexopoulou L, Holt AC, Medzhitov R, Flavell RA (2001) Recognition of double-stranded RNA and activation of NF-kappaB by Toll-like receptor 3. Nature 413:732–738PubMedCrossRefGoogle Scholar
  3. Antonelli LR, Gigliotti Rothfuchs A, Goncalves R, Roffe E, Cheever AW, Bafica A, Salazar AM, Feng CG, Sher A (2010) Intranasal Poly-IC treatment exacerbates tuberculosis in mice through the pulmonary recruitment of a pathogen-permissive monocyte/macrophage population. J Clin Invest 120:1674–1682PubMedCrossRefGoogle Scholar
  4. Barbalat R, Ewald SE, Mouchess ML, Barton GM (2011) Nucleic acid recognition by the innate immune system. Annu Rev Immunol 29:185–214PubMedCrossRefGoogle Scholar
  5. Barton GM, Kagan JC (2009) A cell biological view of Toll-like receptor function: regulation through compartmentalization. Nat Rev Immunol 9:535–542PubMedCrossRefGoogle Scholar
  6. Benveniste EN, Qin H (2007) Type I interferons as anti-inflammatory mediators. Sci STKE 2007(416):70CrossRefGoogle Scholar
  7. Berube J, Bourdon C, Yao Y, Rousseau S (2009) Distinct intracellular signaling pathways control the synthesis of IL-8 and RANTES in TLR1/TLR2, TLR3 or NOD1 activated human airway epithelial cells. Cell Signal 21:448–456PubMedCrossRefGoogle Scholar
  8. Blasius AL, Beutler B (2010) Intracellular toll-like receptors. Immunity 32:305–315PubMedCrossRefGoogle Scholar
  9. Bukholm G, Berdal BP, Haug C, Degre M (1984) Mouse fibroblast interferon modifies Salmonella typhimurium infection in infant mice. Infect Immun 45:62–66PubMedGoogle Scholar
  10. Burdette DL, Monroe KM, Sotelo-Troha K, Iwig JS, Eckert B, Hyodo M, Hayakawa Y, Vance RE (2011) STING is a direct innate immune sensor of cyclic di-GMP. Nature 478:515–518PubMedCrossRefGoogle Scholar
  11. Carrero JA, Calderon B, Unanue ER (2004) Type I interferon sensitizes lymphocytes to apoptosis and reduces resistance to Listeria infection. J Exp Med 200:535–540PubMedCrossRefGoogle Scholar
  12. Carrigan SO, Junkins R, Yang YJ, Macneil A, Richardson C, Johnston B, Lin TJ (2010) IFN regulatory factor 3 contributes to the host response during Pseudomonas aeruginosa lung infection in mice. J Immunol 185:3602–3609PubMedCrossRefGoogle Scholar
  13. Charrel-Dennis M, Latz E, Halmen KA, Trieu-Cuot P, Fitzgerald KA, Kasper DL, Golenbock DT (2008) TLR-independent type I interferon induction in response to an extracellular bacterial pathogen via intracellular recognition of its DNA. Cell Host Microbe 4:543–554PubMedCrossRefGoogle Scholar
  14. Chetty C, Kreger A (1981) Role of autolysin in generating the pneumococcal purpura-producing principle. Infect Immun 31:339–344PubMedGoogle Scholar
  15. Cheung DO, Halsey K, Speert DP (2000) Role of pulmonary alveolar macrophages in defense of the lung against Pseudomonas aeruginosa. Infect Immun 68:4585–4592PubMedCrossRefGoogle Scholar
  16. Chiu YH, Macmillan JB, Chen ZJ (2009) RNA polymerase III detects cytosolic DNA and induces type I interferons through the RIG-I pathway. Cell 138:576–591PubMedCrossRefGoogle Scholar
  17. Cigana C, Curcuru L, Leone MR, Ierano T, Lore NI, Bianconi I, Silipo A, Cozzolino F, Lanzetta R, Molinaro A, Bernardini ML, Bragonzi A (2009) Pseudomonas aeruginosa exploits lipid A and muropeptides modification as a strategy to lower innate immunity during cystic fibrosis lung infection. PLoS One 4:e8439PubMedCrossRefGoogle Scholar
  18. Coers J, Vance RE, Fontana MF, Dietrich WF (2007) Restriction of Legionella pneumophila growth in macrophages requires the concerted action of cytokine and Naip5/Ipaf signalling pathways. Cell Microbiol 9:2344–2357PubMedCrossRefGoogle Scholar
  19. Cole AM, Ganz T, Liese AM, Burdick MD, Liu L, Strieter RM (2001) Cutting edge: IFN-inducible ELR-CXC chemokines display defensin-like antimicrobial activity. J Immunol 167:623–627PubMedGoogle Scholar
  20. Condon TV, Sawyer RT, Fenton MJ, Riches DW (2011) Lung dendritic cells at the innate-adaptive immune interface. J Leukoc Biol 90:883–895PubMedCrossRefGoogle Scholar
  21. Dalod M, Salazar-Mather TP, Malmgaard L, Lewis C, Asselin-Paturel C, Briere F, Trinchieri G, Biron CA (2002) Interferon alpha/beta and interleukin 12 responses to viral infections: ­pathways regulating dendritic cell cytokine expression in vivo. J Exp Med 195:517–528PubMedCrossRefGoogle Scholar
  22. Debes GF, Dahl ME, Mahiny AJ, Bonhagen K, Campbell DJ, Siegmund K, Erb KJ, Lewis DB, Kamradt T, Hamann A (2006) Chemotactic responses of IL-4-, IL-10-, and ­IFN-gamma-producing CD4+ T cells depend on tissue origin and microbial stimulus. J Immunol 176:557–566PubMedGoogle Scholar
  23. Decker T, Muller M, Stockinger S (2005) The yin and yang of type I interferon activity in bacterial infection. Nat Rev Immunol 5:675–687PubMedCrossRefGoogle Scholar
  24. Denis M, Cormier Y, Fournier M, Tardif J, Laviolette M (1991) Tumor necrosis factor plays an essential role in determining hypersensitivity pneumonitis in a mouse model. Am J Respir Cell Mol Biol 5:477–483PubMedGoogle Scholar
  25. Der SD, Zhou A, Williams BR, Silverman RH (1998) Identification of genes differentially ­regulated by interferon alpha, beta, or gamma using oligonucleotide arrays. Proc Natl Acad Sci U S A 95:15623–15628PubMedCrossRefGoogle Scholar
  26. Deshmukh SD, Kremer B, Freudenberg M, Bauer S, Golenbock DT, Henneke P (2011) Macrophages recognize streptococci through bacterial single-stranded RNA. EMBO Rep 12:71–76PubMedCrossRefGoogle Scholar
  27. Diebold SS, Kaisho T, Hemmi H, Akira S, Reis e Sousa C (2004) Innate antiviral responses by means of TLR7-mediated recognition of single-stranded RNA. Science 303:1529–1531PubMedCrossRefGoogle Scholar
  28. Faure K, Sawa T, Ajayi T, Fujimoto J, Moriyama K, Shime N, Wiener-Kronish JP (2004) TLR4 signaling is essential for survival in acute lung injury induced by virulent Pseudomonas ­aeruginosa secreting type III secretory toxins. Respir Res 5:1PubMedCrossRefGoogle Scholar
  29. Fitzgerald KA, Rowe DC, Barnes BJ, Caffrey DR, Visintin A, Latz E, Monks B, Pitha PM, Golenbock DT (2003) LPS-TLR4 signaling to IRF-3/7 and NF-kappaB involves the toll ­adapters TRAM and TRIF. J Exp Med 198:1043–1055PubMedCrossRefGoogle Scholar
  30. Freudenberg MA, Merlin T, Kalis C, Chvatchko Y, Stubig H, Galanos C (2002) Cutting edge: a murine, IL-12-independent pathway of IFN-gamma induction by gram-negative bacteria based on STAT4 activation by Type I IFN and IL-18 signaling. J Immunol 169:1665–1668PubMedGoogle Scholar
  31. Fujita T, Reis LF, Watanabe N, Kimura Y, Taniguchi T, Vilcek J (1989) Induction of the ­transcription factor IRF-1 and interferon-beta mRNAs by cytokines and activators of second-messenger pathways. Proc Natl Acad Sci U S A 86:9936–9940PubMedCrossRefGoogle Scholar
  32. Gomez MI, Lee A, Reddy B, Muir A, Soong G, Pitt A, Cheung A, Prince A (2004) Staphylococcus aureus protein A induces airway epithelial inflammatory responses by activating TNFR1. Nat Med 10:842–848PubMedCrossRefGoogle Scholar
  33. Gomez MI, Sokol SH, Muir AB, Soong G, Bastien J, Prince AS (2005) Bacterial induction of TNF-alpha converting enzyme expression and IL-6 receptor alpha shedding regulates airway inflammatory signaling. J Immunol 175:1930–1936PubMedGoogle Scholar
  34. Gomez MI, Seaghdha MO, Prince AS (2007) Staphylococcus aureus protein A activates TACE through EGFR-dependent signaling. EMBO J 26:701–709PubMedCrossRefGoogle Scholar
  35. Gratz N, Siller M, Schaljo B, Pirzada ZA, Gattermeier I, Vojtek I, Kirschning CJ, Wagner H, ­Akira S, Charpentier E, Kovarik P (2008) Group A streptococcus activates type I interferon ­production and MyD88-dependent signaling without involvement of TLR2, TLR4, and TLR9. J Biol Chem 283:19879–19887PubMedCrossRefGoogle Scholar
  36. Gratz N, Hartweger H, Matt U, Kratochvill F, Janos M, Sigel S, Drobits B, Li XD, Knapp S, Kovarik P (2011) Type I Interferon Production Induced by Streptococcus pyogenes-Derived Nucleic Acids Is Required for Host Protection. PLoS Pathog 7:e1001345PubMedCrossRefGoogle Scholar
  37. Guarda G, Braun M, Staehli F, Tardivel A, Mattmann C, Forster I, Farlik M, Decker T, Du Pasquier RA, Romero P, Tschopp J (2011) Type I interferon inhibits interleukin-1 production and inflammasome activation. Immunity 34:213–223PubMedCrossRefGoogle Scholar
  38. Hacker H, Redecke V, Blagoev B, Kratchmarova I, Hsu LC, Wang GG, Kamps MP, Raz E, Wagner H, Hacker G, Mann M, Karin M (2006) Specificity in Toll-like receptor signalling through distinct effector functions of TRAF3 and TRAF6. Nature 439:204–207PubMedCrossRefGoogle Scholar
  39. Haller O, Staeheli P, Kochs G (2007) Interferon-induced Mx proteins in antiviral host defense. Biochimie 89:812–818PubMedCrossRefGoogle Scholar
  40. Hammad H, Lambrecht BN (2008) Dendritic cells and epithelial cells: linking innate and adaptive immunity in asthma. Nat Rev Immunol 8:193–204PubMedCrossRefGoogle Scholar
  41. Heil F, Hemmi H, Hochrein H, Ampenberger F, Kirschning C, Akira S, Lipford G, Wagner H, Bauer S (2004) Species-specific recognition of single-stranded RNA via toll-like receptor 7 and 8. Science 303:1526–1529PubMedCrossRefGoogle Scholar
  42. Hemmi H, Takeuchi O, Kawai T, Kaisho T, Sato S, Sanjo H, Matsumoto M, Hoshino K, Wagner H, Takeda K, Akira S (2000) A Toll-like receptor recognizes bacterial DNA. Nature 408:740–745PubMedCrossRefGoogle Scholar
  43. Henry T, Kirimanjeswara GS, Ruby T, Jones JW, Peng K, Perret M, Ho L, Sauer JD, Iwakura Y, Metzger DW, Monack DM (2010) Type I IFN signaling constrains IL-17A/F secretion by ­gammadelta T cells during bacterial infections. J Immunol 184:3755–3767PubMedCrossRefGoogle Scholar
  44. Huys L, Van Hauwermeiren F, Dejager L, Dejonckheere E, Lienenklaus S, Weiss S, Leclercq G, Libert C (2009) Type I interferon drives tumor necrosis factor-induced lethal shock. J Exp Med 206:1873–1882PubMedCrossRefGoogle Scholar
  45. Ishikawa H, Ma Z, Barber GN (2009) STING regulates intracellular DNA-mediated, type­ I ­interferon-dependent innate immunity. Nature 461:788–792PubMedCrossRefGoogle Scholar
  46. Joyce EA, Popper SJ, Falkow S (2009) Streptococcus pneumoniae nasopharyngeal colonization induces type I interferons and interferon-induced gene expression. BMC Genomics 10:404PubMedCrossRefGoogle Scholar
  47. Kadioglu A, Weiser JN, Paton JC, Andrew PW (2008) The role of Streptococcus pneumoniae ­virulence factors in host respiratory colonization and disease. Nat Rev Microbiol 6:288–301PubMedCrossRefGoogle Scholar
  48. Kagan JC, Su T, Horng T, Chow A, Akira S, Medzhitov R (2008) TRAM couples endocytosis of Toll-like receptor 4 to the induction of interferon-beta. Nat Immunol 9:361–368PubMedCrossRefGoogle Scholar
  49. Karaghiosoff M, Steinborn R, Kovarik P, Kriegshauser G, Baccarini M, Donabauer B, Reichart U, Kolbe T, Bogdan C, Leanderson T, Levy D, Decker T, Muller M (2003) Central role for type I interferons and Tyk2 in lipopolysaccharide-induced endotoxin shock. Nat Immunol 4:471–477PubMedCrossRefGoogle Scholar
  50. Kawai T, Takeuchi O, Fujita T, Inoue J, Muhlradt PF, Sato S, Hoshino K, Akira S (2001) Lipopolysaccharide stimulates the MyD88-independent pathway and results in activation of IFN-regulatory factor 3 and the expression of a subset of lipopolysaccharide-inducible genes. J Immunol 167:5887–5894PubMedGoogle Scholar
  51. Keating SE, Baran M, Bowie AG (2011) Cytosolic DNA sensors regulating type I interferon induction. Trends Immunol 32:574–581PubMedCrossRefGoogle Scholar
  52. Kelly-Scumpia KM, Scumpia PO, Delano MJ, Weinstein JS, Cuenca AG, Wynn JL, Moldawer LL (2010) Type I interferon signaling in hematopoietic cells is required for survival in mouse polymicrobial sepsis by regulating CXCL10. J Exp Med 207:319–326PubMedCrossRefGoogle Scholar
  53. Kelsen SG, Aksoy MO, Yang Y, Shahabuddin S, Litvin J, Safadi F, Rogers TJ (2004) The chemokine receptor CXCR3 and its splice variant are expressed in human airway epithelial cells. Am J Physiol Lung Cell Mol Physiol 287:L584–L591PubMedCrossRefGoogle Scholar
  54. Kim T, Pazhoor S, Bao M, Zhang Z, Hanabuchi S, Facchinetti V, Bover L, Plumas J, Chaperot L, Qin J, Liu YJ (2010) Aspartate-glutamate-alanine-histidine box motif (DEAH)/RNA helicase A helicases sense microbial DNA in human plasmacytoid dendritic cells. Proc Natl Acad Sci U S A 107:15181–15186PubMedCrossRefGoogle Scholar
  55. Kooguchi K, Hashimoto S, Kobayashi A, Kitamura Y, Kudoh I, Wiener-Kronish J, Sawa T (1998) Role of alveolar macrophages in initiation and regulation of inflammation in Pseudomonas aeruginosa pneumonia. Infect Immun 66:3164–3169PubMedGoogle Scholar
  56. Koppe U, Hogner K, Doehn JM, Muller HC, Witzenrath M, Gutbier B, Bauer S, Pribyl T, Hammerschmidt S, Lohmeyer J, Suttorp N, Herold S, Opitz B (2012) Streptococcus pneumoniae stimulates a STING- and IFN regulatory factor 3-dependent type I IFN production in macrophages, which regulates RANTES production in macrophages, cocultured alveolar ­epithelial cells, and mouse lungs. J Immunol 188:811–817PubMedCrossRefGoogle Scholar
  57. Kudva A, Scheller EV, Robinson KM, Crowe CR, Choi SM, Slight SR, Khader SA, Dubin PJ, Enelow RI, Kolls JK, Alcorn JF (2011) Influenza A inhibits Th17-mediated host defense against bacterial pneumonia in mice. J Immunol 186:1666–1674PubMedCrossRefGoogle Scholar
  58. Le Bon A, Etchart N, Rossmann C, Ashton M, Hou S, Gewert D, Borrow P, Tough DF (2003) Cross-priming of CD8+ T cells stimulated by virus-induced type I interferon. Nat Immunol 4:1009–1015PubMedCrossRefGoogle Scholar
  59. Leber JH, Crimmins GT, Raghavan S, Meyer-Morse NP, Cox JS, Portnoy DA (2008) Distinct TLR- and NLR-mediated transcriptional responses to an intracellular pathogen. PLoS Pathog 4:e6PubMedCrossRefGoogle Scholar
  60. Lee MH, Arrecubieta C, Martin FJ, Prince A, Borczuk AC, Lowy FD (2010) A postinfluenza model of Staphylococcus aureus pneumonia. J Infect Dis 201:508–515PubMedCrossRefGoogle Scholar
  61. Lenardo MJ, Fan CM, Maniatis T, Baltimore D (1989) The involvement of NF-kappa B in ­beta-interferon gene regulation reveals its role as widely inducible mediator of signal ­transduction. Cell 57:287–294PubMedCrossRefGoogle Scholar
  62. Lippmann J, Muller HC, Naujoks J, Tabeling C, Shin S, Witzenrath M, Hellwig K, Kirschning CJ, Taylor GA, Barchet W, Bauer S, Suttorp N, Roy CR, Opitz B (2011) Dissection of a type I interferon pathway in controlling bacterial intracellular infection in mice. Cell Microbiol 13:1668–1682PubMedCrossRefGoogle Scholar
  63. Liu YJ (2005) IPC: professional type 1 interferon-producing cells and plasmacytoid dendritic cell precursors. Annu Rev Immunol 23:275–306PubMedCrossRefGoogle Scholar
  64. Loetscher P, Pellegrino A, Gong JH, Mattioli I, Loetscher M, Bardi G, Baggiolini M, Clark-Lewis I (2001) The ligands of CXC chemokine receptor 3, I-TAC, Mig, and IP10, are natural ­antagonists for CCR3. J Biol Chem 276:2986–2991PubMedCrossRefGoogle Scholar
  65. Longhi MP, Trumpfheller C, Idoyaga J, Caskey M, Matos I, Kluger C, Salazar AM, Colonna M, Steinman RM (2009) Dendritic cells require a systemic type I interferon response to mature and induce CD4+ Th1 immunity with poly IC as adjuvant. J Exp Med 206:1589–1602PubMedCrossRefGoogle Scholar
  66. Maillet I, Schnyder-Candrian S, Couillin I, Quesniaux VF, Erard F, Moser R, Fleury S, Kanda A, Dombrowicz D, Szymkowski DE, Ryffel B (2011) Allergic lung inflammation is mediated by soluble tumor necrosis factor (TNF) and attenuated by dominant-negative TNF biologics. Am J Respir Cell Mol Biol 45:731–739PubMedCrossRefGoogle Scholar
  67. Manca C, Tsenova L, Bergtold A, Freeman S, Tovey M, Musser JM, Barry CE 3rd, Freedman VH, Kaplan G (2001) Virulence of a Mycobacterium tuberculosis clinical isolate in mice is ­determined by failure to induce Th1 type immunity and is associated with induction of ­IFN-alpha /beta. Proc Natl Acad Sci U S A 98:5752–5757PubMedCrossRefGoogle Scholar
  68. Mancuso G, Midiri A, Biondo C, Beninati C, Zummo S, Galbo R, Tomasello F, Gambuzza M, Macri G, Ruggeri A, Leanderson T, Teti G (2007) Type I IFN signaling is crucial for host ­resistance against different species of pathogenic bacteria. J Immunol 178:3126–3133PubMedGoogle Scholar
  69. Mancuso G, Gambuzza M, Midiri A, Biondo C, Papasergi S, Akira S, Teti G, Beninati C (2009) Bacterial recognition by TLR7 in the lysosomes of conventional dendritic cells. Nat Immunol 10:587–594PubMedCrossRefGoogle Scholar
  70. Manicone AM, Burkhart KM, Lu B, Clark JG (2008) CXCR3 ligands contribute to Th1-induced inflammation but not to homing of Th1 cells into the lung. Exp Lung Res 34:391–407PubMedCrossRefGoogle Scholar
  71. Martin FJ, Gomez MI, Wetzel DM, Memmi G, O’Seaghdha M, Soong G, Schindler C, Prince A (2009) Staphylococcus aureus activates type I IFN signaling in mice and humans through the Xr repeated sequences of protein A. J Clin Invest 119:1931–1939PubMedGoogle Scholar
  72. Martin FJ, Parker D, Harfenist BS, Soong G, Prince A (2011) Participation of CD11c(+) leukocytes in methicillin-resistant Staphylococcus aureus clearance from the lung. Infect Immun 79:1898–1904PubMedCrossRefGoogle Scholar
  73. Martinez J, Huang X, Yang Y (2008) Direct action of type I IFN on NK cells is required for their activation in response to vaccinia viral infection in vivo. J Immunol 180:1592–1597PubMedGoogle Scholar
  74. Mayer AK, Muehmer M, Mages J, Gueinzius K, Hess C, Heeg K, Bals R, Lang R, Dalpke AH (2007) Differential recognition of TLR-dependent microbial ligands in human bronchial ­epithelial cells. J Immunol 178:3134–3142PubMedGoogle Scholar
  75. McCaffrey RL, Fawcett P, O’Riordan M, Lee KD, Havell EA, Brown PO, Portnoy DA (2004) A specific gene expression program triggered by Gram-positive bacteria in the cytosol. Proc Natl Acad Sci U S A 101:11386–11391PubMedCrossRefGoogle Scholar
  76. Minisini R, Giarda P, Grossi G, Bitetto D, Toniutto P, Falleti E, Avellini C, Occhino G, Fabris C, Pirisi M (2011) Early activation of interferon-stimulated genes in human liver allografts: ­relationship with acute rejection and histological outcome. J Gastroenterol 46:1307–1315PubMedCrossRefGoogle Scholar
  77. Monroe KM, McWhirter SM, Vance RE (2009) Identification of host cytosolic sensors and b­acterial factors regulating the type I interferon response to Legionella pneumophila. PLoS Pathog 5:e1000665PubMedCrossRefGoogle Scholar
  78. Movitz J (1976) Formation of extracellular protein A by Staphylococcus aureus. Eur J Biochem 68:291–299PubMedCrossRefGoogle Scholar
  79. Muir A, Soong G, Sokol S, Reddy B, Gomez MI, Van Heeckeren A, Prince A (2004) Toll-like receptors in normal and cystic fibrosis airway epithelial cells. Am J Respir Cell Mol Biol 30:777–783PubMedCrossRefGoogle Scholar
  80. Nagarajan UM, Prantner D, Sikes JD, Andrews CW Jr, Goodwin AM, Nagarajan S, Darville T (2008) Type I interferon signaling exacerbates Chlamydia muridarum genital infection in a murine model. Infect Immun 76:4642–4648PubMedCrossRefGoogle Scholar
  81. Nakamura S, Davis KM, Weiser JN (2011) Synergistic stimulation of type I interferons during influenza virus coinfection promotes Streptococcus pneumoniae colonization in mice. J Clin Invest 121:3657–3665PubMedCrossRefGoogle Scholar
  82. Navarini AA, Recher M, Lang KS, Georgiev P, Meury S, Bergthaler A, Flatz L, Bille J, Landmann R, Odermatt B, Hengartner H, Zinkernagel RM (2006) Increased susceptibility to bacterial superinfection as a consequence of innate antiviral responses. Proc Natl Acad Sci U S A 103:15535–15539PubMedCrossRefGoogle Scholar
  83. Novikov A, Cardone M, Thompson R, Shenderov K, Kirschman KD, Mayer-Barber KD, Myers TG, Rabin RL, Trinchieri G, Sher A, Feng CG (2011) Mycobacterium tuberculosis triggers host type I IFN signaling to regulate IL-1beta production in human macrophages. J Immunol 187:2540–2547PubMedCrossRefGoogle Scholar
  84. O’Connell RM, Saha SK, Vaidya SA, Bruhn KW, Miranda GA, Zarnegar B, Perry AK, Nguyen BO, Lane TF, Taniguchi T, Miller JF, Cheng G (2004) Type I interferon production enhances susceptibility to Listeria monocytogenes infection. J Exp Med 200:437–445PubMedCrossRefGoogle Scholar
  85. Opitz B, Vinzing M, van Laak V, Schmeck B, Heine G, Gunther S, Preissner R, Slevogt H, N’Guessan PD, Eitel J, Goldmann T, Flieger A, Suttorp N, Hippenstiel S (2006) Legionella pneumophila induces IFNbeta in lung epithelial cells via IPS-1 and IRF3, which also control bacterial replication. J Biol Chem 281:36173–36179PubMedCrossRefGoogle Scholar
  86. Ordway D, Henao-Tamayo M, Harton M, Palanisamy G, Troudt J, Shanley C, Basaraba RJ, Orme IM (2007) The hypervirulent Mycobacterium tuberculosis strain HN878 induces a potent TH1 response followed by rapid down-regulation. J Immunol 179:522–531PubMedGoogle Scholar
  87. Pandey AK, Yang Y, Jiang Z, Fortune SM, Coulombe F, Behr MA, Fitzgerald KA, Sassetti CM, Kelliher MA (2009) NOD2, RIP2 and IRF5 play a critical role in the type I interferon response to Mycobacterium tuberculosis. PLoS Pathog 5:e1000500PubMedCrossRefGoogle Scholar
  88. Parker D, Prince A (2011) Innate Immunity in the Respiratory Epithelium. Am J Respir Cell Mol Biol 45:189–201PubMedCrossRefGoogle Scholar
  89. Parker, D, Prince A (2011) Type I interferon response to extracellular bacteria in the airway epithelium. Trends Immunol 32:582–588PubMedCrossRefGoogle Scholar
  90. Parker, D, Prince A (2012) Staphylococcus aureus induces type I interferon signaling in dendritic cells via TLR9. J Immunol Online ahead of print September 7.PubMedCrossRefGoogle Scholar
  91. Parker D, Martin FJ, Soong G, Harfenist BS, Aguilar JL, Ratner AJ, Fitzgerald KA, Schindler C, Prince A (2011) Streptococcus pneumoniae DNA initiates type I interferon signaling in the respiratory tract. MBio 2:e00016–e00011PubMedCrossRefGoogle Scholar
  92. Parker D, Cohen TS, Alhede M, Harfenist BS, Martin FJ, Prince A (2012) Induction of type I interferon signaling by Pseudomonas aeruginosa is diminished in cystic fibrosis epithelial cells. Am J Respir Cell Mol Biol 46:6–13PubMedCrossRefGoogle Scholar
  93. Pedroza M, Schneider DJ, Karmouty-Quintana H, Coote J, Shaw S, Corrigan R, Molina JG, Alcorn JL, Galas D, Gelinas R, Blackburn MR (2011) Interleukin-6 contributes to inflammation and remodeling in a model of adenosine mediated lung injury. PLoS One 6:e22667PubMedCrossRefGoogle Scholar
  94. Pfaller CK, Li Z, George CX, Samuel CE (2011) Protein kinase PKR and RNA adenosine ­deaminase ADAR1: new roles for old players as modulators of the interferon response. Curr Opin Immunol 23:573–582PubMedCrossRefGoogle Scholar
  95. Platz J, Beisswenger C, Dalpke A, Koczulla R, Pinkenburg O, Vogelmeier C, Bals R (2004) Microbial DNA induces a host defense reaction of human respiratory epithelial cells. J Immunol 173:1219–1223PubMedGoogle Scholar
  96. Plumlee CR, Lee C, Beg AA, Decker T, Shuman HA, Schindler C (2009) Interferons direct an effective innate response to Legionella pneumophila infection. J Biol Chem 284:30058–30066PubMedCrossRefGoogle Scholar
  97. Poltorak A, He X, Smirnova I, Liu MY, Van Huffel C, Du X, Birdwell D, Alejos E, Silva M, Galanos C, Freudenberg M, Ricciardi-Castagnoli P, Layton B, Beutler B (1998) Defective LPS signaling in C3H/HeJ and C57BL/10ScCr mice: mutations in Tlr4 gene. Science 282:2085–2088PubMedCrossRefGoogle Scholar
  98. Power MR, Li B, Yamamoto M, Akira S, Lin TJ (2007) A role of Toll-IL-1 receptor ­domain-containing adaptor-inducing IFN-beta in the host response to Pseudomonas aeruginosa lung infection in mice. J Immunol 178:3170–3176PubMedGoogle Scholar
  99. Qian C, An H, Yu Y, Liu S, Cao X (2007) TLR agonists induce regulatory dendritic cells to recruit Th1 cells via preferential IP-10 secretion and inhibit Th1 proliferation. Blood 109:3308–3315PubMedCrossRefGoogle Scholar
  100. Qiu H, Fan Y, Joyee AG, Wang S, Han X, Bai H, Jiao L, Van Rooijen N, Yang X (2008) Type I IFNs enhance susceptibility to Chlamydia muridarum lung infection by enhancing apoptosis of local macrophages. J Immunol 181:2092–2102PubMedGoogle Scholar
  101. Quinton LJ, Jones MR, Robson BE, Simms BT, Whitsett JA, Mizgerd JP (2008) Alveolar ­epithelial STAT3, IL-6 family cytokines, and host defense during Escherichia coli pneumonia. Am J Respir Cell Mol Biol 38:699–706PubMedCrossRefGoogle Scholar
  102. Ramphal R, Balloy V, Jyot J, Verma A, Si-Tahar M, Chignard M (2008) Control of Pseudomonas aeruginosa in the lung requires the recognition of either lipopolysaccharide or flagellin. J Immunol 181:586–592PubMedGoogle Scholar
  103. Rate A, Upham JW, Bosco A, McKenna KL, Holt PG (2009) Airway epithelial cells regulate the functional phenotype of locally differentiating dendritic cells: implications for the ­pathogenesis of infectious and allergic airway disease. J Immunol 182:72–83PubMedGoogle Scholar
  104. Ritter M, Mennerich D, Weith A, Seither P (2005) Characterization of Toll-like receptors in ­primary lung epithelial cells: strong impact of the TLR3 ligand poly(I:C) on the regulation of Toll-like receptors, adaptor proteins and inflammatory response. J Inflamm (Lond) 2:16CrossRefGoogle Scholar
  105. Sabbah A, Chang TH, Harnack R, Frohlich V, Tominaga K, Dube PH, Xiang Y, Bose S (2009) Activation of innate immune antiviral responses by Nod2. Nat Immunol 10:1073–1080PubMedCrossRefGoogle Scholar
  106. Sakamoto E, Hato F, Kato T, Sakamoto C, Akahori M, Hino M, Kitagawa S (2005) Type I and type II interferons delay human neutrophil apoptosis via activation of STAT3 and up-regulation of cellular inhibitor of apoptosis 2. J Leukoc Biol 78:301–309PubMedCrossRefGoogle Scholar
  107. Salomon R, Staeheli P, Kochs G, Yen HL, Franks J, Rehg JE, Webster RG, Hoffmann E (2007) Mx1 gene protects mice against the highly lethal human H5N1 influenza virus. Cell Cycle 6:2417–2421PubMedCrossRefGoogle Scholar
  108. Sanda C, Weitzel P, Tsukahara T, Schaley J, Edenberg HJ, Stephens MA, McClintick JN, Blatt LM, Li L, Brodsky L, Taylor MW (2006) Differential gene induction by type I and type II interferons and their combination. J Interferon Cytokine Res 26:462–472PubMedCrossRefGoogle Scholar
  109. Satoh J, Nanri Y, Tabunoki H, Yamamura T (2006) Microarray analysis identifies a set of CXCR3 and CCR2 ligand chemokines as early IFNbeta-responsive genes in peripheral blood ­lymphocytes in vitro: an implication for IFNbeta-related adverse effects in multiple sclerosis. BMC Neurol 6:18PubMedCrossRefGoogle Scholar
  110. Sauer JD, Sotelo-Troha K, von Moltke J, Monroe KM, Rae CS, Brubaker SW, Hyodo M, Hayakawa Y, Woodward JJ, Portnoy DA, Vance RE (2011) The N-ethyl-N-nitrosourea-induced Goldenticket mouse mutant reveals an essential function of Sting in the in vivo interferon response to Listeria monocytogenes and cyclic dinucleotides. Infect Immun 79:688–694PubMedCrossRefGoogle Scholar
  111. Schiavoni G, Mauri C, Carlei D, Belardelli F, Pastoris MC, Proietti E (2004) Type I IFN protects permissive macrophages from Legionella pneumophila infection through an ­IFN-gamma-independent pathway. J Immunol 173:1266–1275PubMedGoogle Scholar
  112. Schmitz F, Heit A, Guggemoos S, Krug A, Mages J, Schiemann M, Adler H, Drexler I, Haas T, Lang R, Wagner H (2007) Interferon-regulatory-factor 1 controls Toll-like receptor 9-mediated IFN-beta production in myeloid dendritic cells. Eur J Immunol 37:315–327PubMedCrossRefGoogle Scholar
  113. Schoggins JW, Wilson SJ, Panis M, Murphy MY, Jones CT, Bieniasz P, Rice CM (2011) A diverse range of gene products are effectors of the type I interferon antiviral response. Nature 472:481–485PubMedCrossRefGoogle Scholar
  114. Sha Q, Truong-Tran AQ, Plitt JR, Beck LA, Schleimer RP (2004) Activation of airway epithelial cells by toll-like receptor agonists. Am J Respir Cell Mol Biol 31:358–364PubMedCrossRefGoogle Scholar
  115. Shahangian A, Chow EK, Tian X, Kang JR, Ghaffari A, Liu SY, Belperio JA, Cheng G, Deng JC (2009) Type I IFNs mediate development of postinfluenza bacterial pneumonia in mice. J Clin Invest 119:1910–1920PubMedCrossRefGoogle Scholar
  116. Shornick LP, Wells AG, Zhang Y, Patel AC, Huang G, Takami K, Sosa M, Shukla NA, Agapov E, Holtzman MJ (2008) Airway epithelial versus immune cell Stat1 function for innate defense against respiratory viral infection. J Immunol 180:3319–3328PubMedGoogle Scholar
  117. Smith EM, Johnson HM, Blalock JE (1983) Staphylococcus aureus protein A induces the ­production of interferon-alpha in human lymphocytes and interferon-alpha/beta in mouse spleen cells. J Immunol 130:773–776PubMedGoogle Scholar
  118. Spurrell JC, Wiehler S, Zaheer RS, Sanders SP, Proud D (2005) Human airway epithelial cells produce IP-10 (CXCL10) in vitro and in vivo upon rhinovirus infection. Am J Physiol Lung Cell Mol Physiol 289:L85–L95PubMedCrossRefGoogle Scholar
  119. Stanley SA, Johndrow JE, Manzanillo P, Cox JS (2007) The Type I IFN response to infection with Mycobacterium tuberculosis requires ESX-1-mediated secretion and contributes to pathogenesis. J Immunol 178:3143–3152PubMedGoogle Scholar
  120. Stetson DB, Medzhitov R (2006) Recognition of cytosolic DNA activates an IRF3-dependent innate immune response. Immunity 24:93–103PubMedCrossRefGoogle Scholar
  121. Swanson CL, Wilson TJ, Strauch P, Colonna M, Pelanda R, Torres RM (2010) Type I IFN enhances follicular B cell contribution to the T cell-independent antibody response. J Exp Med 207:1485–1500PubMedCrossRefGoogle Scholar
  122. Takaoka A, Wang Z, Choi MK, Yanai H, Negishi H, Ban T, Lu Y, Miyagishi M, Kodama T, Honda K, Ohba Y, Taniguchi T (2007) DAI (DLM-1/ZBP1) is a cytosolic DNA sensor and an activator of innate immune response. Nature 448:501–505PubMedCrossRefGoogle Scholar
  123. Takeuchi O, Akira S (2010) Pattern recognition receptors and inflammation. Cell 140:805–820PubMedCrossRefGoogle Scholar
  124. Unterholzner L, Keating SE, Baran M, Horan KA, Jensen SB, Sharma S, Sirois CM, Jin T, Latz E, Xiao TS, Fitzgerald KA, Paludan SR, Bowie AG (2010) IFI16 is an innate immune sensor for intracellular DNA. Nat Immunol 11:997–1004PubMedCrossRefGoogle Scholar
  125. Utaisincharoen P, Anuntagool N, Limposuwan K, Chaisuriya P, Sirisinha S (2003) Involvement of beta interferon in enhancing inducible nitric oxide synthase production and antimicrobial ­activity of Burkholderia pseudomallei-infected macrophages. Infect Immun 71:3053–3057PubMedCrossRefGoogle Scholar
  126. Walberg K, Baron S, Poast J, Schwartz B, Izotova L, Pestka S, Peterson JW (2008) Interferon protects mice against inhalation anthrax. J Interferon Cytokine Res 28:597–601PubMedCrossRefGoogle Scholar
  127. Wang Q, Nagarkar DR, Bowman ER, Schneider D, Gosangi B, Lei J, Zhao Y, McHenry CL, Burgens RV, Miller DJ, Sajjan U, Hershenson MB (2009) Role of double-stranded RNA ­pattern recognition receptors in rhinovirus-induced airway epithelial cell responses. J Immunol 183:6989–6997PubMedCrossRefGoogle Scholar
  128. Watanabe T, Asano N, Fichtner-Feigl S, Gorelick PL, Tsuji Y, Matsumoto Y, Chiba T, Fuss IJ, Kitani A, Strober W (2010) NOD1 contributes to mouse host defense against Helicobacter pylori via induction of type I IFN and activation of the ISGF3 signaling pathway. J Clin Invest 120:1645–1662PubMedCrossRefGoogle Scholar
  129. Weigent DA, Huff TL, Peterson JW, Stanton GJ, Baron S (1986) Role of interferon in ­streptococcal infection in the mouse. Microb Pathog 1:399–407PubMedCrossRefGoogle Scholar
  130. Wenzel J, Schmidt R, Proelss J, Zahn S, Bieber T, Tuting T (2006) Type I interferon-associated skin recruitment of CXCR3+ lymphocytes in dermatomyositis. Clin Exp Dermatol 31:576–582PubMedCrossRefGoogle Scholar
  131. Woodward JJ, Iavarone AT, Portnoy DA (2010) c-di-AMP secreted by intracellular Listeria ­monocytogenes activates a host type I interferon response. Science 328:1703–1705PubMedCrossRefGoogle Scholar
  132. Xing Z, Harper R, Anunciacion J, Yang Z, Gao W, Qu B, Guan Y, Cardona CJ (2010) Host immune and apoptotic responses to avian influenza virus H9N2 in human tracheobronchial epithelial cells. Am J Respir Cell Mol Biol 44:24–33PubMedCrossRefGoogle Scholar
  133. Yang YL, Reis LF, Pavlovic J, Aguzzi A, Schafer R, Kumar A, Williams BR, Aguet M, Weissmann C (1995) Deficient signaling in mice devoid of double-stranded RNA-dependent protein kinase. EMBO J 14:6095–6106PubMedGoogle Scholar
  134. Yang D, Chen Q, Hoover DM, Staley P, Tucker KD, Lubkowski J, Oppenheim JJ (2003) Many chemokines including CCL20/MIP-3alpha display antimicrobial activity. J Leukoc Biol 74:448–455PubMedCrossRefGoogle Scholar
  135. Yang P, An H, Liu X, Wen M, Zheng Y, Rui Y, Cao X (2010) The cytosolic nucleic acid sensor LRRFIP1 mediates the production of type I interferon via a beta-catenin-dependent pathway. Nat Immunol 11:487–494PubMedCrossRefGoogle Scholar
  136. Yao SY, Ljunggren-Rose A, Stratton CW, Mitchell WM, Sriram S (2001) Regulation by IFN-beta of inducible nitric oxide synthase and interleukin-12/p40 in murine macrophages cultured in the presence of Chlamydia pneumoniae antigens. J Interferon Cytokine Res 21:137–146PubMedCrossRefGoogle Scholar
  137. Yarovinsky TO, Monick MM, Husmann M, Hunninghake GW (2008) Interferons increase cell resistance to Staphylococcal alpha-toxin. Infect Immun 76:571–577PubMedCrossRefGoogle Scholar
  138. Yoshikawa T, Hill TE, Yoshikawa N, Popov VL, Galindo CL, Garner HR, Peters CJ, Tseng CT (2010) Dynamic innate immune responses of human bronchial epithelial cells to severe acute respiratory syndrome-associated coronavirus infection. PLoS One 5:e8729PubMedCrossRefGoogle Scholar
  139. Zanoni I, Ostuni R, Marek LR, Barresi S, Barbalat R, Barton GM, Granucci F, Kagan JC (2011) CD14 controls the LPS-induced endocytosis of Toll-like receptor 4. Cell 147:868–880PubMedCrossRefGoogle Scholar
  140. Zhang Z, Clarke TB, Weiser JN (2009) Cellular effectors mediating Th17-dependent clearance of pneumococcal colonization in mice. J Clin Invest 119:1899–1909PubMedGoogle Scholar
  141. Zhang Z, Yuan B, Bao M, Lu N, Kim T, Liu YJ (2011) The helicase DDX41 senses intracellular DNA mediated by the adaptor STING in dendritic cells. Nat Immunol 12(10):959–965PubMedCrossRefGoogle Scholar
  142. Zwaferink H, Stockinger S, Reipert S, Decker T (2008) Stimulation of inducible nitric oxide ­synthase expression by beta interferon increases necrotic death of macrophages upon Listeria monocytogenes infection. Infect Immun 76:1649–1656PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2013

Authors and Affiliations

  1. 1.Department of PediatricsColumbia UniversityNew YorkUSA

Personalised recommendations