Bacterial infections in normal airways
The upper airways represent a primary site for the introduction of pathogenic microorganisms from inspired air. The ciliated epithelium features several powerful mechanisms for prevention of colonization by inhaled bacteria, thus the lower respiratory tract usually remains sterile. Toll-like receptors (TLRs) play a key role in facilitating the innate immune response to bacterial antigens .
Toll-like receptors (TLRs) belong to a family of transmembrane proteins that can recognize and discriminate a diverse array of microbial antigens. Following their activation by specific bacterial ligands, TLRs initiate intracellular signaling cascades that culminate in the activation of transcription factors and ultimately lead to activation of pro-inflammatory gene expression (acute inflammatory response). Epithelial cells content of the airways provide both a physical barrier to infection and an active defense mechanism against invading microoranisms .
TLR2 is the predominant TLR expressed on the apical cell surface, with other TLRs (TLR1, TLR4 and TLR5) residing mainly intracellularly. However, in inflamed lung following stimulation with bacterial ligands TLR5 and TLR4 can be mobilized to the apical surface .
All TLRs, as well as IL-1RI, induce the canonical pathway of NF-kB activation which consists of MyD88/ IRAK4 and IRAK1/2/ TRAF6/ TAB1 and TAB2/ TAK1(MAP3K7)/ NIK(MAP3K14)/ IKK (cat)/ I-kB/ NF-kB cascade , , . TLR2 and TLR4 signaling pathways also require an additional adaptor TIRAP (Mal) , .
TLR signaling and NF-kB activation are commonly involved in the up-regulation of chemotactic molecules and cytokines (such as Interleukins IL-1 beta, IL-6 and IL-8), production of mediators of innate immune response (IFN-gamma and NO that is synthesized by inducible nitric oxide synthase (iNOS), enhanced expression of antimicrobial peptides (such as Beta-defensin 2). IL-1 beta signaling, in turn, regulates the levels of CFTR , .
Of all the TLRs, TLR2 in conjunction with TLR1 recognizes the broadest repertoire of ligands, such as Lipoteichoic acid (LTA) and Glycopeptide (peptidoglycan, PGN) from gram positive bacteria followed by NF-kB activation and interleukin production , , . TLR5 is able to recognize Flagellin (from both gram positive and gram negative bacteria), and also stimulate NF-kB signaling , , .
Pseudomonas aeruginosa has been shown to signal through TLR4/ MD-2/ CD14 complex with its LPS moiety , . Although TLR4 is expressed in airway epithelial cells, it does not appear to be prominently involved in signaling of P. aeruginosa presented at the apical surface of airway epithelial cells , , , . The low level of MD-2 expression is also proposed to limit the responses of human airway epithelia to endotoxin stimulation .
TLR2 can also mediate Beta-defensin 2 expression via NF-kB activation in response to bacterial antigens in human airway epithelia , thus promoting an effective immune response .
CFTR is a chloride channel that regulates chloride transport, fluid hydration and mucociliary clearance in the lung, thus preventing the bacterial growth in normal airways , , . Normal CFTR promotes a rapid expression of FasL(TNFSF6) and FasR(CD95), as well as an apoptotic response to P. aeruginosa infection. Mutant deltaF508 CFTR cells are characterized by inhibited apoptosis and delayed FasL(TNFSF6) and FasR(CD95) expression in response to infection .
Bacterial stimulation also leads to FasR(CD95)-dependent NF-kB activation , . Rapid release of IL-1 beta (most probably NF-kB-dependent) is enhanced in the presence of functional CFTR, but not deltaF508 CFTR in respiratory epithelial cells .
The inducible form of nitric oxide synthase (iNOS) is expressed constitutively in normal human airway epithelium . Both NF-kB and IFN-gamma signaling components are necessary for normal iNOS expression. IFN-gamma activates JAK1 and (JAK2/ STAT1 signaling followed by IRF1 and iNOS expression . Activation of PIAS1 results in reduced IRF1 and iNOS expression in CF, but not healthy, epithelial cells .
| Beta-defensin 2 || Beta-defensin 4A |
| CD14 || Monocyte differentiation antigen CD14 |
| CFTR || Cystic fibrosis transmembrane conductance regulator |
| FasL(TNFSF6) || Tumor necrosis factor ligand superfamily member 6 |
| FasR(CD95) || Tumor necrosis factor receptor superfamily member 6 |
| Flagellin || Bacterial flagellin |
| Glycopeptide || |
| I-kB || I-kappaB Protein group |
| IFN-gamma || Interferon gamma |
| IKK (cat) || IKK (cat) Complex |
| IL-1 beta || Interleukin-1 beta |
| IL-1RI || Interleukin-1 receptor type 1 |
| IL-6 || Interleukin-6 |
| IL-8 || Interleukin-8 |
| IRAK1/2 || Interleukin-1 receptor-associated kinases 1/2 Protein group |
| IRAK4 || Interleukin-1 receptor-associated kinase 4 |
| IRF1 || Interferon regulatory factor 1 |
| JAK1 || Tyrosine-protein kinase JAK1 |
| JAK2 || Tyrosine-protein kinase JAK2 |
| LPS || Chemical IUPAC name lipopolysaccharide |
| MD-2 || Lymphocyte antigen 96 |
| MyD88 || Myeloid differentiation primary response protein MyD88 |
| NF-kB || NF-kB Group of complexes |
| NIK(MAP3K14) || Mitogen-activated protein kinase kinase kinase 14 |
| NO || Chemical IUPAC name Nitric oxide |
| PIAS1 || E3 SUMO-protein ligase PIAS1 |
| STAT1 || Signal transducer and activator of transcription 1-alpha/beta |
| TAB1 || TGF-beta-activated kinase 1 and MAP3K7-binding protein 1 |
| TAB2 || TGF-beta-activated kinase 1 and MAP3K7-binding protein 2 |
| TAK1(MAP3K7) || Mitogen-activated protein kinase kinase kinase 7 |
| TIRAP (Mal) || Toll/interleukin-1 receptor domain-containing adapter protein |
| TLR1 || Toll-like receptor 1 |
| TLR2 || Toll-like receptor 2 |
| TLR4 || Toll-like receptor 4 |
| TLR5 || Toll-like receptor 5 |
| TRAF6 || TNF receptor-associated factor 6 |
| iNOS || Nitric oxide synthase, inducible |
- Gomez MI, Prince A
Opportunistic infections in lung disease: Pseudomonas infections in cystic fibrosis.
Current opinion in pharmacology 2007 Jun;7(3):244-51
- Greene CM, McElvaney NG
Toll-like receptor expression and function in airway epithelial cells.
Archivum immunologiae et therapiae experimentalis 2005 Sep-Oct;53(5):418-27
- Shuto T, Xu H, Wang B, Han J, Kai H, Gu XX, Murphy TF, Lim DJ, Li JD
Activation of NF-kappa B by nontypeable Hemophilus influenzae is mediated by toll-like receptor 2-TAK1-dependent NIK-IKK alpha /beta-I kappa B alpha and MKK3/6-p38 MAP kinase signaling pathways in epithelial cells.
Proceedings of the National Academy of Sciences of the United States of America 2001 Jul 17;98(15):8774-9
- Dziarski R, Gupta D
Role of MD-2 in TLR2- and TLR4-mediated recognition of Gram-negative and Gram-positive bacteria and activation of chemokine genes.
Journal of endotoxin research 2000;6(5):401-5
- Takeda K, Akira S
Microbial recognition by Toll-like receptors.
Journal of dermatological science 2004 Apr;34(2):73-82
- Greene CM, Carroll TP, Smith SG, Taggart CC, Devaney J, Griffin S, O'neill SJ, McElvaney NG
TLR-induced inflammation in cystic fibrosis and non-cystic fibrosis airway epithelial cells.
Journal of immunology (Baltimore, Md. : 1950) 2005 Feb 1;174(3):1638-46
- Brouillard F, Bouthier M, Leclerc T, Clement A, Baudouin-Legros M, Edelman A
NF-kappa B mediates up-regulation of CFTR gene expression in Calu-3 cells by interleukin-1beta.
The Journal of biological chemistry 2001 Mar 23;276(12):9486-91
- Cafferata EG, Guerrico AM, Pivetta OH, Santa-Coloma TA
NF-kappaB activation is involved in regulation of cystic fibrosis transmembrane conductance regulator (CFTR) by interleukin-1beta.
The Journal of biological chemistry 2001 May 4;276(18):15441-4
- Muir A, Soong G, Sokol S, Reddy B, Gomez MI, Van Heeckeren A, Prince A
Toll-like receptors in normal and cystic fibrosis airway epithelial cells.
American journal of respiratory cell and molecular biology 2004 Jun;30(6):777-83
- Shuto T, Furuta T, Oba M, Xu H, Li JD, Cheung J, Gruenert DC, Uehara A, Suico MA, Okiyoneda T, Kai H
Promoter hypomethylation of Toll-like receptor-2 gene is associated with increased proinflammatory response toward bacterial peptidoglycan in cystic fibrosis bronchial epithelial cells.
The FASEB journal : official publication of the Federation of American Societies for Experimental Biology 2006 Apr;20(6):782-4
- Hayashi F, Smith KD, Ozinsky A, Hawn TR, Yi EC, Goodlett DR, Eng JK, Akira S, Underhill DM, Aderem A
The innate immune response to bacterial flagellin is mediated by Toll-like receptor 5.
Nature 2001 Apr 26;410(6832):1099-103
- Zhang Z, Louboutin JP, Weiner DJ, Goldberg JB, Wilson JM
Human airway epithelial cells sense Pseudomonas aeruginosa infection via recognition of flagellin by Toll-like receptor 5.
Infection and immunity 2005 Nov;73(11):7151-60
- Hajjar AM, Ernst RK, Tsai JH, Wilson CB, Miller SI
Human Toll-like receptor 4 recognizes host-specific LPS modifications.
Nature immunology 2002 Apr;3(4):354-9
- Backhed F, Normark S, Schweda EK, Oscarson S, Richter-Dahlfors A
Structural requirements for TLR4-mediated LPS signalling: a biological role for LPS modifications.
Microbes and infection / Institut Pasteur 2003 Oct;5(12):1057-63
- Becker MN, Diamond G, Verghese MW, Randell SH
CD14-dependent lipopolysaccharide-induced beta-defensin-2 expression in human tracheobronchial epithelium.
The Journal of biological chemistry 2000 Sep 22;275(38):29731-6
- Sadikot RT, Blackwell TS, Christman JW, Prince AS
Pathogen-host interactions in Pseudomonas aeruginosa pneumonia.
American journal of respiratory and critical care medicine 2005 Jun 1;171(11):1209-23
- Jia HP, Kline JN, Penisten A, Apicella MA, Gioannini TL, Weiss J, McCray PB Jr
Endotoxin responsiveness of human airway epithelia is limited by low expression of MD-2.
American journal of physiology. Lung cellular and molecular physiology 2004 Aug;287(2):L428-37
- Wang X, Zhang Z, Louboutin JP, Moser C, Weiner DJ, Wilson JM
Airway epithelia regulate expression of human beta-defensin 2 through Toll-like receptor 2.
The FASEB journal : official publication of the Federation of American Societies for Experimental Biology 2003 Sep;17(12):1727-9
- Rowe SM, Miller S, Sorscher EJ
The New England journal of medicine 2005 May 12;352(19):1992-2001
- Dubin PJ, McAllister F, Kolls JK
Is cystic fibrosis a TH17 disease?
Inflammation research : official journal of the European Histamine Research Society ... [et al.] 2007 Jun;56(6):221-7
- Cannon CL, Kowalski MP, Stopak KS, Pier GB
Pseudomonas aeruginosa-induced apoptosis is defective in respiratory epithelial cells expressing mutant cystic fibrosis transmembrane conductance regulator.
American journal of respiratory cell and molecular biology 2003 Aug;29(2):188-97
- Reiniger N, Lee MM, Coleman FT, Ray C, Golan DE, Pier GB
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.
Infection and immunity 2007 Apr;75(4):1598-608
- Guo FH, De Raeve HR, Rice TW, Stuehr DJ, Thunnissen FB, Erzurum SC
Continuous nitric oxide synthesis by inducible nitric oxide synthase in normal human airway epithelium in vivo.
Proceedings of the National Academy of Sciences of the United States of America 1995 Aug 15;92(17):7809-13
- Kelley TJ, Elmer HL
In vivo alterations of IFN regulatory factor-1 and PIAS1 protein levels in cystic fibrosis epithelium.
The Journal of clinical investigation 2000 Aug;106(3):403-10