Pseudomonas aeruginosa: Role in the Pathogenesis of the CF Lung Lesion

Andrew J. Currie; David P. Speert; Donald J. Davidson

doi:10.1055/s-2004-815663

Seminars in Respiratory and Critical Care Medicine, Table of Contents

Semin Respir Crit Care Med 2003; 24(6): 671-680
DOI: 10.1055/s-2004-815663

Pseudomonas aeruginosa: Role in the Pathogenesis of the CF Lung Lesion

Andrew J. Currie, David P. Speert, Donald J. Davidson

Division of Infectious and Immunological Diseases, Department of Pediatrics and the British Columbia Research Institute for Children's and Women's Health, University of British Columbia, Vancouver, British Columbia, Canada

Abstract

ABSTRACT

Lung disease is the leading cause of morbidity and mortality in individuals with cystic fibrosis (CF), with P. aeruginosa the main pulmonary infectious agent. Although CF patients can become infected with other microorganisms (such as Burkholderia cepacia complex, Staphylococcus aureus, Haemophilus influenzae, and atypical mycobacteria), P. aeruginosa predominates, eventually infecting ~80% of patients. Once established, P. aeruginosa infection usually persists until death. The interaction between the CF host and this opportunistic pathogen is unique and most likely directly contributes to the classical end-stage pathology of CF lung disease. However, the extent to which this constitutes success by the pathogen or failure by the host, or both, is yet to be determined. Many important questions remain regarding host susceptibility, the role of both innate and adaptive immune defenses, bacterial infectivity and transmission, and pathogen virulence factors. Here, we discuss some recent advances toward understanding this complex interaction between host and pathogen and how the interplay influences the CF lung lesion.

KEYWORDS

Inflammation - airway surface liquid - epithelial cells - {Pseudomonas aeruginosa, cystic fibrosis - biofilm - mucoid - lipopolysaccharide

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References

REFERENCES

1 Vankeerberghen A, Cuppens H, Cassiman J. The cystic fibrosis transmembrane conductance regulator: an intriguing protein with peiotropic functions. J Cystic Fibrosis . 2002; 1 13-29
2 Maselli J H, Sontag M K, Norris J M, MacKenzie T, Wagener J S, Accurso F J. Risk factors for initial acquisition of Pseudomonas aeruginosa in children with cystic fibrosis identified by newborn screening. Pediatr Pulmonol . 2003; 35 257-262
3 Johansen H K, Nir M, Hoiby N, Koch C, Schwartz M. Severity of cystic fibrosis in patients homozygous and heterozygous for delta F508 mutation. Lancet . 1991; 337 631-634
4 Kubesch P, Dork T, Wulbrand U. et al . Genetic determinants of airways' colonisation with Pseudomonas aeruginosa in cystic fibrosis. Lancet . 1993; 341 189-193
5 Lester L A, Kraut J, Lloyd-Still J. et al . Delta F508 genotype does not predict disease severity in an ethnically diverse cystic fibrosis population. Pediatrics . 1994; 93 114-118
6 Doring G, Krogh-Johansen H, Weidinger S, Hoiby N. Allotypes of alpha 1-antitrypsin in patients with cystic fibrosis, homozygous and heterozygous for delta F508. Pediatr Pulmonol . 1994; 18 3-7
7 Garred P, Pressler T, Madsen H O. et al . Association of mannose-binding lectin gene heterogeneity with severity of lung disease and survival in cystic fibrosis. J Clin Invest . 1999; 104 431-437
8 Bonfield T L, Panuska J R, Konstan M W. et al . Inflammatory cytokines in cystic fibrosis lungs. Am J Respir Crit Care Med . 1995; 152 2111-2118
9 Khan T Z, Wagener J S, Bost T, Martinez J, Accurso F J, Riches D W. Early pulmonary inflammation in infants with cystic fibrosis. Am J Respir Crit Care Med . 1995; 151 1075-1082
10 Armstrong D S, Grimwood K, Carlin J B. et al . Lower airway inflammation in infants and young children with cystic fibrosis. Am J Respir Crit Care Med . 1997; 156 1197-1204
11 Burns J L, Gibson R L, McNamara S. et al . Longitudinal assessment of Pseudomonas aeruginosa in young children with cystic fibrosis. J Infect Dis . 2001; 183 444-452
12 DiMango E, Ratner A J, Bryan R, Tabibi S, Prince A. Activation of NF-kappaB by adherent Pseudomonas aeruginosa in normal and cystic fibrosis respiratory epithelial cells. J Clin Invest . 1998; 101 2598-2605
13 Tabary O, Escotte S, Couetil J P. et al . Relationship between IkappaBalpha deficiency, NFkappaB activity and interleukin-8 production in CF human airway epithelial cells. Pflugers Arch . 2001; 443 (suppl 1) S40-S44
14 Scheid P, Kempster L, Griesenbach U. et al . Inflammation in cystic fibrosis airways: relationship to increased bacterial adherence. Eur Respir J . 2001; 17 27-35
15 Berger M. Lung inflammation early in cystic fibrosis: bugs are indicted, but the defense is guilty. Am J Respir Crit Care Med . 2002; 165 857-858
16 Moser C, Kjaergaard S, Pressler T, Kharazmi A, Koch C, Hoiby N. The immune response to chronic Pseudomonas aeruginosa lung infection in cystic fibrosis patients is predominantly of the TH2 type. APMIS . 2000; 108 329-335
17 Worgall S, Martushova K, Busch A, Lande L, Crystal R G. Apoptosis induced by Pseudomonas aeruginosa in antigen presenting cells is diminished by genetic modification with CD40 ligand. Pediatr Res . 2002; 52 636-644
18 Kikuchi T, Worgall S, Singh R, Moore M A, Crystal R G. Dendritic cells genetically modified to express CD40 ligand and pulsed with antigen can initiate antigen-specific humoral immunity independent of CD4+ T cells. Nat Med . 2000; 6 1154-1159
19 Chertov O, Yang D, Howard O M, Oppenheim J J. Leukocyte granule proteins mobilize innate host defenses and adaptive immune responses. Immunol Rev . 2000; 177 68-78
20 Birrer P, McElvaney N G, Rudeberg A. et al . Protease- antiprotease imbalance in the lungs of children with cystic fibrosis. Am J Respir Crit Care Med . 1994; 150 207-213
21 Berger M, Sorensen R U, Tosi M F, Dearborn D G, Doring G. Complement receptor expression on neutrophils at an inflammatory site, the Pseudomonas-infected lung in cystic fibrosis. J Clin Invest . 1989; 84 1302-1313
22 Vandivier R W, Fadok V A, Hoffmann P R. et al . Elastase-mediated phosphatidylserine receptor cleavage impairs apoptotic cell clearance in cystic fibrosis and bronchiectasis. J Clin Invest . 2002; 109 661-670
23 Linsdell P, Hanrahan J W. Glutathione permeability of CFTR. Am J Physiol . 1998; 275 C323-C326
24 Corvol H, Fitting C, Chadelat K. et al . Distinct cytokine production by lung and blood neutrophils from children with cystic fibrosis. Am J Physiol Lung Cell Mol Physiol . 2003; 284 L997-1003
25 Saba S, Soong G, Greenberg S, Prince A. Bacterial stimulation of epithelial G-CSF and GM-CSF expression promotes PMN survival in CF airways. Am J Respir Cell Mol Biol . 2002; 27 561-567
26 Pilewski J M, Frizzell R A. Role of CFTR in airway disease. Physiol Rev . 1999; 79 S215-S255
27 Wine J. The genesis of cystic fibrosis lung disease. J Clin Invest . 1999; 103 309-312
28 Guggino W B. Cystic fibrosis and the salt controversy. Cell . 1999; 96 607-610
29 Zabner J, Smith J J, Karp P H, Widdicombe J H, Welsh M J. Loss of CFTR chloride channels alters salt absorption by cystic fibrosis airway epithelia in vitro. Mol Cell . 1998; 2 397-403
30 Smith J J, Travis S M, Greenberg E P, Welsh M J. Cystic fibrosis airway epithelia fail to kill bacteria because of abnormal airway surface fluid. Cell . 1996; 85 229-236
31 Travis S M, Conway B A, Zabner J. et al . Activity of abundant antimicrobials of the human airway. Am J Respir Cell Mol Biol . 1999; 20 872-879
32 Goldman M J, Anderson G M, Stolzenberg E D, Kari U P, Zasloff M, Wilson J M. Human beta-defensin-1 is a salt-sensitive antibiotic in lung that is inactivated in cystic fibrosis. Cell . 1997; 88 553-560
33 Stutts M J, Canessa C M, Olsen J C. et al . CFTR as a cAMP-dependent regulator of sodium channels. Science . 1995; 269 847-850
34 Matsui H, Grubb B R, Tarran R. et al . Evidence for periciliary liquid layer depletion, not abnormal ion composition, in the pathogenesis of cystic fibrosis airways disease. Cell . 1998; 95 1005-1015
35 Worlitzsch D, Tarran R, Ulrich M. et al . Effects of reduced mucus oxygen concentration in airway Pseudomonas infections of cystic fibrosis patients. J Clin Invest . 2002; 109 317-325
36 Knowles M R, Robinson J M, Wood R E. et al . Ion composition of airway surface liquid of patients with cystic fibrosis as compared with normal and disease-control subjects. J Clin Invest . 1997; 100 2588-2595
37 Gilljam H, Ellin A, Strandvik B. Increased bronchial chloride concentration in cystic fibrosis. Scand J Clin Lab Invest . 1989; 49 121-124
38 Hull J, Skinner W, Robertson C, Phelan P. Elemental content of airway surface liquid from infants with cystic fibrosis. Am J Respir Crit Care Med . 1998; 157 10-14
39 Verkman A S, Song Y, Thiagarajah J R. Role of airway surface liquid and submucosal glands in cystic fibrosis lung disease. Am J Physiol Cell Physiol . 2003; 284 C2-15
40 Tarran R, Grubb B R, Parsons D. et al . The CF salt controversy: in vivo observations and therapeutic approaches. Mol Cell . 2001; 8 149-158
41 Bals R, Weiner D J, Meegalla R L, Accurso F, Wilson J M. Salt-independent abnormality of antimicrobial activity in cystic fibrosis airway surface fluid. Am J Respir Cell Mol Biol . 2001; 25 21-25
42 Meng Q H, Springall D R, Bishop A E. et al . Lack of inducible nitric oxide synthase in bronchial epithelium: a possible mechanism of susceptibility to infection in cystic fibrosis. J Pathol . 1998; 184 323-331
43 Kelley T J, Drumm M L. Inducible nitric oxide synthase expression is reduced in cystic fibrosis murine and human airway epithelial cells. J Clin Invest . 1998; 102 1200-1207
44 Hancock R E. Peptide antibiotics. Lancet . 1997; 349 418-422
45 Li J D, Dohrman A F, Gallup M. et al . Transcriptional activation of mucin by Pseudomonas aeruginosa lipopolysaccharide in the pathogenesis of cystic fibrosis lung disease. Proc Natl Acad Sci USA . 1997; 94 967-972
46 Afzelius B A. Ciliary dysfunction. In: Crystal RG, West JB, Weibel ER, Barnes PJ, eds. The Lung: Scientific Foundations New York, NY: Raven Press 1997: 2573-2578
47 Puchelle E, Bajolet O, Abely M. Airway mucus in cystic fibrosis. Paediatr Respir Rev . 2002; 3 115-119
48 Yeates D B, Sturgess J M, Kahn S R, Levison H, Aspin N. Mucociliary transport in trachea of patients with cystic fibrosis. Arch Dis Child . 1976; 51 28-33
49 Regnis J A, Robinson M, Bailey D L. et al . Mucociliary clearance in patients with cystic fibrosis and in normal subjects. Am J Respir Crit Care Med . 1994; 150 66-71
50 Saiman L, Prince A. Pseudomonas aeruginosa pili bind to asialoGM₁ which is increased on the surface of cystic fibrosis epithelial cells. J Clin Invest . 1993; 92 1875-1880
51 de Bentzmann S, Roger P, Dupuit F. et al . Asialo GM₁ is a receptor for Pseudomonas aeruginosa adherence to regenerating respiratory epithelial cells. Infect Immun . 1996; 64 1582-1588
52 Davies J, Dewar A, Bush A. et al . Reduction in the adherence of Pseudomonas aeruginosa to native cystic fibrosis epithelium with anti-asialoGM₁ antibody and neuraminidase inhibition. Eur Respir J . 1999; 13 565-570
53 Davies J C, Stern M, Dewar A. et al . CFTR gene transfer reduces the binding of Pseudomonas aeruginosa to cystic fibrosis respiratory epithelium. Am J Respir Cell Mol Biol . 1997; 16 657-663
54 Ichikawa J K, Norris A, Bangera M G. et al . Interaction of Pseudomonas aeruginosa with epithelial cells: identification of differentially regulated genes by expression microarray analysis of human cDNAs. Proc Natl Acad Sci USA . 2000; 97 9659-9664
55 Schroeder T H, Zaidi T, Pier G B. Lack of adherence of clinical isolates of Pseudomonas aeruginosa to asialo-GM(1) on epithelial cells. Infect Immun . 2001; 69 719-729
56 Jeffery P K, Brain A P. Surface morphology of human airway mucosa: normal, carcinoma or cystic fibrosis. Scanning Microsc . 1988; 2 553-560
57 Pier G B, Grout M, Zaidi T S. et al . Role of mutant CFTR in hypersusceptibility of cystic fibrosis patients to lung infections. Science . 1996; 271 64-67
58 Pier G B, Grout M, Zaidi T S. Cystic fibrosis transmembrane conductance regulator is an epithelial cell receptor for clearance of Pseudomonas aeruginosa from the lung. Proc Natl Acad Sci USA . 1997; 94 12088-12093
59 Schroeder T H, Lee M M, Yacono P W. et al . CFTR is a pattern recognition molecule that extracts Pseudomonas aeruginosa LPS from the outer membrane into epithelial cells and activates NF-kappa B translocation. Proc Natl Acad Sci USA . 2002; 99 6907-6912
60 Schroeder T H, Reiniger N, Meluleni G, Grout M, Coleman F T, Pier G B. Transgenic cystic fibrosis mice exhibit reduced early clearance of Pseudomonas aeruginosa from the respiratory tract. J Immunol . 2001; 166 7410-7418
61 Massengale A R, Quinn F J, Williams A, Gallagher S, Aronoff S C. The effect of alginate on the invasion of cystic fibrosis respiratory epithelial cells by clinical isolates of Pseudomonas aeruginosa Exp Lung Res . 2000; 26 163-178
62 Grassme H, Kirschnek S, Riethmueller J. et al . CD95/CD95 ligand interactions on epithelial cells in host defense to Pseudomonas aeruginosa Science . 2000; 290 527-530
63 Tang H, Kays M, Prince A. Role of Pseudomonas aeruginosa pili in acute pulmonary infection. Infect Immun . 1995; 63 1278-1285
64 Scharfman A, Van Brussel E, Houdret N, Lamblin G, Roussel P. Interactions between glycoconjugates from human respiratory airways and Pseudomonas aeruginosa Am J Respir Crit Care Med . 1996; 154 S163-S169
65 Abman S H, Ogle J W, Harbeck R J, Butler-Simon N, Hammond K B, Accurso F J. Early bacteriologic, immunologic, and clinical courses of young infants with cystic fibrosis identified by neonatal screening. J Pediatr . 1991; 119 211-217
65a Duan K, Duplisea R, Surette M G. The effect of cystic fibrosis normal flora strains on Pseudomonas aeruginosa gene expression. UA-AC Conference on Infectious Diseases 2002; Abstract 24
66 Davidson D J, Rolfe M. Mouse models of cystic fibrosis. Trends Genet . 2001; 17 S29-S37
67 Coleman F T, Mueschenborn S, Meluleni G. et al . Hypersusceptibility of cystic fibrosis mice to chronic Pseudomonas aeruginosa oropharyngeal colonization and lung infection. Proc Natl Acad Sci USA . 2003; 100 1949-1954
68 Govan J RW, Deretic V. Microbial pathogenesis in cystic fibrosis: mucoid Pseudomonas aeruginosa and Burkholderia cepacia Microbiol Rev . 1996; 60 539-574
69 Parad R B, Gerard C J, Zurakowski D, Nichols D P, Pier G B. Pulmonary outcome in cystic fibrosis is influenced primarily by mucoid Pseudomonas aeruginosa infection and immune status and only modestly by genotype. Infect Immun . 1999; 67 4744-4750
70 Sherbrock-Cox V, Russell N J. Gacesa, P. The purification and chemical characterisation of the alginate present in extracellular material produced by mucoid strains of Pseudomonas aeruginosa Carbohydr Res . 1984; 135 147-154
71 Gacesa P. Bacterial alginate biosynthesis: recent progress and future prospects. Microbiology . 1998; 144 1133-1143
72 Boucher J C, Yu H, Mudd M H, Deretic V. Mucoid Pseudomonas aeruginosa in cystic fibrosis: characterisation of muc mutations in clinical isolates and analysis of clearance in a mouse model of respiratory infection. Infect Immun . 1997; 65 3838-3846
73 Mathee K, Ciofu O, Sternberg C. et al . Mucoid conversion of Pseudomonas aeruginosa by hydrogen peroxide: a mechanism for virulence activation in the cystic fibrosis lung. Microbiology . 1999; 145(Pt 6) 1349-1357
74 Speert D P, Farmer S W, Campbell M E, Musser J M, Selander R K, Kuo S. Conversion of Pseudomonas aeruginosa to the phenotype characteristic of strains from patients with cystic fibrosis. J Clin Microbiol . 1990; 28 188-194
75 Baltimore R S, Mitchell M. Immunologic investigations of mucoid strains of Pseudomonas aeruginosa: comparison of susceptibility to opsonic antibody in mucoid and nonmucoid strains. J Infect Dis . 1980; 141 238-247
76 Pier G B, Coleman F, Grout M, Franklin M, Ohman D E. Role of alginate O acetylation in resistance of mucoid Pseudomonas aeruginosa to opsonic phagocytosis. Infect Immun . 2001; 69 1895-1901
77 Cabral D A, Loh B A, Speert D P. Mucoid Pseudomonas aeruginosa resists nonopsonic phagocytosis by human neutrophils and macrophages. Pediatr Res . 1987; 22 429-431
78 Simpson J A, Smith S E, Dean R T. Scavenging by alginate of free radicals released by macrophages. Free Radic Biol Med . 1989; 6 347-353
79 Learn D B, Brestel E P, Seetharama S. Hypochlorite scavenging by Pseudomonas aeruginosa alginate. Infect Immun . 1987; 55 1813-1818
80 Bayer A S, Speert D P, Park S. et al . Functional role of mucoid exopolysaccharide (alginate) in antibiotic-induced and polymorphonuclear leukocyte-mediated killing of Pseudomonas aeruginosa Infect Immun . 1991; 59 302-308
81 Stiver H G, Zachidniak K, Speert D P. Inhibition of polymorphonuclear leukocyte chemotaxis by the mucoid exopolysaccharide of Pseudomonas aeruginosa Clin Invest Med . 1988; 11 247-252
82 Pedersen S S, Kharazmi A, Espersen F, Hoiby N. Pseudomonas aeruginosa alginate in cystic fibrosis sputum and the inflammatory response. Infect Immun . 1990; 58 3363-3368
83 Konig B, Pedersen S S, Konig W. Effect of Pseudomonas aeruginosa alginate on Escherichia coli- and Staphylococcus aureus-induced inflammatory mediator release from human cells. Int Arch Allergy Immunol . 1993; 100 144-150
84 Nivens D E, Ohman D E, Williams J, Franklin M J. Role of alginate and its O acetylation in formation of Pseudomonas aeruginosa microcolonies and biofilms. J Bacteriol . 2001; 183 1047-1057
85 Hentzer M, Teitzel G M, Balzer G J. et al . Alginate overproduction affects Pseudomonas aeruginosa biofilm structure and function. J Bacteriol . 2001; 183 5395-5401
86 Garret E S, Perlegas D, Wozniak D J. Negative control of flagellum synthesis in Pseudomonas aeruginosa is modulated by the alterantive sigma factor AlgT (AlgU). J Bacteriol . 1999; 181 7401-7404
87 Mahenthiralingam E, Speert D P. Nonopsonic phagocytosis of Pseudomonas aeruginosa by macrophages and polymorphonuclear leukocytes requires the presence of the bacterial flagellum. Infect Immun . 1995; 63 4519-4523
88 Lizewski S E, Lundberg D S, Schurr M J. The transcriptional regulator AlgR is essential for Pseudomonas aeruginosa pathogenesis. Infect Immun . 2002; 70 6083-6093
89 Firoved A M, Boucher J C, Deretic V. Global genomic analysis of AlgU (se)-dependent promoters (sigmulon) in Pseudomonas aeruginosa and implications for inflammatory processes in cytsic fibrosis. J Bacteriol . 2002; 184 1057-1064
90 Firoved A M, Deretic V. Microarray analysis of global gene expression in mucoid Pseudomonas aeruginosa J Bacteriol . 2003; 185 1071-1081
91 Costerton J W, Stewart P S, Greenberg E P. Bacterial biofilms: a common cause of persistent infections. Science . 1999; 284 1318-1322
92 Singh P K, Schaefer A L, Parsek M R, Moniger T O, Welsh M J, Greenberg E P. Quorom-sensing signals indicate that cystic fibrosis lungs are infected with bacterial biofilms. Nature . 2000; 407 762-764
93 Whiteley M, Bangera M G, Bumgarner R E. et al . Gene expression in Pseudomonas aeruginosa biofilms. Nature . 2001; 413 860-864
94 Drenkard E, Ausubel F M. Pseudomonas biofilm formation and antibiotic resistance are linked to phenotypic variation. Nature . 2002; 416 740-743
95 Rumbaugh K, Griswold P JA, Hamood A N. The role of quorom sensing in the in vivo virulence of Pseudomonas aeruginosa Microbes Infect . 2000; 2 1721-1731
96 Erickson D L, Endersby R, Kirkham A. et al . Pseudomonas aeruginosa quorom-sensing systems may control virulence factor expression in the lungs of patients with cystic fibrosis. Infect Immun . 2002; 70 1783-1790
97 Alexander C, Rietschel E T. Bacterial lipopolysaccharides and innate immunity. J Endotoxin Res . 2001; 7 167-202
98 Chow J C, Young D W, Golenbock D T, Christ W J, Gusovsky F. Toll-like receptor-4 mediates lipopolysaccharide-induced signal transduction. J Biol Chem . 1999; 274 10689-10692
99 Liu P V. Extracellular toxins of Pseudomonas aeruginosa J Infect Dis . 1974; 130(suppl) S94-S99
100 Wieland C W, Siegmund B, Senaldi G, Vasil M L, Dinarello C A, Fantuzzi G. Pulmonary inflammation induced by Pseudomonas aeruginosa lipopolysaccharide, phospholipase C, and exotoxin A: role of interferon regulatory factor 1. Infect Immun . 2002; 70 1352-1358
101 Rocchetta H L, Burrows L L, Lam J S. Genetics of O-antigen biosynthesis in Pseudomonas aeruginosa Microbiol Mol Biol Rev . 1999; 63 523-553
102 Hancock R E, Mutharia L M, Chan L, Darveau R P, Speert D P, Pier G B. Pseudomonas aeruginosa isolates from patients with cystic fibrosis: a class of serum-sensitive, nontypable strains deficient in lipopolysaccharide O side chains. Infect Immun . 1983; 42 170-177
103 Pier G B, Ames P. Mediatoin of the killing of rough, mucoid isolates of Pseudomonas aeruginosa from patients with cystic fibrosis by the alternative pathway of complement. J Infect Dis . 1984; 150 223-228
104 Ernst R K, Yi E C, Guo L. et al . Specific lipopolysaccharide found in cystic fibrosis airway Pseudomonas aeruginosa Science . 1999; 286 1561-1565
105 Hajjar A M, Ernst R K, Tsai J H, Wilson C B, Miller S I. Human Toll-like receptor 4 recognizes host-specific LPS modificatons. Nat Immunol . 2002; 3 354-359
106 Mathiak G, Kabir K, Grass G. et al . Lipopolysaccharides from different bacterial sources elicit disparate cytokine responses in whole blood assays. Int J Mol Med . 2003; 11 41-44
107 Koyama S, Sato E, Nomura H. et al . The potential of various lipopolysaccharides to release monocyte chemotactic activity from lung epithelial cells and fibroblasts. Eur Respir J . 1999; 14 545-552