Table 2. Virulence factors of P. aeruginosa in respiratory infections.
| Class | Virulence factor | Gene(s) | General function(s) | HAE-specific function(s) | Type of cells used to evidence HAE-specific function(s) |
Molecular host target | SS | Reference |
|---|---|---|---|---|---|---|---|---|
| Motility/Adhesion | Flagella | fliC | Swimming and swarming motility Host cell adhesion and internalization |
Motility and basal adhesion to HAE cells HAE infection progression |
Primary nasal cells, cell lines (Calu 3, 1HAEo-), mice pneumonia | Heparan sulfate, proteoglycans, AsialoGM1 | - | [127,130,138,172] |
| Type IV pili | pilA | Twitching motility Host cell adhesion, biofilm formation |
Motility and apical adhesion to HAE cells Allow T3SS injection. HAE infection progression |
Cell lines (Calu 3) | N-glycans | - | [138,173,174] | |
| LPS | waa, wzy, wzz, wbp, wzx | Resistance to serum killing and phagocytosis, inflammatory response Binding to CFTR Cell junctions’ disruptions and apoptosis |
Apical adhesion to HAE cells Disruption of HAE tight junctions HAE cell apoptosis |
Cell lines (A549, NCL-H292, Beas-2b) | CFTR, Tight junctions (ZO-1) | - | [54,118,175–177] | |
| Lectin A Lectin B |
lecA
lecB |
Host cell adhesion: binding to galactose (LecA) and fucose (LecB) Internalization (LecA) Cytotoxicity (LecA and LecB) |
Apical and basal adhesion to HAE cells HAE cell internalization HAE cell cytotoxicity |
Primary nasal cells, cell lines (H1299, A549), mice pneumonia | Globotriaosylceramide Gb3 (CD77) | - | [132,134,178] | |
| Protection/Persistence | Exopolysaccharides (Alginate, Psl, Pel) |
alg, muc, psl, pel | Biofilm main component: polymeric matrix Persistence, bacteria protection (from IS and antibiotics) |
Biofilm persistence in chronic HAE infection | - | - | - | [167,179–181] |
| Iron uptake | Siderophores: - Pyoverdin - Pyochelin |
pvd
pch |
Iron siderophore, green pigment (pyoverdine) Cytotoxicity (ROS production) |
- | - | DNA, lipid membrane, proteins | - | [182–185] |
| Heme uptake systems: - Pseudomonas heme uptake - Heme assimilation systems |
phu
has |
Extracellular heme acquisition (uptake in the cytoplasm) | - | - | - | - | [185–187] | |
| Oxidative stress | Pyocyanin | phz | Cytotoxicity (ROS production: O2−, H2O2) IS regulation (apoptosis), blue-green pigment |
Inhibition of ciliated HAE function | Primary sheep cells | DNA, lipid membrane, proteins | - | [188–190] |
| Biosurfactant | Rhamnolipid | rhl | Amphiphilic: detergent and solubilizing properties Disruption cell junctions IS regulation (neutrophils lysis) Biofilm formation, motility |
Solubilization of airway surfactant Disruption of HAE tight junctions |
Primary nasal cells | Tight junctions (ZO-1, occludin, JAM-A) | - | [120,191–193] |
| Esterase EstA | estA | Autotransporter enzyme: Hydrolyze glycerol esters Rhamnolipids production |
Disruption of HAE tight junctions | See Rhamnolipid | See Rhamnolipid | - | [194] | |
| Excreted toxins | Alkaline protease | aprA | Protease activity: IS inactivation (antibodies, neutrophils, complement, cytokines) and laminin | Degradation of HAE extracellular matrix: (basement membrane: laminin) | - | Laminin | T1SS | [195,196] |
| Elastase | lasB, (lasA) | Protease activity: elastin, collagen, transferrin, antibodies, complement → Tissue damage Disruption of cell junctions |
Degradation of HAE extracellular matrix (basement membrane and alveolar septum: elastin and collagen) Disruption of HAE tight junctions |
Primary nasal cells, cell lines (Calu 3) | Elastin, Collagen, tight junction (ZO-1, claudin, occludin) | T2SS | [113,114,117,197] | |
| Exotoxin A | toxA | Host cells protein synthesis inhibition: eEF2 inhibition by ADP-ribosylation → Cell death |
HAE cell death | Cell lines (CuFi-1) | eEF2 | T2SS | [198,199] | |
| Phospholipase C | plcH | Hydrolysis of phospholipids (erythrocyte and leukocyte cytolysis), surfactant degradation | Pulmonary surfactant degradation | - | Phosphatidylcholine, Sphingomyelin | T2SS | [200–203] | |
| Exolysin | exlA | Pore-forming toxin: cell membrane disruptions (erythrocytes, leukocytes, epithelial cells) | HAE cell death and retraction | Cell lines (A549), mice pneumonia | Phophoslipid bilayers | - | [108,204,205] | |
| CFTR inhibitory factor | cif | - | TAP-1 mediated-MHC class 1 antigen presentation and CFTR-mediated chloride secretion inhibition | Cell lines (CFBE41o-, A549) | CFTR and TAP-1 | OMV | [206,207] | |
| Injected toxins | Exo S (exoenzyme S) | exoS | GTPase-activating protein activity and ADP ribosyltransferase activity: inhibition of several host cell functions (cell apoptosis, cell division and cell migration inhibitions, junctions and actin cytoskeleton disruptions) | HAE cell death and retraction | Mice pneumonia | Rho family of GTPases, Ras superfamily GTPases | T3SS | [163,208,209] |
| Exo T (exoenzyme T) | exoT | |||||||
| Exo U (exoenzyme U) | exoU | Phospholipase A2 activity: membrane phospholipids hydrolysis (rapid cell necrosis) | Rapid HAE cell death and retraction | Mice pneumonia, cell lines (Beas-2b) | Phospholipids | T3SS | [163,208,210] | |
| Exo Y (exoenzyme Y) | exoY | Adenylate cyclase activity: actin cytoskeleton disruptions | HAE cell death and retraction | Mice pneumonia, cell lines (PMVECR1) | Tau protein (microtubule) | T3SS | [211–214] | |
| Phospholipase D | pldA, pldB | - Host cell internalization - Bacterial competition |
HAE cell internalization | Cell lines (Calu 3) | Akt kinase | H2 (pldA) H3 (pldB) T6SS |
[110,215,216] | |
| VgrG2b | vgrG | - Host cell internalization - Bacterial competition |
HAE cell internalization | Cell lines (Calu 3 | γ-tubulin ring complex (γTuRCn microtubule component) | H2 T6SS | [110,217] | |
| Phospholipase TplE | TplE | - Host cells endoplasmic reticulum disruption - Bacterial competition |
- | - | Endoplasmic reticulum apparatus | H2 T6SS | [218] | |
| Tse1-3 | Tse1-3 | Bacterial competition (peptidoglycan degradation) | - | - | - | H1 T6SS | [215] | |
| Short RNA | sRNA52320 | - | - | Decrease of IL-8 secretion | Bronchial primary cells | Kinases of the LPS-stimulated MAPK pathway | OMV | [219] |
| Global regulatory system | Quorum sensing | las, rhl, pqs, iqs | Autoinducer peptides (for instance, homoserines lactones 3O–C12–HS) detect critical density → activation of 4 regulation systems: impact on virulence factors production and biofilm formation | Disruption of tight junctionsa | - | Tight junctions (ZO-1, ZO-3, JAM-A, occludin) | - | [122,123,164,165,220] |
aDisruption of cells’ tight junction described in the intestinal epithelial model (Caco2 cells), not yet in HAE.
CFTR, cystic fibrosis transmembrane regulator; eEF2, eukaryotic elongation factor 2; HAE, human airway epithelium; H2O2, hydrogen peroxide; LPS, lipopolysaccharide; MHC, major histocompatibility complex; OMV, outer membrane vesicle; O2, superoxide; IS, immune system; ROS, reactive oxygen species; SS, secretion system; TAP, transporter associated with antigen processing; TxSS, type x secretion system.