5,805
Views
22
CrossRef citations to date
0
Altmetric
Review Article

An Organ System-Based Synopsis of Pseudomonas aeruginosa Virulence

, , , &
Pages 1469-1507 | Received 03 Feb 2021, Accepted 30 Apr 2021, Published online: 27 Jun 2021

References

  • Gaynes R, Edwards JR. National Nosocomial Infections Surveillance S. Overview of nosocomial infections caused by gram-negative bacilli. Clin Infect Dis. 2005;41:848–854.
  • Weiner LM, Webb AK, Limbago B, et al. Antimicrobial-Resistant Pathogens Associated With Healthcare-Associated Infections: summary of Data Reported to the National Healthcare Safety Network at the Centers for Disease Control and Prevention, 2011–2014. Infect Control Hosp Epidemiol. 2016;37(11):1288–1301.
  • Murphy TF. Pseudomonas aeruginosa in adults with chronic obstructive pulmonary disease. Curr Opin Pulm Med. 2009;15(2):138–142.
  • Folkesson A, Jelsbak L, Yang L, et al. Adaptation of Pseudomonas aeruginosa to the cystic fibrosis airway: an evolutionary perspective. Nat Rev Microbiol. 2012;10(12):841–851.
  • Wisplinghoff H, Bischoff T, Tallent SM, et al. Nosocomial bloodstream infections in US hospitals: analysis of 24,179 cases from a prospective nationwide surveillance study. Clin Infect Dis. 2004;39(3):309–317.
  • Luyt C-E, Hekimian G, Koulenti D, et al. Microbial cause of ICU-acquired pneumonia: hospital-acquired pneumonia versus ventilator-associated pneumonia. Curr Opin Crit Care. 2018;24(5):332–338.
  • Barbier F, Andremont A, Wolff M, et al. Hospital-acquired pneumonia and ventilator-associated pneumonia: recent advances in epidemiology and management. Curr Opin Pulm Med. 2013;19(3):216–228.
  • Gellatly SL, Hancock REW. Pseudomonas aeruginosa : new insights into pathogenesis and host defenses. Pathog Dis. 2013;67(3):159–173.
  • Lin T-I, Huang Y-F, Liu P-Y, et al. Pseudomonas aeruginosa infective endocarditis in patients who do not use intravenous drugs: analysis of risk factors and treatment outcomes. J Microbiol Immunol Infect. 2016;49(4):516–522.
  • Venkatesan A, Spalding C, Speedie A, et al. Pseudomonas aeruginosa infective endocarditis presenting as bacterial meningitis. J Infect. 2005;51(4):e199–202.
  • Rodriguez-Lucas C, Fernandez J, Martinez-Sela M, et al. Pseudomonas aeruginosa nosocomial meningitis in neurosurgical patients with intraventricular catheters: therapeutic approach and review of the literature. Enfermedades Infecciosas Y Microbiología Clínica. 2020;38(2):54–58.
  • Lee K, Yoon SS. Pseudomonas aeruginosa Biofilm, a Programmed Bacterial Life for Fitness. J Microbiol Biotechnol. 2017;27(6):1053–1064.
  • Filloux A. Protein Secretion Systems in Pseudomonas aeruginosa: an Essay on Diversity, Evolution, and Function. Front Microbiol.2011;2:155.
  • Pena RT, Blasco L, Ambroa A, et al. Relationship Between Quorum Sensing and Secretion Systems. Front Microbiol.2019;10:1100.
  • Galle M, Carpentier I, Beyaert R. Structure and function of the Type III secretion system of Pseudomonas aeruginosa. Current Protein and Peptide Science. 2012;13(8):831–842.
  • Elsen S, Huber P, Bouillot S, et al. A type III secretion negative clinical strain of Pseudomonas aeruginosa employs a two-partner secreted exolysin to induce hemorrhagic pneumonia. Cell Host Microbe. 2014;15(2):164–176.
  • Sana TG, Berni B, Bleves S. The T6SSs of Pseudomonas aeruginosa Strain PAO1 and Their Effectors: beyond Bacterial-Cell Targeting. Front Cell Infect Microbiol. 2016;6:61.
  • Lau GW, Hassett DJ, Ran H, et al. The role of pyocyanin in Pseudomonas aeruginosa infection. Trends Mol Med. 2004;10(12):599–606.
  • Abdel-Mawgoud AM, Hausmann R, Lépine F, et al. Rhamnolipids: detection, characterization, biosynthesis, genetic regulation and bioengineering of production. In: Soberón-Chávez G, editor. Biosurfactants: from genes to applications. Berlin, Heidelberg: Springer; 2011. p. 13–55.
  • Soberon-Chavez G, Gonzalez-Valdez A, Soto-Aceves MP, et al. Rhamnolipids produced by Pseudomonas: from molecular genetics to the market. Microb Biotechnol. 2021;14(1):136–146.
  • Fuqua C, Parsek MR, Greenberg EP. Regulation of gene expression by cell-to-cell communication: acyl-homoserine lactone quorum sensing. Annu Rev Genet. 2001;35(1):439–468.
  • Williams P, Winzer K, Chan WC, et al. Look who’s talking: communication and quorum sensing in the bacterial world. Philos Trans R Soc Lond B Biol Sci. 2007;362(1483):1119–1134.
  • Ahator SD, Zhang L. Small Is Mighty—Chemical Communication Systems in Pseudomonas aeruginosa. Annu Rev Microbiol. 2019;73(1):559–578.
  • Diggle SP, Whiteley M. Microbe Profile: Pseudomonas aeruginosa: opportunistic pathogen and lab rat. Microbiology. 2020;166(1):30–33.
  • Juhas M, Eberl L, Tummler B. Quorum sensing: the power of cooperation in the world of Pseudomonas. Environ Microbiol. 2005;7(4):459–471.
  • Déziel E, Lépine F, Milot S, et al. Analysis of Pseudomonas aeruginosa 4-hydroxy-2-alkylquinolines (HAQs) reveals a role for 4-hydroxy-2-heptylquinoline in cell-to-cell communication. Proc Natl Acad Sci USA. 2004; 101:1339–1344.
  • Pesci EC, Milbank JBJ, Pearson JP, Pesci EC, Milbank JBJ, Pearson JP, McKnight S, Kende AS, Greenberg EP, et al. Quinolone signaling in the cell-to-cell communication system of Pseudomonas aeruginosa. Proc Natl Acad Sci USA. 1999;96(20):11229–11234.
  • Gallagher LA, McKnight SL, Kuznetsova MS, et al. Functions required for extracellular quinolone signaling by Pseudomonas aeruginosa. J Bacteriol. 2002;184(23):6472–6480.
  • Xiao G, Déziel E, He J, et al. MvfR, a key Pseudomonas aeruginosa pathogenicity LTTR-class regulatory protein, has dual ligands. Mol Microbiol. 2006;62(6):1689–1699.
  • Schertzer JW, Brown SA, Whiteley M. Oxygen levels rapidly modulate Pseudomonas aeruginosa social behaviours via substrate limitation of PqsH. Mol Microbiol. 2010;77(6):1527–1538.
  • Wade DS, Calfee MW, Rocha ER, Wade DS, Calfee MW, Rocha ER, Ling EA, Engstrom E, Coleman JP, et al. Regulation of Pseudomonas quinolone signal synthesis in Pseudomonas aeruginosa. J Bacteriol. 2005;187(13):4372–4380.
  • Bjarnsholt T, Givskov M. The role of quorum sensing in the pathogenicity of the cunning aggressor Pseudomonas aeruginosa. Anal Bioanal Chem. 2007;387(2):409–414.
  • Rumbaugh KP, Griswold JA, Hamood AN. The role of quorum sensing in the in vivo virulence of Pseudomonas aeruginosa. Microbes Infect. 2000;2(14):1721–1731.
  • Smith RS. P. aeruginosa quorum-sensing systems and virulence. Curr Opin Microbiol. 2003;6(1):56–60.
  • Hentzer M, Wu H, Andersen JB, et al. Attenuation of Pseudomonas aeruginosa virulence by quorum sensing inhibitors. EMBO J. 2003;22(15):3803–3815.
  • Wagner VE, Bushnell D, Passador L, et al. Microarray Analysis of Pseudomonas aeruginosa Quorum-Sensing Regulons: effects of Growth Phase and Environment. J Bacteriol. 2003;185(7):2080–2095.
  • Whiteley M, Lee KM, Greenberg EP. Identification of genes controlled by quorum sensing in Pseudomonas aeruginosa. Proc Natl Acad Sci USA. 1999;96(24):13904–13909.
  • Jimenez PN, Koch G, Thompson JA, et al. The multiple signaling systems regulating virulence in Pseudomonas aeruginosa. Microbiol Mol Biol Rev. 2012;76(1):46–65.
  • Gambello MJ, Iglewski B. Cloning and characterization of the Pseudomonas aeruginosa lasR gene, a transcriptional activator of elastase expression. J Bacteriol. 1991;173(9):3000–3009.
  • Brint JM, Ohman DE. Synthesis of multiple exoproducts in Pseudomonas aeruginosa is under the control of RhlR-RhlI, another set of regulators in strain PAO1 with homology to the autoinducer-responsive LuxR-LuxI family. J Bacteriol. 1995;177(24):7155–7163.
  • Ochsner UA, Reiser J. Autoinducer-mediated regulation of rhamnolipid biosurfactant synthesis in Pseudomonas aeruginosa. Proc Natl Acad Sci USA. 1995;92(14):6424–6428.
  • Davies DG, Davies DG, Parsek MR, Pearson JP, Iglewski BH, Costerton JW, Greenberg EP. The involvement of cell-to-cell signals in the development of a bacterial biofilm. Science. 1998;280(5361):295–298.
  • Lesic B, Starkey M, He J, et al. Quorum sensing differentially regulates Pseudomonas aeruginosa type VI secretion locus I and homologous loci II and III, which are required for pathogenesis. Microbiology. 2009;155(9):2845–2855.
  • Sana TG, Hachani A, Bucior I, et al. The second type VI secretion system of Pseudomonas aeruginosa strain PAO1 is regulated by quorum sensing and Fur and modulates internalization in epithelial cells. J Biol Chem. 2012;287(32):27095–27105.
  • Cornelis P, Dingemans J. Pseudomonas aeruginosa adapts its iron uptake strategies in function of the type of infections. Front Cell Infect Microbiol. 2013;3:75.
  • Otero‐Asman JR, García‐García AI, Civantos C, et al. Pseudomonas aeruginosa possesses three distinct systems for sensing and using the host molecule haem. Environ Microbiol. 2019;21(12):4629–4647.
  • Herlihey FA, Clarke AJ. Controlling Autolysis During Flagella Insertion in Gram-Negative Bacteria. Adv Exp Med Biol. 2017;925:41–56.
  • Burrows LL. Pseudomonas aeruginosa Twitching Motility: type IV Pili in Action. Annu Rev Microbiol. 2012;66(1):493–520.
  • Giraud C, De Bentzmann S. Inside the complex regulation of Pseudomonas aeruginosa chaperone usher systems. Environ Microbiol. 2012;14(8):1805–1816.
  • Imberty A, Wimmerova M, Mitchell EP, et al. Structures of the lectins from Pseudomonas aeruginosa: insights into the molecular basis for host glycan recognition. Microbes Infect. 2004;6(2):221–228.
  • Huszczynski SM, Lam JS, Khursigara CM. The Role of Pseudomonas aeruginosa Lipopolysaccharide in Bacterial Pathogenesis and Physiology. Pathogens. 2020;9(1):6.
  • Tata PR, Rajagopal J. Plasticity in the lung: making and breaking cell identity. Development. 2017;144(5):755–766.
  • Travaglini KJ, Nabhan AN, Penland L, et al. A molecular cell atlas of the human lung from single-cell RNA sequencing. Nature. 2020;587(7835):619–625.
  • Puttur F, Denney L, Gregory LG, et al. Pulmonary environmental cues drive group 2 innate lymphoid cell dynamics in mice and humans. Sci Immunol. 2019;4(36):eaav7638.
  • Button B, Cai L-H, Ehre C, et al. A periciliary brush promotes the lung health by separating the mucus layer from airway epithelia. Science. 2012;337(6097):937–941.
  • Sheehan JK, Kesimer M, Pickles R. Innate immunity and mucus structure and function. Novartis Found Symp. 2006; 279:155–66.
  • Ehre C, Worthington EN, Liesman RM, et al. Overexpressing mouse model demonstrates the protective role of Muc5ac in the lungs. Proc Natl Acad Sci U S A. 2012;109(41):16528–16533.
  • Roy MG, Livraghi-Butrico A, Fletcher AA, et al. Muc5b is required for airway defence. Nature. 2014;505(7483):412–416.
  • Bonser LR, Zlock L, Finkbeiner W, et al. Epithelial tethering of MUC5AC-rich mucus impairs mucociliary transport in asthma. J Clin Invest. 2016;126(6):2367–2371.
  • Rose MC, Voynow JA. Respiratory tract mucin genes and mucin glycoproteins in health and disease. Physiol Rev. 2006;86(1):245–278.
  • Tilley AE, Walters MS, Shaykhiev R, et al. Cilia dysfunction in lung disease. Annu Rev Physiol. 2015;77(1):379–406.
  • Choi W, Choe S, Lau GW. Inactivation of FOXA2 by Respiratory Bacterial Pathogens and Dysregulation of Pulmonary Mucus Homeostasis. Front Immunol. 2020;11:515.
  • Malhotra S, Hayes D, Jr., Wozniak DJ. Cystic Fibrosis and Pseudomonas aeruginosa: the Host-Microbe Interface. Clin Microbiol Rev. 2019;32(3).
  • Burns JL, Gibson RL, McNamara S, et al. Longitudinal Assessment of Pseudomonas aeruginosa in Young Children with Cystic Fibrosis. J Infect Dis. 2001;183(3):444–452.
  • Quaderi SA, Hurst JR. The unmet global burden of COPD. Global Health, Epidemiology and Genomics. 2018;3:e4.
  • Halbert RJ, Natoli JL, Gano A, et al. Global burden of COPD: systematic review and meta-analysis. Eur Respir J. 2006;28(3):523–532.
  • Eisner MD, Anthonisen N, Coultas D, et al. An official American Thoracic Society public policy statement: novel risk factors and the global burden of chronic obstructive pulmonary disease. Am J Respir Crit Care Med. 2010;182(5):693–718.
  • Thompson WH, St-Hilaire S. Prevalence of chronic obstructive pulmonary disease and tobacco use in veterans at Boise Veterans Affairs Medical Center. Respir Care. 2010;55(5):555–560.
  • Sood A, Petersen H, Blanchette CM, et al. Wood smoke exposure and gene promoter methylation are associated with increased risk for COPD in smokers. Am J Respir Crit Care Med. 2010;182(9):1098–1104.
  • Brulotte CA, Lang ES. Acute exacerbations of chronic obstructive pulmonary disease in the emergency department. Emergency Medicine Clinics of North America. 2012;30(2):223–247. vii.
  • Anzueto A, Miravitlles M. Chronic Obstructive Pulmonary Disease Exacerbations: a Need for Action. Am J Med. 2018;131(9):15–22.
  • Rodrigo-Troyano A, Melo V, Marcos PJ, et al. Pseudomonas aeruginosa in Chronic Obstructive Pulmonary Disease Patients with Frequent Hospitalized Exacerbations: a Prospective Multicentre Study. Respiration. 2018;96(5):417–424.
  • Doring G, Parameswaran IG, Murphy TF. Differential adaptation of microbial pathogens to airways of patients with cystic fibrosis and chronic obstructive pulmonary disease. FEMS Microbiol Rev. 2011;35(1):124–146.
  • Jensen PØ, Kolpen M, Kragh KN, et al. Microenvironmental characteristics and physiology of biofilms in chronic infections of CF patients are strongly affected by the host immune response. APMIS. 2017;125(4):276–288.
  • Martin DW, Schurr MJ, Mudd MH, et al. Mechanism of conversion to mucoidy in Pseudomonas aeruginosa infecting cystic fibrosis patients. Proc Natl Acad Sci U S A. 1993;90(18):8377–8381.
  • Starkey M, Hickman JH, Ma L, et al. Pseudomonas aeruginosa rugose small-colony variants have adaptations that likely promote persistence in the cystic fibrosis lung. J Bacteriol. 2009;191(11):3492–3503.
  • Li Z, Kosorok MR, Farrell PM, et al. Longitudinal Development of Mucoid Pseudomonas aeruginosa Infection and Lung Disease Progression in Children With Cystic Fibrosis. JAMA. 2005;293(5):581–588..
  • Hodges NA, Gordon CA. Protection of Pseudomonas aeruginosa against ciprofloxacin and beta-lactams by homologous alginate. Antimicrob Agents Chemother. 1991;35(11):2450–2452.
  • Hengzhuang W, Wu H, Ciofu O, et al. Pharmacokinetics/pharmacodynamics of colistin and imipenem on mucoid and nonmucoid Pseudomonas aeruginosa biofilms. Antimicrob Agents Chemother. 2011;55(9):4469–4474.
  • Leid JG, Willson CJ, Shirtliff ME, et al. The Exopolysaccharide Alginate Protects Pseudomonas aeruginosa Biofilm Bacteria from IFN-γ-Mediated Macrophage Killing. J Immunol. 2005;175(11):7512–7518.
  • Malhotra S, Limoli DH, English AE, Parsek MR, Wozniak DJ. Mixed Communities of Mucoid and Nonmucoid Pseudomonas aeruginosa Exhibit Enhanced Resistance to Host Antimicrobials. mBio. 2018;9(2):e00275–18.
  • Malhotra S, Hayes D Jr., Wozniak DJ. Mucoid Pseudomonas aeruginosa and regional inflammation in the cystic fibrosis lung. J Cyst Fibros. 2019;18(6):796–803.
  • DeVries CA, Ohman DE. Mucoid-to-nonmucoid conversion in alginate-producing Pseudomonas aeruginosa often results from spontaneous mutations in algT, encoding a putative alternate sigma factor, and shows evidence for autoregulation. J Bacteriol. 1994;176(21):6677–6687.
  • Price CE, Brown DG, Limoli DH, et al. Exogenous Alginate Protects Staphylococcus aureus from Killing by Pseudomonas aeruginosa. J Bacteriol. 2020;202(8):e00559–19.
  • Chattoraj SS, Murthy R, Ganesan S, et al. Pseudomonas aeruginosa alginate promotes Burkholderia cenocepacia persistence in cystic fibrosis transmembrane conductance regulator knockout mice. Infect Immun. 2010;78(3):984–993.
  • Jones AM. Which pathogens should we worry about? Paediatr Respir Rev. 2019;31:15–17.
  • Evans TJ. Small colony variants of Pseudomonas aeruginosa in chronic bacterial infection of the lung in cystic fibrosis. Future Microbiology. 2015;10(2):231–239.
  • Von götz F, Häussler S, Jordan D, et al. Expression analysis of a highly adherent and cytotoxic small colony variant of Pseudomonas aeruginosa isolated from a lung of a patient with cystic fibrosis. J Bacteriol. 2004;186(12):3837–3847.
  • Rohde M. Small-colony variants of Pseudomonas aeruginosa in cystic fibrosis. Clin Infect Dis. 1999;29(3):621–625.
  • Pestrak MJ, Chaney SB, Eggleston HC, et al. Pseudomonas aeruginosa rugose small-colony variants evade host clearance, are hyper-inflammatory, and persist in multiple host environments. PLoS Pathog. 2018;14(2):e1006842.
  • Gifford AH, Willger SD, Dolben EL, et al. Use of a Multiplex Transcript Method for Analysis of Pseudomonas aeruginosa Gene Expression Profiles in the Cystic Fibrosis Lung. Infect Immun. 2016;84(10):2995–3006..
  • Yang L, Hengzhuang W, Wu H, et al. Polysaccharides serve as scaffold of biofilms formed by mucoid Pseudomonas aeruginosa. FEMS Immunol Med Microbiol. 2012;65(2):366–376.
  • Fernandez-Barat L, Torres A. Biofilms in ventilator-associated pneumonia. Future Microbiology. 2016;11(12):1599–1610.
  • Inglis TJ, Millar MR, Jones JG, et al. Tracheal tube biofilm as a source of bacterial colonization of the lung. J Clin Microbiol. 1989;27(9):2014–2018.
  • Fricks-Lima J, Hendrickson CM, Allgaier M, et al. Differences in biofilm formation and antimicrobial resistance of Pseudomonas aeruginosa isolated from airways of mechanically ventilated patients and cystic fibrosis patients. Int J Antimicrob Agents. 2011;37(4):309–315.
  • Déziel E, Gopalan S, Tampakaki AP, et al. The contribution of MvfR to Pseudomonas aeruginosa pathogenesis and quorum sensing circuitry regulation: multiple quorum sensing-regulated genes are modulated without affecting lasRI, rhlRI or the production of N-acyl- l-homoserine lactones. Mol Microbiol. 2004;55(4):998–1014.
  • Lesprit P, Faurisson F, Join-Lambert O, et al. Role of the Quorum-sensing System in Experimental Pneumonia due to Pseudomonas aeruginosa in Rats. Am J Respir Crit Care Med. 2003;167(11):1478–1482.
  • Pearson JP, Feldman M, Iglewski BH, et al. Pseudomonas aeruginosa cell-to-cell signaling is required for virulence in a model of acute pulmonary infection. Infect Immun. 2000;68(7):4331–4334.
  • Rumbaugh KP, Griswold JA, Iglewski BH, et al. Contribution of Quorum Sensing to the Virulence of Pseudomonas aeruginosa in Burn Wound Infections. Infect Immun. 1999;67(11):5854–5862.
  • Smith RS, Harris SG, Phipps R, et al. The Pseudomonas aeruginosa quorum-sensing molecule N-(3-oxododecanoyl)homoserine lactone contributes to virulence and induces inflammation in vivo. J Bacteriol. 2002;184(4):1132–1139.
  • Wu H, Song Z, Givskov M, et al. Pseudomonas aeruginosa mutations in lasI and rhlI quorum sensing systems result in milder chronic lung infection. Microbiology. 2001;147(5):1105–1113.
  • Tang HB, DiMango E, Bryan R, et al. Contribution of specific Pseudomonas aeruginosa virulence factors to pathogenesis of pneumonia in a neonatal mouse model of infection. Infect Immun. 1996;64(1):37–43.
  • Collier DN, Anderson L, McKnight SL, et al. A bacterial cell to cell signal in the lungs of cystic fibrosis patients. FEMS Microbiol Lett. 2002;215(1):41–46.
  • Erickson DL, Endersby R, Kirkham A, et al. Pseudomonas aeruginosa quorum-sensing systems may control virulence factor expression in the lungs of patients with cystic fibrosis. Infect Immun. 2002;70(4):1783–1790.
  • D’Argenio DA, Wu M, Hoffman LR, et al. Growth phenotypes of Pseudomonas aeruginosa lasR mutants adapted to the airways of cystic fibrosis patients. Mol Microbiol. 2007;64(2):512–533.
  • Hoffman LR, Kulasekara HD, Emerson J, et al. Pseudomonas aeruginosa lasR mutants are associated with cystic fibrosis lung disease progression. J Cystic Fibrosis. 2009;8(1):66–70.
  • Smith EE, Buckley DG, Wu Z, et al. Genetic adaptation by Pseudomonas aeruginosa to the airways of cystic fibrosis patients. Proc Natl Acad Sci U S A. 2006; 103(22):8487–8492.
  • Ciofu O, Mandsberg LF, Bjarnsholt T, et al. Genetic adaptation of Pseudomonas aeruginosa during chronic lung infection of patients with cystic fibrosis: strong and weak mutators with heterogeneous genetic backgrounds emerge in mucA and/or lasR mutants. Microbiology. 2010;156(4):1108–1119.
  • Winstanley C, O’Brien S, Brockhurst MA. Pseudomonas aeruginosa Evolutionary Adaptation and Diversification in Cystic Fibrosis Chronic Lung Infections. Trends Microbiol. 2016;24(5):327–337.
  • Feltner JB, Wolter DJ, Pope CE, et al. LasR Variant Cystic Fibrosis Isolates Reveal an Adaptable Quorum-Sensing Hierarchy in Pseudomonas aeruginosa. mBio. 2016;7(5):e01513–16.
  • Turkina MV, Vikstrom E. Bacteria-Host Crosstalk: sensing of the Quorum in the Context of Pseudomonas aeruginosa Infections. J Innate Immun. 2019;11(3):263–279.
  • Kariminik A, Baseri-Salehi M, Kheirkhah B. Pseudomonas aeruginosa quorum sensing modulates immune responses: an updated review article. Immunol Lett. 2017;190:1–6.
  • Wagner C, Zimmermann S, Brenner-Weiss G, et al. The quorum-sensing molecule N-3-oxododecanoyl homoserine lactone (3OC12-HSL) enhances the host defence by activating human polymorphonuclear neutrophils (PMN). Anal Bioanal Chem. 2007;387(2):481–487.
  • Holm A, Magnusson K-E, Vikstrom E. Pseudomonas aeruginosa N-3-oxo-dodecanoyl-homoserine Lactone Elicits Changes in Cell Volume, Morphology, and AQP9 Characteristics in Macrophages. Front Cell Infect Microbiol. 2016;6:32.
  • Tateda K, Ishii Y, Horikawa M, et al. The Pseudomonas aeruginosa autoinducer N-3-oxododecanoyl homoserine lactone accelerates apoptosis in macrophages and neutrophils. Infect Immun. 2003;71(10):5785–5793.
  • Josephson H, Ntzouni M, Skoglund C, et al. Pseudomonas aeruginosa N-3-Oxo-Dodecanoyl-Homoserine Lactone Impacts Mitochondrial Networks Morphology, Energetics, and Proteome in Host Cells. Front Microbiol. 2020;11:1069.
  • Ritchie AJ, Yam AOW, Tanabe KM, et al. Modification of in vivo and in vitro T- and B-cell-mediated immune responses by the Pseudomonas aeruginosa quorum-sensing molecule N-(3-oxododecanoyl)-L-homoserine lactone. Infect Immun. 2003;71(8):4421–4431.
  • Ritchie AJ, Jansson A, Stallberg J, et al. The Pseudomonas aeruginosa quorum-sensing molecule N-3-(oxododecanoyl)-L-homoserine lactone inhibits T-cell differentiation and cytokine production by a mechanism involving an early step in T-cell activation. Infect Immun. 2005;73(3):1648–1655.
  • Singh PK, Schaefer AL, Parsek MR, Singh PK, Schaefer AL, Parsek MR, Moninger TO, Welsh MJ, Greenberg EP. Quorum-sensing signals indicate that cystic fibrosis lungs are infected with bacterial biofilms. Nature. 2000;407(6805):762–764.
  • Chambers CE, Visser MB, Schwab U, et al. Identification of N -acylhomoserine lactones in mucopurulent respiratory secretions from cystic fibrosis patients. FEMS Microbiol Lett. 2005;244(2):297–304.
  • Zhang S, McCormack FX, Levesque RC, et al. The flagellum of Pseudomonas aeruginosa is required for resistance to clearance by surfactant protein A. PLoS One. 2007;2(6):e564.
  • Kuang Z, Hao Y, Hwang S, et al. The Pseudomonas aeruginosa flagellum confers resistance to pulmonary surfactant protein-A by impacting the production of exoproteases through quorum-sensing. Mol Microbiol. 2011;79(5):1220–1235.
  • Balloy V, Verma A, Kuravi S, et al. The Role of Flagellin versus Motility in Acute Lung Disease Caused by Pseudomonas aeruginosa. J Infect Dis. 2007;196(2):289–296.
  • Lillehoj EP, Kim BT, Kim KC. Identification of Pseudomonas aeruginosa flagellin as an adhesin for Muc1 mucin. Am J Physiol Lung Cell Mol Physiol. 2002;282(4):L751–6.
  • Comolli JC, Hauser AR, Waite L, et al. Pseudomonas aeruginosa gene products PilT and PilU are required for cytotoxicity in vitro and virulence in a mouse model of acute pneumonia. Infect Immun. 1999;67(7):3625–3630.
  • Tan RM, Kuang Z, Hao Y, et al. Type IV pilus glycosylation mediates resistance of Pseudomonas aeruginosa to opsonic activities of the pulmonary surfactant protein A. Infect Immun. 2015;83(4):1339–1346..
  • Kus JV, Tullis E, Cvitkovitch DG, et al. Significant differences in type IV pilin allele distribution among Pseudomonas aeruginosa isolates from cystic fibrosis (CF) versus non-CF patients. Microbiology (Reading). 2004;150(5):1315–1326.
  • O’Toole GA, Kolter R. Flagellar and twitching motility are necessary for Pseudomonas aeruginosa biofilm development. Mol Microbiol. 1998;30(2):295–304.
  • Bucior I, Pielage JF, Engel JN. Pseudomonas aeruginosa pili and flagella mediate distinct binding and signaling events at the apical and basolateral surface of airway epithelium. PLoS Pathog. 2012;8(4):e1002616.
  • Lorenz A, Preusse M, Bruchmann S, et al. Importance of flagella in acute and chronic Pseudomonas aeruginosa infections. Environ Microbiol. 2019;21(3):883–897.
  • Lovewell RR, Patankar YR, Berwin B. Mechanisms of phagocytosis and host clearance of Pseudomonas aeruginosa. Am J Physiol Lung Cell Mol Physiol. 2014;306(7):L591–603.
  • Tart AH, Blanks MJ, Wozniak DJ. The AlgT-dependent transcriptional regulator AmrZ (AlgZ) inhibits flagellum biosynthesis in mucoid, nonmotile Pseudomonas aeruginosa cystic fibrosis isolates. J Bacteriol. 2006;188(18):6483–6489.
  • Cohen TS, Prince AS. Activation of inflammasome signaling mediates pathology of acute P.aeruginosa pneumonia. Journal of Clinical Investigation. 2013;123(4):1630–1637.
  • Chemani C, Imberty A, De Bentzmann S, et al. Role of LecA and LecB lectins in Pseudomonas aeruginosa-induced lung injury and effect of carbohydrate ligands. Infect Immun. 2009;77(5):2065–2075.
  • Zheng S, Eierhoff T, Aigal S, et al. The Pseudomonas aeruginosa lectin LecA triggers host cell signalling by glycosphingolipid-dependent phosphorylation of the adaptor protein CrkII. Biochim Biophys Acta Mol Cell Res. 2017;1864(7):1236–1245.
  • Diggle SP, Stacey RE, Dodd C, et al. The galactophilic lectin, LecA, contributes to biofilm development in Pseudomonas aeruginosa. Environ Microbiol. 2006;8(6):1095–1104.
  • Tielker D, Hacker S, Loris R, et al. Pseudomonas aeruginosa lectin LecB is located in the outer membrane and is involved in biofilm formation. Microbiology (Reading). 2005;151(5):1313–1323.
  • Passos Da Silva D, Matwichuk ML, Townsend DO, et al. The Pseudomonas aeruginosa lectin LecB binds to the exopolysaccharide Psl and stabilizes the biofilm matrix. Nat Commun. 2019;10(1):2183.
  • Thuenauer R, Landi A, Trefzer A, et al. The Pseudomonas aeruginosa Lectin LecB Causes Integrin Internalization and Inhibits Epithelial Wound Healing. mBio. 2020;11(2):e03260–19.
  • Cott C, Thuenauer R, Landi A, et al. Pseudomonas aeruginosa lectin LecB inhibits tissue repair processes by triggering β-catenin degradation. Biochim Biophys Acta. 2016;1863(6):1106–1118.
  • Bardoel BW, Van Der Ent S, Pel MJC, et al. Pseudomonas evades immune recognition of flagellin in both mammals and plants. PLoS Pathog. 2011;7(8):e1002206.
  • Kim S-J, Park R-Y, Kang S-M, et al. Pseudomonas aeruginosa alkaline protease can facilitate siderophore-mediated iron-uptake via the proteolytic cleavage of transferrins. Biol Pharm Bull. 2006;29(11):2295–2300.
  • Kuang Z, Hao Y, Walling BE, Kuang Z, Hao Y, Walling BE, Jeffries JL, Ohman DE, Lau GW. Pseudomonas aeruginosa elastase provides an escape from phagocytosis by degrading the pulmonary surfactant protein-A. PLoS One. 2011;6(11):e27091.
  • Chapon‐Hervé V, Akrim M, Latifi A, et al. Regulation of the xcp secretion pathway by multiple quorum-sensing modulons in Pseudomonas aeruginosa. Mol Microbiol. 1997;24(6):1169–1178.
  • Shaver CM, Hauser AR. Relative contributions of Pseudomonas aeruginosa ExoU, ExoS, and ExoT to virulence in the lung. Infect Immun. 2004;72(12):6969–6977.
  • Vance RE, Rietsch A, Mekalanos JJ. Role of the type III secreted exoenzymes S, T, and Y in systemic spread of Pseudomonas aeruginosa PAO1 in vivo. Infect Immun. 2005;73(3):1706–1713.
  • Diaz MH, Hauser AR. Pseudomonas aeruginosa cytotoxin ExoU is injected into phagocytic cells during acute pneumonia. Infect Immun. 2010;78(4):1447–1456.
  • Howell HA, Logan LK, Hauser AR. Type III secretion of ExoU is critical during early Pseudomonas aeruginosa pneumonia. mBio. 2013;4(2):e00032–13.
  • Janjua HA, Segata N, Bernabo P, et al. Clinical populations of Pseudomonas aeruginosa isolated from acute infections show a wide virulence range partially correlated with population structure and virulence gene expression. Microbiology (Reading). 2012;158(8):2089–2098.
  • Tingpej P, Smith L, Rose B, et al. Phenotypic characterization of clonal and nonclonal Pseudomonas aeruginosa strains isolated from lungs of adults with cystic fibrosis. J Clin Microbiol. 2007;45(6):1697–1704.
  • Munder A, Rothschuh J, Schirmer B, et al. The Pseudomonas aeruginosa ExoY phenotype of high-copy-number recombinants is not detectable in natural isolates. Open Biol. 2018;8(1):170250.
  • Stevens TC, Ochoa CD, Morrow KA, et al. The Pseudomonas aeruginosa exoenzyme Y impairs endothelial cell proliferation and vascular repair following lung injury. Am J Physiol Lung Cell Mol Physiol. 2014;306(10):L915–24.
  • Morrow KA, Ochoa CD, Balczon R, et al. Pseudomonas aeruginosa exoenzymes U and Y induce a transmissible endothelial proteinopathy. Am J Physiol Lung Cell Mol Physiol. 2016;310(4):L337–53.
  • Galle M, Jin S, Bogaert P, et al. The Pseudomonas aeruginosa Type III Secretion System Has an Exotoxin S/T/Y Independent Pathogenic Role during Acute Lung Infection. PLoS One. 2012;7(7):e41547.
  • Bertrand Q, Job V, Maillard AP, et al. Exolysin (ExlA) from Pseudomonas aeruginosa Punctures Holes into Target Membranes Using a Molten Globule Domain. J Mol Biol. 2020;432(16):4466–4480.
  • Bouillot S, Munro P, Gallet B, et al. Pseudomonas aeruginosa Exolysin promotes bacterial growth in lungs, alveolar damage and bacterial dissemination. Sci Rep. 2017;7(1):2120.
  • Russell AB, LeRoux M, Hathazi K, et al. Diverse type VI secretion phospholipases are functionally plastic antibacterial effectors. Nature. 2013;496(7446):508–512..
  • Jiang F, Waterfield NR, Yang J, et al. A Pseudomonas aeruginosa type VI secretion phospholipase D effector targets both prokaryotic and eukaryotic cells. Cell Host Microbe. 2014;15(5):600–610.
  • Wilderman PJ, Vasil AI, Johnson Z, et al. Genetic and biochemical analyses of a eukaryotic-like phospholipase D of Pseudomonas aeruginosa suggest horizontal acquisition and a role for persistence in a chronic pulmonary infection model. Mol Microbiol. 2001;39(2):291–303.
  • Fujita K, Akino T, Yoshioka H. Characteristics of heat-stable extracellular hemolysin from Pseudomonas aeruginosa. Infect Immun. 1988;56(5):1385–1387.
  • Johnson MK, Boese-Marrazzo D. Production and properties of heat-stable extracellular hemolysin from Pseudomonas aeruginosa. Infect Immun. 1980;29(3):1028–1033.
  • Kurioka S, Liu PV. Effect of the hemolysin of Pseudomonas aeruginosa on phosphatides and on phospholipase c activity. J Bacteriol. 1967;93(2):670–674.
  • Sierra G. Hemolytic effect of a glycolipid produced byPseudomonas aeruginosa. Antonie Van Leeuwenhoek. 1960;26(1):189–192.
  • Stutts MJ, Schwab JH, Chen MG, et al. Effects of Pseudomonas aeruginosa on bronchial epithelial ion transport. Am Rev Respir Dis. 1986;134(1):17–21.
  • Kownatzki R, Tummler B, Doring G. Rhamnolipid of Pseudomonas aeruginosa in sputum of cystic fibrosis patients. Lancet. 1987;329(8540):1026–1027.
  • Read RC, Roberts P, Munro N, et al. Effect of Pseudomonas aeruginosa rhamnolipids on mucociliary transport and ciliary beating. J Appl Physiol. 1992;72(6):2271–2277.
  • Kohler T, Guanella R, Carlet J, et al. Quorum sensing-dependent virulence during Pseudomonas aeruginosa colonisation and pneumonia in mechanically ventilated patients. Thorax. 2010;65(8):703–710.
  • Van Gennip M, Christensen LD, Alhede M, et al. Inactivation of the rhlA gene in Pseudomonas aeruginosa prevents rhamnolipid production, disabling the protection against polymorphonuclear leukocytes. APMIS. 2009;117(7):537–546..
  • Hingley S, Hastie A, Kueppers F, et al. Effect of ciliostatic factors from Pseudomonas aeruginosa on rabbit respiratory cilia. Infect Immun. 1986;51(1):254–262.
  • Kanthakumar K, Taylor GW, Cundell DR, et al. The effect of bacterial toxins on levels of intracellular adenosine nucleotides and human ciliary beat frequency. Pulmonary Pharmacology. 1996;9(4):223–230..
  • Fung DC, Somerville M, Richardson PS, et al. Mucus glycoconjugate complexes released from feline trachea by a bacterial toxin. Am J Respir Cell Mol Biol. 1995;12(3):296–306.
  • Somerville M, Taylor G, Watson D, et al. Release of Mucus Glycoconjugates by Pseudomonas aeruginosa Rhamnolipids into Feline Trachea In Vivo and Human Bronchus In Vitro. Am J Respir Cell Mol Biol. 1992;6(1):116–122..
  • Graham A, Steel DM, Wilson R, et al. Effects of purified Pseudomonas rhamnolipids on bioelectric properties of sheep tracheal epithelium. Exp Lung Res. 1993;19(1):77–89.
  • Wallace CJ, Medina SH, ElSayed MEH. Effect of rhamnolipids on permeability across Caco-2 cell monolayers. Pharm Res. 2014;31(4):887–894.
  • Zulianello L, Canard C, Köhler T, et al. Rhamnolipids are virulence factors that promote early infiltration of primary human airway epithelia by Pseudomonas aeruginosa. Infect Immun. 2006;74(6):3134–3147.
  • Halldorsson S, Gudjonsson T, Gottfredsson M, et al. Azithromycin Maintains Airway Epithelial Integrity during Pseudomonas aeruginosa Infection. Am J Respir Cell Mol Biol. 2010;42(1):62–68.
  • Aranda FJ, Espuny MJ, Marques A, et al. Thermodynamics of the Interaction of a Dirhamnolipid Biosurfactant Secreted by Pseudomonas aeruginosa with Phospholipid Membranes. Langmuir. 2007;23(5):2700–2705.
  • Ortiz A, Teruel JA, Espuny MJ, et al. Effects of dirhamnolipid on the structural properties of phosphatidylcholine membranes. Int J Pharm. 2006;325(1–2):99–107.
  • McClure CD, Schiller NL. Inhibition of macrophage phagocytosis by Pseudomonas aeruginosa rhamnolipids in vitro and in vivo. Curr Microbiol. 1996;33(2):109–117.
  • McClure CD, Schiller NL. Effects of Pseudomonas aeruginosa rhamnolipids on human monocyte-derived macrophages. J Leukoc Biol. 1992;51(2):97–102.
  • Jensen PØ, Bjarnsholt T, Phipps R, et al. Rapid necrotic killing of polymorphonuclear leukocytes is caused by quorum-sensing-controlled production of rhamnolipid by Pseudomonas aeruginosa. Microbiology. 2007;153(5):1329–1338.
  • Shryock TR, Silver SA, Banschbach MW, et al. Effect of Pseudomonas aeruginosa rhamnolipid on human neutrophil migration. Curr Microbiol. 1984;10(6):323–328.
  • Bergmann U, Scheffer J, Koller M, et al. Induction of inflammatory mediators (histamine and leukotrienes) from rat peritoneal mast cells and human granulocytes by Pseudomonas aeruginosa strains from burn patients. Infect Immun. 1989;57(7):2187–2195.
  • Konig B, Bergmann U, Konig W. Induction of inflammatory mediator release (serotonin and 12-hydroxyeicosatetraenoic acid) from human platelets by Pseudomonas aeruginosa glycolipid. Infect Immun. 1992;60(8):3150–3155.
  • Bédard M, McClure CD, Schiller NL, et al. Release of Interleukin-8, Interleukin-6, and Colony-stimulating Factors by Upper Airway Epithelial Cells: implications for Cystic Fibrosis. Am J Respir Cell Mol Biol. 1993;9(4):455–462.
  • Nickzad A, Déziel E. The involvement of rhamnolipids in microbial cell adhesion and biofilm development - an approach for control? Lett Appl Microbiol. 2014;58(5):447–453.
  • Boles BR, Thoendel M, Singh PK. Rhamnolipids mediate detachment of Pseudomonas aeruginosa from biofilms. Mol Microbiol. 2005;57(5):1210–1223.
  • Déziel E, Lépine F, Milot S, et al. rhlA is required for the production of a novel biosurfactant promoting swarming motility in Pseudomonas aeruginosa: 3-(3-hydroxyalkanoyloxy)alkanoic acids (HAAs), the precursors of rhamnolipids. Microbiology. 2003;149(8):2005–2013.
  • Neu TR. Significance of bacterial surface-active compounds in interaction of bacteria with interfaces. Microbiol Rev. 1996;60(1):151–166.
  • Pamp SJ, Tolker-Nielsen T. Multiple roles of biosurfactants in structural biofilm development by Pseudomonas aeruginosa. J Bacteriol. 2007;189(6):2531–2539.
  • Schooling SR, Charaf UK, Allison DG, et al. A role for rhamnolipid in biofilm dispersion. Biofilms. 2004;1(2):91–99.
  • Davey ME, Caiazza NC, O’Toole GA. Rhamnolipid surfactant production affects biofilm architecture in Pseudomonas aeruginosa PAO1. J Bacteriol. 2003;185(3):1027–1036.
  • Wilson R, Sykes DA, Watson D, et al. Measurement of Pseudomonas aeruginosa phenazine pigments in sputum and assessment of their contribution to sputum sol toxicity for respiratory epithelium. Infect Immun. 1988;56(9):2515–2517.
  • Hunter RC, Klepac-Ceraj V, Lorenzi MM, et al. Phenazine content in the cystic fibrosis respiratory tract negatively correlates with lung function and microbial complexity. Am J Respir Cell Mol Biol. 2012;47(6):738–745.
  • Forteza R, Lauredo IT, Burch R, et al. Extracellular metabolites of Pseudomonas aeruginosa produce bronchoconstriction by different mechanisms. Am J Respir Crit Care Med. 1994;149(3):687–693.
  • Lauredo IT, Sabater JR, Ahmed A, et al. Mechanism of pyocyanin- and 1-hydroxyphenazine-induced lung neutrophilia in sheep airways. J Appl Physiol. 1985;1998(85):2298–2304.
  • Munro NC, Barker A, Rutman A, et al. Effect of pyocyanin and 1-hydroxyphenazine on in vivo tracheal mucus velocity. J Appl Physiol. 1985;1989(67):316–323.
  • Dormehl I, Ras G, Taylor G, et al. Effect of Pseudomonas aeruginosa-derived pyocyanin and 1-hydroxyphenazine on pulmonary mucociliary clearance monitored scintigraphically in the baboon model. International Journal of Radiation Applications and Instrumentation. Part B. Nuclear Medicine and Biology. 1991;18(5):455–459.
  • Lau GW, Ran H, Kong F, et al. Pseudomonas aeruginosa pyocyanin is critical for lung infection in mice. Infect Immun. 2004;72(7):4275–4278.
  • Caldwell CC, Chen Y, Goetzmann HS, et al. Pseudomonas aeruginosa exotoxin pyocyanin causes cystic fibrosis airway pathogenesis. Am J Pathol. 2009;175(6):2473–2488.
  • Wan H, Kaestner KH, Ang S-L, et al. Foxa2 regulates alveolarization and goblet cell hyperplasia. Development. 2004;131(4):953–964.
  • Hao Y, Kuang Z, Walling BE, Hao Y, Kuang Z, Walling BE, Bhatia S, Sivaguru M, Chen Y, et al. Pseudomonas aeruginosa pyocyanin causes airway goblet cell hyperplasia and metaplasia and mucus hypersecretion by inactivating the transcriptional factor FoxA2. Cell Microbiol. 2012;14(3):401–415.
  • Rada B, Gardina P, Myers TG, et al. Reactive oxygen species mediate inflammatory cytokine release and EGFR-dependent mucin secretion in airway epithelial cells exposed to Pseudomonas pyocyanin. Mucosal Immunol. 2011;4(2):158–171.
  • Choi W, Yang AX, Waltenburg MA, et al. FOXA2 depletion leads to mucus hypersecretion in canine airways with respiratory diseases. Cell Microbiol. 2019;21(1):e12957.
  • Choi W, Choe S, Lin J, et al. Exendin-4 restores airway mucus homeostasis through the GLP1R-PKA-PPARγ-FOXA2-phosphatase signaling. Mucosal Immunol. 2020;13(4):637–651.
  • Hao Y, Kuang Z, Xu Y, Hao Y, Kuang Z, Xu Y, Walling BE, Lau GW. Pyocyanin-induced mucin production is associated with redox modification of FOXA2. Respir Res. 2013;14(1):82.
  • Damron FH, Oglesby-Sherrouse AG, Wilks A, et al. Dual-seq transcriptomics reveals the battle for iron during Pseudomonas aeruginosa acute murine pneumonia. Sci Rep. 2016;6(1):39172.
  • Hunt TA, Peng W-T, Loubens I, et al. The Pseudomonas aeruginosa alternative sigma factor PvdS controls exotoxin A expression and is expressed in lung infections associated with cystic fibrosis. Microbiology (Reading). 2002;148(10):3183–3193.
  • Banin E, Vasil ML, Greenberg EP. From The Cover: iron and Pseudomonas aeruginosa biofilm formation. Proc Natl Acad Sci U S A. 2005;102(31):11076–11081.
  • Beare PA, For RJ, Martin LW, et al. Siderophore-mediated cell signalling in Pseudomonas aeruginosa : divergent pathways regulate virulence factor production and siderophore receptor synthesis. Mol Microbiol. 2003;47(1):195–207.
  • Ochsner UA, Johnson Z, Lamont IL, et al. Exotoxin A production in Pseudomonas aeruginosa requires the iron-regulated pvdS gene encoding an alternative sigma factor. Mol Microbiol. 1996;21(5):1019–1028.
  • Minandri F, Imperi F, Frangipani E, et al. Role of Iron Uptake Systems in Pseudomonas aeruginosa Virulence and Airway Infection. Infect Immun. 2016;84(8):2324–2335..
  • Oeemig JS, Ollila OHS, Iwai H. NMR structure of the C-terminal domain of TonB protein from Pseudomonas aeruginosa. PeerJ. 2018;6:e5412.
  • Kang D, Revtovich AV, Chen Q, et al. Pyoverdine-Dependent Virulence of Pseudomonas aeruginosa Isolates From Cystic Fibrosis Patients. Front Microbiol. 2019;10:2048.
  • Andersen SB, Marvig RL, Molin S, et al. Long-term social dynamics drive loss of function in pathogenic bacteria. Proc Natl Acad Sci U S A. 2015;112(34):10756–10761.
  • Nguyen AT, O’Neill MJ, Watts AM, et al. Adaptation of iron homeostasis pathways by a Pseudomonas aeruginosa pyoverdine mutant in the cystic fibrosis lung. J Bacteriol. 2014;196(12):2265–2276.
  • Gabrielaite M, Johansen HK, Molin S, et al. Gene Loss and Acquisition in Lineages of Pseudomonas aeruginosa Evolving in Cystic Fibrosis Patient Airways. mBio. 2020;11(5):e02359–20.
  • Colque CA, Albarracin Orio AG, Feliziani S, et al. Hypermutator Pseudomonas aeruginosa Exploits Multiple Genetic Pathways To Develop Multidrug Resistance during Long-Term Infections in the Airways of Cystic Fibrosis Patients. Antimicrob Agents Chemother. 2020;64(5):e02142–19.
  • Nolan LM, Turnbull L, Katrib M, et al. Pseudomonas aeruginosa is capable of natural transformation in biofilms. Microbiology (Reading). 2020;166(10):995–1003.
  • San Millan A, Toll-Riera M, Qi Q, et al. Integrative analysis of fitness and metabolic effects of plasmids in Pseudomonas aeruginosa PAO1. ISME J. 2018;12(12):3014–3024.
  • Del Barrio-Tofino E, Lopez-Causape C, Oliver A. Pseudomonas aeruginosa epidemic high-risk clones and their association with horizontally-acquired β-lactamases: 2020 update. Int J Antimicrob Agents. 2020;56(6):106196. update.
  • Freschi L, Vincent AT, Jeukens J, et al. The Pseudomonas aeruginosa Pan-Genome Provides New Insights on Its Population Structure, Horizontal Gene Transfer, and Pathogenicity. Genome Biol Evol. 2019;11(1):109–120.
  • Martínez‐Solano L, Macia MD, Fajardo A, et al. Chronic Pseudomonas aeruginosa Infection in Chronic Obstructive Pulmonary Disease. Clin Infect Dis. 2008;47(12):1526–1533.
  • Ngo CC, Massa HM, Thornton RB, et al. Predominant Bacteria Detected from the Middle Ear Fluid of Children Experiencing Otitis Media: a Systematic Review. PLoS One. 2016;11(3):e0150949.
  • Nogues JC, Pérez‐Losada M, Preciado D. Review of otitis media microbiome studies: what do they tell us? Laryngoscope Investigative Otolaryngology. 2020;5(5):936–940.
  • Thornton RB, Hakansson A, Hood DW, et al. Panel 7 – pathogenesis of otitis media – a review of the literature between 2015 and 2019. Int J Pediatr Otorhinolaryngol. 2020;130(Suppl 1):109838.
  • Verhoeff M, Van Der Veen EL, Rovers MM, et al. Chronic suppurative otitis media: a review. Int J Pediatr Otorhinolaryngol. 2006;70(1):1–12.
  • Mittal R, Lisi CV, Gerring R, et al. Current concepts in the pathogenesis and treatment of chronic suppurative otitis media. J Med Microbiol. 2015;64(10):1103–1116..
  • Smith JA, Danner CJ. Complications of Chronic Otitis Media and Cholesteatoma. Otolaryngol Clin North Am. 2006;39(6):1237–1255.
  • Roland PS, Stroman DW. Microbiology of acute otitis externa. The Laryngoscope. 2002;112(7):1166–1177.
  • Schaefer P, Baugh RF. Acute otitis externa: an update. Am Fam Physician. 2012;86(11):1055–1061.
  • Carfrae MJ, Kesser BW. Malignant otitis externa. Otolaryngol Clin North Am. 2008;41(3):viii–ix.
  • Long DA, Koyfman A, Long B. An emergency medicine-focused review of malignant otitis externa. Am J Emerg Med. 2020;38(8):1671–1678.
  • Hafidh MA, Keogh I, Walsh RM, et al. Otogenic intracranial complications. a 7-year retrospective review. Am J Otolaryngol. 2006;27:390–395.
  • Malagutti N, Rotondo JC, Cerritelli L, et al. High Human Papillomavirus DNA loads in Inflammatory Middle Ear Diseases. Pathogens. 2020;9(3):224.
  • Avidano MA, Cotter CS, Stringer SP, et al. Analysis of protease activity in human otitis media. Otolaryngol Head Neck Surg. 1998;119(4):346–351.
  • Jin CS, Hamaguchi Y, Sakakura Y. ELISA to Determine Immunoreactive Pseudomonas aeruginosa Elastase in Chronic Suppurative Otitis Media. Int Arch Allergy Appl Immunol. 1991;96(3):193–198.
  • Cotter CS, Avidano MA, Stringer SP, et al. Inhibition of proteases in Pseudomonas otitis media in chinchillas. Otolaryngol Head Neck Surg. 1996;115(4):342–351.
  • Park M-H, Kim SY, Roh EY, et al. Difference of Type 3 secretion system (T3SS) effector gene genotypes (exoU and exoS) and its implication to antibiotics resistances in isolates of Pseudomonas aeruginosa from chronic otitis media. Auris Nasus Larynx. 2017;44(3):258–265.
  • Lundman L, Harada T, Santi PA, et al. Inner Ear Damage and Passage through the round Window Membrane of Pseudomonas aeruginosa Exotoxin a in a Chinchilla Model. Ann Otol Rhinol Laryngol. 1992;101(5):437–444.
  • Stenqvist M, Anniko M, Rask-Andersen H. Middle ear mucosa changes following exposure to Pseudomonas aeruginosa exotoxin A. Eur Arch Otorhinolaryngol. 1999;256(10):484–490.
  • Yunus TM, Molina RM, Prevatt AR, et al. Hearing loss with semicircular canal fistula in exotoxin A-deficient Pseudomonas otitis media. Otolaryngol Head Neck Surg. 2004;130(4):430–436.
  • Reimer. Concentrations of the Pseudomonas aeruginosa toxin pyocyanin in human ear secretions. Acta Oto-Laryngologica. 2000;120(543):86–88.
  • Elsheikh MN, Mahfouz ME. Up-regulation of MUC5AC and MUC5B mucin genes in nasopharyngeal respiratory mucosa and selective up-regulation of MUC5B in middle ear in pediatric otitis media with effusion. The Laryngoscope. 2006;116(3):365–369.
  • Samuels TL, Yan JC, Khampang P, et al. Association of Gel-Forming Mucins and Aquaporin Gene Expression With Hearing Loss, Effusion Viscosity, and Inflammation in Otitis Media With. Effusion. 2017;143(8):810–817.
  • Preciado D, Goyal S, Rahimi M, et al. MUC5B Is the predominant mucin glycoprotein in chronic otitis media fluid. Pediatr Res. 2010;68(3):231–236.
  • Lee MR, Pawlowski KS, Luong A, et al. Biofilm presence in humans with chronic suppurative otitis media. Otolaryngol Head Neck Surg. 2009;141(5):567–571.
  • Gu X, Keyoumu Y, Long L, et al. Detection of bacterial biofilms in different types of chronic otitis media. Eur Arch Otorhinolaryngol. 2014;271(11):2877–2883.
  • Hall-Stoodley L, Hu FZ, Gieseke A, et al. Direct detection of bacterial biofilms on the middle-ear mucosa of children with chronic otitis media. Jama.2006;296(2):202–211.
  • Dohar JE, Hebda PA, Veeh R, et al. Mucosal biofilm formation on middle-ear mucosa in a nonhuman primate model of chronic suppurative otitis media. The Laryngoscope. 2005;115(8):1469–1472.
  • Byrd MS, Pang B, Hong W, et al. Direct evaluation of Pseudomonas aeruginosa biofilm mediators in a chronic infection model. Infect Immun. 2011;79(8):3087–3095.
  • Chole RA, Gagnon PM, Vogel JP. Inactivation of specific Pseudomonas aeruginosa biofilm factors does not alter virulence in infected cholesteatomas. Otol Neurotol. 2014;35(9):1585–1591.
  • Kao WTK, Gagnon PM, Vogel JP, et al. FleQ, a Transcriptional Activator, Is Required for Biofilm Formation In Vitro But Does Not Alter Virulence in a Cholesteatomas Model. Otol Neurotol. 2016;37(7):977–983.
  • Jung JY, Lee DH, Wang EW, et al. P.aeruginosa infection increases morbidity in experimental cholesteatomas. Laryngoscope. 2011;121:2449–2454.
  • Yadav MK, Chae S-W, Go YY, et al. In vitro Multi-Species Biofilms of Methicillin-Resistant Staphylococcus aureus and Pseudomonas aeruginosa and Their Host Interaction during In vivo Colonization of an Otitis Media Rat Model. Front Cell Infect Microbiol. 2017;7:125.
  • Jeon E-J, Park Y-S, Lee SK, et al. Effect of nitric oxide and peroxynitrite on mucociliary transport function of experimental otitis media. Otolaryngol Head Neck Surg. 2006;134(1):126–131.
  • Schousboe LP, Ovesen T, Eckhardt L, et al. How does endotoxin trigger inflammation in otitis media with effusion? The Laryngoscope. 2001;111(2):297–300.
  • Zielnik-Jurkiewicz B, Stankiewicz-Szymczak W. Pro-inflammatory interleukins in middle ear effusions from atopic and non-atopic children with chronic otitis media with effusion. Eur Arch Otorhinolaryngol. 2016;273(6):1369–1378.
  • MacArthur CJ, Hefeneider SH, Kempton JB, et al. C3H/HeJ mouse model for spontaneous chronic otitis media. The Laryngoscope. 2006;116(7):1071–1079.
  • Jotic A, Jesic S, Zivkovic M, et al. Polymorphisms in Toll-like receptors 2 and 4 genes and their expression in chronic suppurative otitis media. Auris Nasus Larynx. 2015;42(6):431–437.
  • Si Y, Zhang ZG, Chen SJ, et al. Attenuated TLRs in middle ear mucosa contributes to susceptibility of chronic suppurative otitis media. Hum Immunol. 2014;75(8):771–776..
  • Nason R, Lee DH, Jung JY, et al. Radiographic and Micro—Computed Tomographic Imaging of Lipopolysaccharide-Mediated Bone Resorption. Ann Otol Rhinol Laryngol. 2009;118(5):391–396.
  • Mittal R, Grati M, Yan D, et al. Pseudomonas aeruginosa Activates PKC-Alpha to Invade Middle Ear Epithelial Cells. Front Microbiol. 2016;7:255.
  • Mun JJ, Tam C, Kowbel D, et al. Clearance of Pseudomonas aeruginosa from a healthy ocular surface involves surfactant protein D and is compromised by bacterial elastase in a murine null-infection model. Infect Immun. 2009;77(6):2392–2398.
  • Augustin DK, Heimer SR, Tam C, et al. Role of Defensins in Corneal Epithelial Barrier Function against Pseudomonas aeruginosa Traversal. Infect Immun. 2011;79(2):595–605.
  • Tam C, LeDue J, Mun JJ, et al. 3D quantitative imaging of unprocessed live tissue reveals epithelial defense against bacterial adhesion and subsequent traversal requires MyD88. PLoS One. 2011;6(8):e24008.
  • Green M, Apel A, Stapleton F. Risk factors and causative organisms in microbial keratitis. Cornea. 2008;27(1):22–27.
  • Galentine PG, Cohen EJ, Laibson PR, et al. Corneal ulcers associated with contact lens wear. Arch Ophthalmol. 1984;102(6):891–894.
  • Sy A, Srinivasan M, Mascarenhas J, et al. Pseudomonas aeruginosa Keratitis: outcomes and Response to Corticosteroid Treatment. Invest Ophthalmol Vis Sci. 2012;53(1):267–272.
  • Bharathi MJ, Ramakrishnan R, Shivakumar C, et al. Etiology and antibacterial susceptibility pattern of community-acquired bacterial ocular infections in a tertiary eye care hospital in south India. Indian J Ophthalmol. 2010;58(6):497–507.
  • Yilmaz S, Ozturk I, Maden A. Microbial keratitis in West Anatolia, Turkey: a retrospective review. Int Ophthalmol. 2007;27(4):261–268.
  • Fleiszig SMJ, Kroken AR, Nieto V, et al. Contact lens-related corneal infection: intrinsic resistance and its compromise. Prog Retin Eye Res. 2020;76:100804.
  • Preston MJ, Fleiszig SM, Zaidi TS, et al. Rapid and sensitive method for evaluating Pseudomonas aeruginosa virulence factors during corneal infections in mice. Infect Immun. 1995;63(9):3497–3501.
  • Toska J, Sun Y, Carbonell DA, et al. Diversity of virulence phenotypes among type III secretion negative Pseudomonas aeruginosa clinical isolates. PLoS One. 2014;9(1):e86829.
  • Zolfaghar I, Angus AA, Kang PJ, et al. Mutation of retS, encoding a putative hybrid two-component regulatory protein in Pseudomonas aeruginosa, attenuates multiple virulence mechanisms. Microbes Infect. 2005;7(13):1305–1316.
  • Metruccio MME, Wan SJ, Horneman H, et al. A novel murine model for contact lens wear reveals clandestine IL-1R dependent corneal parainflammation and susceptibility to microbial keratitis upon inoculation with Pseudomonas aeruginosa. Ocul Surf. 2019;17(1):119–133.
  • Zaidi TS, Lyczak J, Preston M, et al. Cystic Fibrosis Transmembrane Conductance Regulator-Mediated Corneal Epithelial Cell Ingestion of Pseudomonas aeruginosaIs a Key Component in the Pathogenesis of Experimental Murine Keratitis. Infect Immun. 1999;67(3):1481–1492.
  • Zaidi T, Bajmoczi M, Zaidi T, et al. Disruption of CFTR-Dependent Lipid Rafts Reduces Bacterial Levels and Corneal Disease in a Murine Model of Pseudomonas aeruginosa Keratitis. Invest Ophthalmol Vis Sci. 2008;49(3):1000–1009.
  • Fletcher EL, Fleiszig SM, Brennan NA. Lipopolysaccharide in adherence of Pseudomonas aeruginosa to the cornea and contact lenses. Invest Ophthalmol Vis Sci. 1993;34(6):1930–1936.
  • Evans D, Kuo T, Kwong M, et al. Pseudomonas aeruginosa strains with lipopolysaccharide defects exhibit reduced intracellular viability after invasion of corneal epithelial cells. Exp Eye Res. 2002;75(6):635–643.
  • Kierbel A, Gassama-Diagne A, Rocha C, et al. Pseudomonas aeruginosa exploits a PIP3-dependent pathway to transform apical into basolateral membrane. J Cell Biol. 2007;177(1):21–27..
  • Fletcher EL, Weissman BA, Efron N, et al. The role of pili in the attachment of Pseudomonas aeruginosa to unworn hydrogel contact lenses. Curr Eye Res. 1993;12(12):1067–1071.
  • Hazlett LD, Zucker M, Berk RS. Distribution and kinetics of the inflammatory cell response to ocular challenge with Pseudomonas aeruginosa in susceptible versus resistant mice. Ophthalmic Res. 1992;24(1):32–39.
  • Rudner XL, Zheng Z, Berk RS, et al. Corneal epithelial glycoproteins exhibit Pseudomonas aeruginosa pilus binding activity. Invest Ophthalmol Vis Sci. 1992;33(7):2185–2193.
  • Fleiszig SM, The Glenn A. Fry award lecture 2005. The pathogenesis of contact lens-related keratitis. Optom Vis Sci. 2006;83:866–873.
  • Alarcon I, Evans DJ, Fleiszig SMJ. The Role of Twitching Motility in Pseudomonas aeruginosa Exit from and Translocation of Corneal Epithelial Cells. Invest Ophthalmol Vis Sci. 2009;50(5):2237–2244.
  • Nieto V, Kroken AR, Grosser MR, et al. Type IV Pili Can Mediate Bacterial Motility within Epithelial Cells. mBio. 2019;10(4):e02880–18.
  • Robertson DM, Rogers NA, Petroll WM, et al. Second harmonic generation imaging of corneal stroma after infection by Pseudomonas aeruginosa. Sci Rep. 2017;7(1):46116.
  • Fleiszig SMJ, Arora SK, Van R, et al. FlhA, a component of the flagellum assembly apparatus of Pseudomonas aeruginosa, plays a role in internalization by corneal epithelial cells. Infect Immun. 2001;69(8):4931–4937.
  • Kroken AR, Chen CK, Evans DJ, et al. The Impact of ExoS on Pseudomonas aeruginosa Internalization by Epithelial Cells Is Independent of fleQ and Correlates with Bistability of Type Three Secretion System Gene Expression. mBio. 2018;9(3):e00668–18.
  • Fleiszig SM, Wiener-Kronish JP, Miyazaki H, et al. Pseudomonas aeruginosa-mediated cytotoxicity and invasion correlate with distinct genotypes at the loci encoding exoenzyme S. Infect Immun. 1997;65(2):579–586.
  • Lomholt JA, Poulsen K, Kilian M. Epidemic population structure of Pseudomonas aeruginosa: evidence for a clone that is pathogenic to the eye and that has a distinct combination of virulence factors. Infect Immun. 2001;69(10):6284–6295.
  • Lakkis C, Fleiszig SM. Resistance of Pseudomonas aeruginosa isolates to hydrogel contact lens disinfection correlates with cytotoxic activity. J Clin Microbiol. 2001;39(4):1477–1486.
  • Zhu H, Conibear TCR, Bandara R, et al. Type III Secretion System–Associated Toxins, Proteases, Serotypes, and Antibiotic Resistance of Pseudomonas aeruginosa Isolates Associated with Keratitis. Curr Eye Res. 2006;31(4):297–306.
  • Borkar DS, Acharya NR, Leong C, et al. Cytotoxic clinical isolates of Pseudomonas aeruginosaidentified during the Steroids for Corneal Ulcers Trial show elevated resistance to fluoroquinolones. BMC Ophthalmology. 2014;14(1):54.
  • Cowell BA, Chen DY, Frank DW, et al. ExoT of Cytotoxic Pseudomonas aeruginosa Prevents Uptake by Corneal Epithelial Cells. Infect Immun. 2000;68(1):403–406.
  • Cowell BA, Evans DJ, Fleiszig SMJ. Actin cytoskeleton disruption by ExoY and its effects on Pseudomonas aeruginosa invasion. FEMS Microbiol Lett. 2005;250(1):71–76.
  • Sun Y, Karmakar M, Taylor PR, et al. ExoS and ExoT ADP Ribosyltransferase Activities Mediate Pseudomonas aeruginosa Keratitis by Promoting Neutrophil Apoptosis and Bacterial Survival. J Immunol. 2012;188(4):1884–1895.
  • Vareechon C, Zmina SE, Karmakar M, et al. Pseudomonas aeruginosa Effector ExoS Inhibits ROS Production in Human Neutrophils. Cell Host Microbe. 2017;21(5):611–8 e5.
  • Fleiszig SM, Zaidi TS, Preston MJ, et al. Relationship between cytotoxicity and corneal epithelial cell invasion by clinical isolates of Pseudomonas aeruginosa. Infect Immun. 1996;64(6):2288–2294.
  • Tam C, Lewis SE, Li WY, et al. Mutation of the phospholipase catalytic domain of the Pseudomonas aeruginosa cytotoxin ExoU abolishes colonization promoting activity and reduces corneal disease severity. Exp Eye Res. 2007;85(6):799–805.
  • Ramirez JC, Fleiszig SMJ, Sullivan AB, et al. Traversal of Multilayered Corneal Epithelia by Cytotoxic Pseudomonas aeruginosa Requires the Phospholipase Domain of ExoU. Invest Ophthalmol Vis Sci. 2012;53(1):448–453.
  • Zolfaghar I, Evans DJ, Ronaghi R, et al. Type III secretion-dependent modulation of innate immunity as one of multiple factors regulated by Pseudomonas aeruginosa RetS. Infect Immun. 2006;74(7):3880–3889.
  • Twining SS, Kirschner SE, Mahnke LA, Frank DW, Twining SS, Kirschner SE, Mahnke LA. Effect of Pseudomonas aeruginosa elastase, alkaline protease, and exotoxin A on corneal proteinases and proteins. Invest Ophthalmol Vis Sci. 1993;34(9):2699–2712.
  • Marquart ME, Dajcs JJ, Caballero AR, et al. Calcium and magnesium enhance the production of Pseudomonas aeruginosa protease IV, a corneal virulence factor. Med Microbiol Immunol. 2005;194(1–2):39–45.
  • Kreger AS, Gray LD. Purification of Pseudomonas aeruginosa proteases and microscopic characterization of pseudomonal protease-induced rabbit corneal damage. Infect Immun. 1978;19(2):630–648.
  • Ijiri Y, Yamamoto T, Kamata R, et al. The role of Pseudomonas aeruginosa elastase in corneal ring abscess formation in pseudomonal keratitis. Graefes Arch Clin Exp Ophthalmol. 1993;231(9):521–528.
  • Marquart ME, Caballero AR, Chomnawang M, Marquart ME, Caballero AR, Chomnawang M, Thibodeaux BA, Twining SS, O’Callaghan RJ. Identification of a Novel Secreted Protease from Pseudomonas aeruginosa that Causes Corneal Erosions. Invest Ophthalmol Vis Sci. 2005;46(10):3761–3768.
  • Engel LS, Hill JM, Moreau JM, et al. Pseudomonas aeruginosa protease IV produces corneal damage and contributes to bacterial virulence. Invest Ophthalmol Vis Sci. 1998;39(3):662–665.
  • Tang A, Marquart ME, Fratkin JD, et al. Properties of PASP: a Pseudomonas Protease Capable of Mediating Corneal Erosions. Invest Ophthalmol Vis Sci. 2009;50(8):3794–3801.
  • Mochizuki Y, Suzuki T, Oka N, et al. Pseudomonas aeruginosa MucD Protease Mediates Keratitis by Inhibiting Neutrophil Recruitment and Promoting Bacterial Survival. Invest Ophthalmol Vis Sci. 2014;55(1):240–246..
  • White CD, Alionte LG, Cannon BM, et al. Corneal Virulence of LasA Protease-deficient Pseudomonas aeruginosa PAO1. Cornea. 2001;20(6):643–646.
  • Azghani AO. Pseudomonas aeruginosa and epithelial permeability: role of virulence factors elastase and exotoxin A. Am J Respir Cell Mol Biol. 1996;15(1):132–140.
  • Iglewski BH, Burns RP, Gipson IK. Pathogenesis of corneal damage from Pseudomonas exotoxin A. Invest Ophthalmol Vis Sci. 1977;16(1):73–76.
  • Pillar CM, Hobden JA. Pseudomonas aeruginosa exotoxin A and keratitis in mice. Invest Ophthalmol Vis Sci. 2002;43(5):1437–1444.
  • Tam C, Mun JJ, Evans DJ, et al. The Impact of Inoculation Parameters on the Pathogenesis of Contact Lens–Related Infectious Keratitis. Invest Ophthalmol Vis Sci. 2010;51(6):3100–3106.
  • Wu YT-Y, Willcox M, Zhu H, et al. Contact lens hygiene compliance and lens case contamination: a review. Cont Lens Anterior Eye. 2015;38(5):307–316.
  • Ha D-G, O’Toole GA. c-di-GMP and its Effects on Biofilm Formation and Dispersion: a Pseudomonas aeruginosa Review. Microbiol Spectr. 2015;3(2):MB-0003-2014.
  • Hickman JW, Harwood CS. Identification of FleQ from Pseudomonas aeruginosa as a c-di-GMP-responsive transcription factor. Mol Microbiol. 2008;69(2):376–389.
  • Lamont IL, Beare PA, Ochsner U, et al. Siderophore-mediated signaling regulates virulence factor production in Pseudomonas aeruginosa. Proc Natl Acad Sci U S A. 2002;99(10):7072–7077.
  • Suzuki T, Okamoto S, Oka N, et al. Role of pvdE Pyoverdine Synthesis in Pseudomonas aeruginosa Keratitis. Cornea. 2018;37(Suppl 1):S99–S105.
  • St Sauver JL, Warner DO, Yawn BP, et al. Why Patients Visit Their Doctors: assessing the Most Prevalent Conditions in a Defined American Population. Mayo Clin Proc. 2013;88(1):56–67.
  • Maradit Kremers H, Larson DR, Crowson CS, et al. Prevalence of Total Hip and Knee Replacement in the United States. J Bone Jt Surg. 2015;97(17):1386–1397.
  • Fehring TK, Odum SM, Troyer JL, et al. Joint Replacement Access in 2016: a Supply Side Crisis. J Arthroplasty. 2010;25(8):1175–1181.
  • Kurtz S, Ong K, Lau E, et al. Projections of Primary and Revision Hip and Knee Arthroplasty in the United States from 2005 to 2030. J Bone Jt Surg. 2007;89(4):780–785.
  • Kurtz SM, Ong KL, Lau E, et al. Prosthetic joint infection risk after TKA in the Medicare population. Clin Orthop Relat Res. 2010;468(1):52–56.
  • Ong KL, Kurtz SM, Lau E, et al. Prosthetic joint infection risk after total hip arthroplasty in the Medicare population. J Arthroplasty. 2009;24(6):105–109.
  • Nowicki B, Runyan RS, Smith N, et al. Kinetics of colonization of a porous vitreous carbon percutaneous implant. Biomaterials. 1990;11(6):389–392.
  • Pendegrass CJ, Goodship AE, Price JS, et al. Nature’s answer to breaching the skin barrier: an innovative development for amputees. J Anat. 2006;209(1):59–67.
  • Juhnke D-L, Beck JP, Jeyapalina S, et al. Fifteen years of experience with Integral-Leg-Prosthesis: cohort study of artificial limb attachment system. J Rehabil Res Dev. 2015;52(4):407–420.
  • Kingshott P, Wei J, Bagge-Ravn D, et al. Covalent Attachment of Poly(ethylene glycol) to Surfaces, Critical for Reducing Bacterial Adhesion.Langmuir.2003;19(17):6912-6921.
  • Neoh KG, Kang ET. Combating Bacterial Colonization on Metals via Polymer Coatings: relevance to Marine and Medical Applications. ACS Appl Mater Interfaces. 2011;3(8):2808–2819.
  • Zilberman M, Elsner JJ. Antibiotic-eluting medical devices for various applications. J Control Release. 2008;130(3):202–215.
  • Hetrick EM, Schoenfisch MH. Reducing implant-related infections: active release strategies. Chem Soc Rev. 2006;35(9):780–789.
  • Fuchs T, Stange R, Schmidmaier G, et al. The use of gentamicin-coated nails in the tibia: preliminary results of a prospective study. Arch Orthop Trauma Surg. 2011;131(10):1419–1425.
  • Williams DL, Lerdahl JM, Haymond BS, et al. In Vitro Efficacy of a Novel Active-Release Antimicrobial Coating To Eradicate Biofilms of Pseudomonas aeruginosa. Antimicrob Agents Chemother. 2014;58(4):2400–2404.
  • Shin Y, Akao M. Tissue Reactions to Various Percutaneous Materials with Different Surface Properties and Structures. Artif Organs. 2008;21(9):995–1001.
  • Chou TGR, Petti CA, Szakacs J, et al. Evaluating antimicrobials and implant materials for infection prevention around transcutaneous osseointegrated implants in a rabbit model. J Biomed Mater Res A. 2010;92A:942–952.
  • Allyn G, Bloebaum RD, Epperson RT, et al. Ability of a wash regimen to remove biofilm from the exposed surface of materials used in osseointegrated implants. J Orthop Res. 2019;37(1):248–257.
  • Neu HC. The Crisis in Antibiotic Resistance. Science. 1992;257(5073):1064–1073.
  • Fernández L, Breidenstein EBM, Hancock REW. Creeping baselines and adaptive resistance to antibiotics. Drug Resist Updat. 2011;14:1–21.
  • Campoccia D, Montanaro L, Speziale P, et al. Antibiotic-loaded biomaterials and the risks for the spread of antibiotic resistance following their prophylactic and therapeutic clinical use. Biomaterials. 2010;31(25):6363–6377.
  • Brånemark RP, Hagberg K, Kulbacka-Ortiz K, et al. Osseointegrated Percutaneous Prosthetic System for the Treatment of Patients With Transfemoral Amputation: a Prospective Five-year Follow-up of Patient-reported Outcomes and Complications. J Am Acad Orthop Surg. 2019;27(16):e743–e51.
  • Atallah R, Leijendekkers RA, Hoogeboom TJ, et al. Complications of bone-anchored prostheses for individuals with an extremity amputation: a systematic review. Plos One. 2018;13(8):e0201821.
  • Overmann AL, Aparicio C, Richards JT, et al. Orthopaedic osseointegration: implantology and future directions. J Orthop Res. 2020;38(7):1445–1454.
  • Andonian S, Rabah DM, Aprikian AG. Pseudomonas aeruginosa sacroiliitis and osteomyelitis of pelvic bones after radical prostatectomy. Urology. 2002;60(4):698.
  • Hartemann-Heurtier A, Senneville E. Diabetic foot osteomyelitis. Diabetes & Metabolism. 2008;34(2):87–95.
  • Arciola CR, An YH, Campoccia D, et al. Etiology of implant orthopedic infections: a survey on 1027 clinical isolates. Int J Artif Organs. 2005;28(11):1091–1100.
  • Masters EA, Trombetta RP, De Mesy Bentley KL, et al. Evolving concepts in bone infection: redefining “biofilm”, “acute vs. chronic osteomyelitis”, “the immune proteome” and “local antibiotic therapy”. Bone Research. 2019;7(1). DOI:10.1038/s41413-019-0061-z.
  • Blyth CC, Gomes L, Sorrell TC, et al. Skull-base osteomyelitis: fungal vs. bacterial infection. Clinical Microbiology and Infection. 2011;17(2):306–311.
  • Parvizi J, Azzam K, Ghanem E, et al. Periprosthetic infection due to resistant staphylococci: serious problems on the horizon. Clin Orthop Relat Res. 2009;467(7):1732–1739.
  • Carrega G, Bartolacci V, Burastero G, et al. Etiology of prosthetic joint infections in a tertiary care centre in Italy. Infez Med. 2008;16(4):204–208.
  • Zmistowski B, Fedorka CJ, Sheehan E, et al. Prosthetic joint infection caused by gram-negative organisms. J Arthroplasty. 2011;26(6):104–108.
  • Hsieh P-H, Lee MS, Hsu K-Y, et al. Gram-negative prosthetic joint infections: risk factors and outcome of treatment. Clin Infect Dis. 2009;49(7):1036–1043.
  • Wegner AM, Wuellner JC, Haus BM Pseudomonas aeruginosa Septic Arthritis and Osteomyelitis after Closed Reduction and Percutaneous Pinning of a Supracondylar Humerus Fracture: a Case Report and Review of the Literature. Case Rep Orthop 2017; 2017:8721835.
  • Smith JW, Chalupa P, Shabaz Hasan M. Infectious arthritis: clinical features, laboratory findings and treatment. Clin Microbiol Infect. 2006;12(4):309–314.
  • Goldenberg DL, Brandt KD, Cathcart ES, et al. Acute arthritis caused by gram-negative bacilli: a clinical characterization. Medicine (Baltimore). 1974;53(3):197–208.
  • Thompson JM, Miller RJ, Ashbaugh AG, et al. Mouse model of Gram-negative prosthetic joint infection reveals therapeutic targets. JCI Insight. 2018;3(17):e121737.
  • Mahmood F, Hakimiyan A, Jayaraman V, et al. A novel human antimicrobial factor targets Pseudomonas aeruginosa through its type III secretion system. J Med Microbiol. 2013;62(4):531–539.
  • Jin T, Mohammad M, Hu Z, et al. A novel mouse model for septic arthritis induced by Pseudomonas aeruginosa. Sci Rep. 2019;9(1):16868..
  • Marshall JC, Christou NV, Meakins JL. The gastrointestinal tract. The “undrained abscess” of multiple organ failure. Ann Surg. 1993;218:111–119.
  • Falcao DP, Mendonca CP, Scrassolo A, et al. Nursery outbreak of severe diarrhoea due to multiple strains of Pseudomonas aeruginosa. Lancet. 1972;300(7766):38–40.
  • Florman AL, Schifrin N. Observations on a small outbreak of infantile diarrhea associated with Pseudomonas aeruginosa. J Pediatr. 1950;36(6):758–766.
  • Chuang C-H, Janapatla RP, Wang Y-H, et al. Pseudomonas aeruginosa-associated Diarrheal Diseases in Children. Pediatr Infect Dis J. 2017;36(12):1119–1123.
  • Adlard PA, Kirov SM, Sanderson K, et al. Pseudomonas aeruginosa as a cause of infectious diarrhoea. Epidemiol Infect. 1998;121(1):237–241.
  • Kim SW, Peck KR, Jung SI, et al. Pseudomonas aeruginosa as a Potential Cause of Antibiotic-Associated Diarrhea. J Korean Med Sci. 2001;16(6):742–744.
  • Nelson RK, Poroyko V, Morowitz MJ, et al. Effect of Dietary Monosaccharides on Pseudomonas aeruginosa Virulence. Surg Infect (Larchmt). 2013;14(1):35–42.
  • Chuang C-H, Wang Y-H, Chang H-J, et al. Shanghai fever: a distinct Pseudomonas aeruginosa enteric disease. Gut. 2014;63(5):736–743.
  • Herve RC. Endoscopy in the twenty-first century: minimally invasive state-of-the-art medical technology or a future main vector of hospital-acquired infections? J Hosp Infect. 2017;97(4):329–330.
  • Chen C-Y, Chen Y-C, Pu H-N, et al. Bacteriology of acute appendicitis and its implication for the use of prophylactic antibiotics. Surg Infect (Larchmt). 2012;13(6):383–390.
  • Andrey V, Crisinel P-A, Prod’hom G, et al. Impact of co-amoxicillin-resistant Escherichia coli and Pseudomonas aeruginosa on the rate of infectious complications in paediatric complicated appendicitis. Swiss Med Wkly. 2019;149:w20055.
  • Chan EYH, Borzych-Duzalka D, Alparslan C, et al. Colostomy in children on chronic peritoneal dialysis. Pediatr Nephrol. 2020;35(1):119–126.
  • Vikstrom E, Tafazoli F, Magnusson K-E. Pseudomonas aeruginosa quorum sensing molecule N -(3 oxododecanoyl)- l -homoserine lactone disrupts epithelial barrier integrity of Caco-2 cells. FEBS Lett. 2006;580(30):6921–6928.
  • Vikstrom E, Bui L, Konradsson P, et al. Role of calcium signalling and phosphorylations in disruption of the epithelial junctions by Pseudomonas aeruginosa quorum sensing molecule. Eur J Cell Biol. 2010;89(8):584–597.
  • Karlsson T, Turkina MV, Yakymenko O, et al. The Pseudomonas aeruginosa N-acylhomoserine lactone quorum sensing molecules target IQGAP1 and modulate epithelial cell migration. PLoS Pathog. 2012;8(10):e1002953.
  • Coquant G, Grill J-P, Seksik P. Impact of N-Acyl-Homoserine Lactones, Quorum Sensing Molecules, on Gut Immunity. Front Immunol. 2020;11:1827.
  • Laughlin RS, Musch MW, Hollbrook CJ, et al. The key role of Pseudomonas aeruginosa PA-I lectin on experimental gut-derived sepsis. Ann Surg. 2000;232(1):133–142.
  • Alverdy J, Holbrook C, Rocha F, et al. Gut-derived sepsis occurs when the right pathogen with the right virulence genes meets the right host: evidence for in vivo virulence expression in Pseudomonas aeruginosa. Ann Surg. 2000;232(4):480–489.
  • Zaborin A, Gerdes S, Holbrook C, et al. Pseudomonas aeruginosa overrides the virulence inducing effect of opioids when it senses an abundance of phosphate. PLoS One. 2012;7(4):e34883.
  • Hayashi N, Nishizawa H, Kitao S, et al. Pseudomonas aeruginosa injects type III effector ExoS into epithelial cells through the function of type IV pili. FEBS Lett. 2015;589(8):890–896.
  • Okuda J, Hayashi N, Okamoto M, et al. Translocation of Pseudomonas aeruginosa from the intestinal tract is mediated by the binding of ExoS to an Na,K-ATPase regulator, FXYD3. Infect Immun. 2010;78(11):4511–4522.
  • Okuda J, Okamoto M, Hayashi N, et al. Complementation of the exoS gene in the pvdE pyoverdine synthesis gene-deficient mutant of Pseudomonas aeruginosa results in recovery of the pvdE gene-mediated penetration through the intestinal epithelial cell barrier but not the pvdE-mediated virulence in silkworms. J Infect Chemother. 2012;18(3):332–340.
  • Skurnik D, Roux D, Aschard H, et al. A comprehensive analysis of in vitro and in vivo genetic fitness of Pseudomonas aeruginosa using high-throughput sequencing of transposon libraries. PLoS Pathog. 2013;9(9):e1003582.
  • Koh AY, Mikkelsen PJ, Smith RS, et al. Utility of in vivo transcription profiling for identifying Pseudomonas aeruginosa genes needed for gastrointestinal colonization and dissemination. PLoS One. 2010;5(12):e15131.
  • Wheeler KM, Carcamo-Oyarce G, Turner BS, et al. Mucin glycans attenuate the virulence of Pseudomonas aeruginosa in infection. Nat Microbiol. 2019;4(12):2146–2154.
  • Hoffman CL, Lalsiamthara J, Aballay A. Host Mucin Is Exploited by Pseudomonas aeruginosa To Provide Monosaccharides Required for a Successful Infection. mBio. 2020;11(2):e00060–20.
  • Newman JW, Floyd RV, Fothergill JL. The contribution of Pseudomonas aeruginosa virulence factors and host factors in the establishment of urinary tract infections. FEMS Microbiol Lett. 2017;364(15):364.
  • Mittal R, Aggarwal S, Sharma S, et al. Urinary tract infections caused by Pseudomonas aeruginosa: a minireview. J Infect Public Health. 2009;2(3):101–111.
  • Olejnickova K, Hola V, Ruzicka F. Catheter-related infections caused by Pseudomonas aeruginosa: virulence factors involved and their relationships. Pathog Dis. 2014;72(2):87–94.
  • Tielen P, Narten M, Rosin N, et al. Genotypic and phenotypic characterization of Pseudomonas aeruginosa isolates from urinary tract infections. Int J Med Microbiol. 2011;301(4):282–292.
  • Cole SJ, Records AR, Orr MW, et al. Catheter-associated urinary tract infection by Pseudomonas aeruginosa is mediated by exopolysaccharide-independent biofilms. Infect Immun. 2014;82(5):2048–2058.
  • Pedersen SS. Lung infection with alginate-producing, mucoid Pseudomonas aeruginosa in cystic fibrosis. APMIS Suppl. 1992;28:1–79.
  • Tielen P, Rosin N, Meyer A-K, et al. Regulatory and metabolic networks for the adaptation of Pseudomonas aeruginosa biofilms to urinary tract-like conditions. PLoS One. 2013;8(8):e71845.
  • Gupta RK, Harjai K, Chhibber S. Rhl quorum sensing affects the virulence potential of Pseudomonas aeruginosa in an experimental urinary tract infection. Antonie Van Leeuwenhoek. 2016;109(12):1535–1544.
  • Kumar R, Chhibber S, Harjai K. Quorum sensing is necessary for the virulence of Pseudomonas aeruginosa during urinary tract infection. Kidney Int. 2009;76(3):286–292.
  • Bala A, Chhibber S, Harjai K. Pseudomonas quinolone signalling system: a component of quorum sensing cascade is a crucial player in the acute urinary tract infection caused by Pseudomonas aeruginosa. Int J Med Microbiol. 2014;304(8):1199–1208.
  • Cole SJ, Hall CL, Schniederberend M, et al. Host suppression of quorum sensing during catheter-associated urinary tract infections. Nat Commun. 2018;9(1):4436.
  • Shand GH, Anwar H, Kadurugamuwa J, et al. In vivo evidence that bacteria in urinary tract infection grow under iron-restricted conditions. Infect Immun. 1985;48(1):35–39.
  • Visca P, Chiarini F, Mansi A, et al. Virulence determinants in Pseudomonas aeruginosa strains from urinary tract infections. Epidemiol Infect. 1992;108(2):323–336.
  • Wolz C, Hohloch K, Ocaktan A, et al. Iron release from transferrin by pyoverdin and elastase from Pseudomonas aeruginosa. Infect Immun. 1994;62(9):4021–4027.
  • Mittal R, Khandwaha RK, Gupta V, et al. Phenotypic characters of urinary isolates of Pseudomonas aeruginosa & their association with mouse renal colonization. Indian J Med Res. 2006;123(1):67–72.
  • Woods DE, Schaffer MS, Rabin HR, et al. Phenotypic comparison of Pseudomonas aeruginosa strains isolated from a variety of clinical sites. J Clin Microbiol. 1986;24(2):260–264.
  • Hamood AN, Griswold JA, Duhan CM. Production of Extracellular Virulence Factors byPseudomonas aeruginosaIsolates Obtained from Tracheal, Urinary Tract, and Wound Infections. J Surg Res. 1996;61(2):425–432.
  • Mossine VV, Waters JK, Chance DL, et al. Transient Proteotoxicity of Bacterial Virulence Factor Pyocyanin in Renal Tubular Epithelial Cells Induces ER-Related Vacuolation and Can Be Efficiently Modulated by Iron Chelators. Toxicol Sci. 2016;154(2):403–415.
  • Magill SS, Edwards JR, Bamberg W, et al. Multistate Point-Prevalence Survey of Health Care–Associated Infections. N Engl J Med. 2014;370(13):1198–1208.
  • Thaden JT, Park LP, Maskarinec SA, et al. Results from a 13-Year Prospective Cohort Study Show Increased Mortality Associated with Bloodstream Infections Caused by Pseudomonas aeruginosa Compared to Other Bacteria. Antimicrob Agents Chemother. 2017;61(6):e02671–16.
  • Veve MP, McCurry ED, Cooksey GE, et al. Epidemiology and outcomes of non-HACEK infective endocarditis in the southeast United States. PLoS One. 2020;15(3):e0230199.
  • Dawson NL, Brumble LM, Pritt BS, et al. Left-sided Pseudomonas aeruginosa endocarditis in patients without injection drug use. Medicine (Baltimore). 2011;90(4):250–255.
  • Yoon E-J, Kim D, Lee H, et al. Mortality dynamics of Pseudomonas aeruginosa bloodstream infections and the influence of defective OprD on mortality: prospective observational study. J Antimicrob Chemother. 2019;74(9):2774–2783.
  • Shi Q, Huang C, Xiao T, et al. A retrospective analysis of Pseudomonas aeruginosa bloodstream infections: prevalence, risk factors, and outcome in carbapenem-susceptible and -non-susceptible infections. Antimicrob Resist Infect Control. 2019;8(1):68.
  • Micek ST, Lloyd AE, Ritchie DJ, et al. Pseudomonas aeruginosa bloodstream infection: importance of appropriate initial antimicrobial treatment. Antimicrob Agents Chemother. 2005;49(4):1306–1311.
  • McCarthy KL, Wailan AM, Jennison AV, et al. P. aeruginosa blood stream infection isolates: a “full house” of virulence genes in isolates associated with rapid patient death and patient survival. Microb Pathog. 2018;119:81–85.
  • Hickey C, Schaible B, Nguyen S, Hurley D, Srikumar S, Fanning S, et al. Increased Virulence of Bloodstream Over Peripheral Isolates of P. aeruginosa Identified Through Post-transcriptional Regulation of Virulence Factors. Front Cell Infect Microbiol. 2018;8:357.
  • Harrison EM, Carter MEK, Luck S, et al. Pathogenicity islands PAPI-1 and PAPI-2 contribute individually and synergistically to the virulence of Pseudomonas aeruginosa strain PA14. Infect Immun. 2010;78(4):1437–1446.
  • Peña C, Cabot G, Gómez-Zorrilla S, et al. Influence of virulence genotype and resistance profile in the mortality of Pseudomonas aeruginosa bloodstream infections. Clin Infect Dis. 2015;60(4):539–548.
  • Finck‐Barbançon V, Goranson J, Zhu L, et al. ExoU expression by Pseudomonas aeruginosa correlates with acute cytotoxicity and epithelial injury. Mol Microbiol. 1997;25(3):547–557.
  • Javanmardi F, Emami A, Pirbonyeh N, et al. A systematic review and meta-analysis on Exo-toxins prevalence in hospital acquired Pseudomonas aeruginosa isolates. Infect Genet Evol. 2019;75:104037.
  • Sato H, Frank DW, Hillard CJ, et al. The mechanism of action of the Pseudomonas aeruginosa-encoded type III cytotoxin, ExoU. EMBO J. 2003;22(12):2959–2969.
  • Berube BJ, Rangel SM, Hauser AR. Pseudomonas aeruginosa: breaking down barriers. Curr Genet. 2016;62(1):109–113.
  • Bayer AS, Park S, Ramos MC, et al. Effects of alginase on the natural history and antibiotic therapy of experimental endocarditis caused by mucoid Pseudomonas aeruginosa. Infect Immun. 1992;60(10):3979–3985.
  • Xiong Y-Q, Vasil ML, Johnson Z, et al. The Oxygen- and Iron-Dependent Sigma Factor pvdS of Pseudomonas aeruginosa Is an Important Virulence Factor in Experimental Infective Endocarditis. J Infect Dis. 2000;181(3):1020–1026.
  • Pai S, Bedford L, Ruramayi R, et al. Pseudomonas aeruginosa meningitis/ventriculitis in a UK tertiary referral hospital. QJM. 2016;109(2):85–89.
  • Balczon R, Pittet J-F, Wagener BM, et al. Infection-induced endothelial amyloids impair memory. FASEB J. 2019;33(9):10300–10314.
  • Tapiola T, Alafuzoff I, Herukka S-K, et al. Cerebrospinal Fluid β-Amyloid 42 and Tau Proteins as Biomarkers of Alzheimer-Type Pathologic Changes in the Brain. Arch Neurol. 2009;66(3):382–389..
  • Yahr TL, Vallis AJ, Hancock MK, et al. ExoY, an adenylate cyclase secreted by the Pseudomonas aeruginosa type III system. Proc Natl Acad Sci U S A. 1998;95(23):13899–13904.
  • Carlyle BC, Nairn AC, Wang M, et al. cAMP-PKA phosphorylation of tau confers risk for degeneration in aging association cortex. Proc Natl Acad Sci U S A. 2014;111(13):5036–5041.
  • Balczon R, Prasain N, Ochoa C, et al. Pseudomonas aeruginosa exotoxin Y-mediated tau hyperphosphorylation impairs microtubule assembly in pulmonary microvascular endothelial cells. PLoS One. 2013;8(9):e74343.
  • Saliba AM, De Assis M-C, Nishi R, et al. Implications of oxidative stress in the cytotoxicity of Pseudomonas aeruginosa ExoU. Microbes Infect. 2006;8(2):450–459.
  • King ME, Gamblin TC, Kuret J, King ME, Gamblin TC, Kuret J, Binder LI. Differential assembly of human tau isoforms in the presence of arachidonic acid. J Neurochem. 2000;74(4):1749–1757.
  • Turner KH, Everett J, Trivedi U, et al. Requirements for Pseudomonas aeruginosa Acute Burn and Chronic Surgical Wound Infection. Plos Genetics. 2014;10(10):e1004743..
  • Azzopardi EA, Azzopardi E, Camilleri L, et al. Gram Negative Wound Infection in Hospitalised Adult Burn Patients-Systematic Review and Metanalysis-. PLoS One. 2014;9(4):e95042.
  • Brandenburg KS, Weaver AJ Jr., Karna SLR, et al. Formation of Pseudomonas aeruginosa Biofilms in Full-thickness Scald Burn Wounds in Rats. Sci Rep. 2019;9(1):13627.
  • Rumbaugh KP, Griswold JA, Iglewski BH, et al. Contribution of Quorum Sensing to the Virulence ofPseudomonas aeruginosa in Burn Wound Infections. Infect Immun. 1999;67(11):5854–5862.
  • Schaber JA, Triffo WJ, Suh SJ, et al. Pseudomonas aeruginosa forms biofilms in acute infection independent of cell-to-cell signaling. Infect Immun. 2007;75(8):3715–3721.
  • Cox CD, Parker J. Use of 2-aminoacetophenone production in identification of Pseudomonas aeruginosa. J Clin Microbiol. 1979;9(4):479–484.
  • Kesarwani M, Hazan R, He J, et al. A quorum sensing regulated small volatile molecule reduces acute virulence and promotes chronic infection phenotypes. PLoS Pathog. 2011;7(8):e1002192.
  • Bandyopadhaya A, Kesarwani M, Que YA, et al. The Quorum Sensing Volatile Molecule 2-Amino Acetophenon Modulates Host Immune Responses in a Manner that Promotes Life with Unwanted Guests. Plos Pathogens. 2012;8(11):e1003024.
  • Kim M, Christley S, Khodarev NN, et al. Pseudomonas aeruginosa wound infection involves activation of its iron acquisition system in response to fascial contact. J Trauma Acute Care Surg. 2015;78(4):823–829.
  • Muller M, Li Z, Maitz PKM. Pseudomonas pyocyanin inhibits wound repair by inducing premature cellular senescence: role for p38 mitogen-activated protein kinase. Burns. 2009;35(4):500–508.
  • Sato H, Okinaga K, Saito H. Role of Pili in the Pathogenesis of Pseudomonas aeruginosa Burn Infection. Microbiol Immunol. 1988;32(2):131–139.
  • Arora SK, Neely AN, Blair B, et al. Role of motility and flagellin glycosylation in the pathogenesis of Pseudomonas aeruginosa burn wound infections. Infect Immun. 2005;73(7):4395–4398.
  • Garcia M, Morello E, Garnier J, et al. Pseudomonas aeruginosa flagellum is critical for invasion, cutaneous persistence and induction of inflammatory response of skin epidermis. Virulence. 2018;9(1):1163–1175.
  • Kruczek C, Kottapalli KR, Dissanaike S, et al. Major Transcriptome Changes Accompany the Growth of Pseudomonas aeruginosa in Blood from Patients with Severe Thermal Injuries. PLoS One. 2016;11(3):e0149229.
  • Gonzalez MR, Ducret V, Leoni S, et al. Transcriptome Analysis of Pseudomonas aeruginosa Cultured in Human Burn Wound Exudates. Front Cell Infect Microbiol. 2018;8:39
  • Bjarnsholt T, Kirketerp-Moller K, Jensen PØ, et al. Why chronic wounds will not heal: a novel hypothesis. Wound Repair Regen. 2008;16(1):2–10..
  • Zhao G, Hochwalt PC, Usui ML, et al. Delayed wound healing in diabetic (db/db) mice with Pseudomonas aeruginosa biofilm challenge: a model for the study of chronic wounds. Wound Repair Regen. 2010;18(5):467–477.
  • Zhao G, Usui ML, Underwood RA, et al. Time course study of delayed wound healing in a biofilm-challenged diabetic mouse model. Wound Repair Regen. 2012;20(3):342–352.
  • Prasad ASB, Shruptha P, Prabhu V, et al. Pseudomonas aeruginosa virulence proteins pseudolysin and protease IV impede cutaneous wound healing. Lab Invest. 2020;100(12):1532–1550.
  • Jacobsen JN, Andersen AS, Krogfelt KA. Impact of Pseudomonas aeruginosa quorum sensing on cellular wound healing responses in vitro. Scand J Infect Dis. 2012;44(8):615–619.
  • Goldufsky J, Wood SJ, Jayaraman V, et al. Pseudomonas aeruginosa uses T3SS to inhibit diabetic wound healing. Wound Repair Regen. 2015;23(4):557–564..
  • Jacobson JA. Pool-Associated Pseudomonas aeruginosa Dermatitis and Other Bathing-Associated Infections. Infection Control. 1985;6(10):398–401.
  • Vaiman M, Lasarovitch T, Heller L, et al. Ecthyma gangrenosum versus ecthyma-like lesions: should we separate these conditions? Acta Dermatovenerol Alp Pannonica Adriat. 2015;24(4):69–72.
  • Maniatis AN, Karkavitsas C, Maniatis NA, et al. Pseudomonas aeruginosa folliculitis due to non-O:11 serogroups: acquisition through use of contaminated synthetic sponges. Clin Infect Dis. 1995;21(2):437–439.
  • Highsmith AK, Le PN, Khabbaz RF, et al. Characteristics of Pseudomonas aeruginosa Isolated From Whirlpools and Bathers. Infection Control. 1985;6(10):407–412.
  • Berrouane YF, McNutt L-A, Buschelman BJ, et al. Outbreak of Severe Pseudomonas aeruginosa Infections Caused by a Contaminated Drain in a Whirlpool Bathtub. Clin Infect Dis. 2000;31(6):1331–1337.
  • Faure K, Shimabukuro D, Ajayi T, et al. O-antigen serotypes and type III secretory toxins in clinical isolates of Pseudomonas aeruginosa. J Clin Microbiol. 2003;41(5):2158–2160.
  • Stewart RMK, Wiehlmann L, Ashelford KE, et al. Genetic Characterization Indicates that a Specific Subpopulation of Pseudomonas aeruginosa Is Associated with Keratitis Infections. J Clin Microbiol. 2011;49(3):993–1003.
  • Berube BJ, Murphy KR, Torhan MC, et al. Impact of Type III Secretion Effectors and of Phenoxyacetamide Inhibitors of Type III Secretion on Abscess Formation in a Mouse Model of Pseudomonas aeruginosa Infection. Antimicrob Agents Chemother. 2017;61(11):e01202–17.
  • Hebert F-O, Boyle B, Levesque RC. Direct In Vivo Microbial Transcriptomics During Infection. Trends Microbiol. 2018;26(9):732–735.
  • Cornforth DM, Dees JL, Ibberson CB, et al. Pseudomonas aeruginosa transcriptome during human infection. Proc Natl Acad Sci U S A. 2018;115(22):E5125–E34.
  • Ailloud F, Didelot X, Woltemate S, et al. Within-host evolution of Helicobacter pylori shaped by niche-specific adaptation, intragastric migrations and selective sweeps. Nat Commun. 2019;10(1):2273..
  • Wang T, Zhang X, Liu Z, et al. Single-cell RNA sequencing reveals the sustained immune cell dysfunction in the pathogenesis of sepsis secondary to bacterial pneumonia. Genomics. 2021;113(3):1219–1233.
  • Marti-Figueroa CR, Ashton RS. The case for applying tissue engineering methodologies to instruct human organoid morphogenesis. Acta Biomater. 2017;54:35–44.
  • Vandamme TF. Use of rodents as models of human diseases. J Pharm Bioallied Sci. 2014;6(1):2–9.
  • Ishida S. Organs-on-a-chip: current applications and consideration points for in vitro ADME-Tox studies. Drug Metab Pharmacokinet. 2018;33(1):49–54.
  • Ji S, Guvendiren M. Recent Advances in Bioink Design for 3D Bioprinting of Tissues and Organs. Front Bioeng Biotechnol. 2017;5:23.
  • Grigoryan B, Sazer DW, Avila A, et al. Development, characterization, and applications of multi-material stereolithography bioprinting. Sci Rep. 2021;11(1):3171.
  • Zheng F, Xiao Y, Liu H, et al. Patient-Specific Organoid and Organ-on-a-Chip: 3D Cell-Culture Meets 3D Printing and Numerical Simulation. Advanced Biology. 2021;e2000024. doi:10.1002/adbi.202000024
  • Mithal A, Hume AJ, Lindstrom-Vautrin J, et al. Human Pluripotent Stem Cell-Derived Intestinal Organoids Model SARS-CoV-2 Infection Revealing a Common Epithelial Inflammatory Response. Stem Cell Reports. 2021;16(4):940–953.
  • Miller AJ, Dye BR, Ferrer-Torres D, et al. Generation of lung organoids from human pluripotent stem cells in vitro. Nat Protoc. 2019;14(2):518–540.
  • Vickovic S, Eraslan G, Salmen F, et al. High-definition spatial transcriptomics for in situ tissue profiling. Nat Methods. 2019;16(10):987–990.
  • Stickels RR, Murray E, Kumar P, et al. Highly sensitive spatial transcriptomics at near-cellular resolution with Slide-seqV2. Nat Biotechnol. 2021;39(3):313–319.
  • Baccin C, Al-Sabah J, Velten L, et al. Combined single-cell and spatial transcriptomics reveal the molecular, cellular and spatial bone marrow niche organization. Nat Cell Biol. 2020;22(1):38–48..
  • Van Den Brink SC, Alemany A, Van Batenburg V, et al. Single-cell and spatial transcriptomics reveal somitogenesis in gastruloids. Nature. 2020;582(7812):405–409.
  • Khan MM, Ernst O, Manes NP, et al. Multi-Omics Strategies Uncover Host–Pathogen Interactions. ACS Infect Dis. 2019;5(4):493–505.
  • Zhou W, Sailani MR, Contrepois K, et al. Longitudinal multi-omics of host–microbe dynamics in prediabetes. Nature. 2019;569(7758):663–671.
  • DiGiandomenico A, Keller AE, Gao C, et al. A multifunctional bispecific antibody protects against Pseudomonas aeruginosa. Sci Transl Med. 2014;6(262):262ra155–262ra155. 262ra155.
  • Patel A, DiGiandomenico A, Keller AE, et al. An engineered bispecific DNA-encoded IgG antibody protects against Pseudomonas aeruginosa in a pneumonia challenge model. Nat Commun. 2017;8(1):637.