Genetic changes due to host-pathogen interaction quantified by microarrays of mRNA.
Abstract
Pseudomonas aeruginosa is an opportunistic bacterium that can proliferate in the soil, water, and even humans if they are immunologically depressed. During lung infections, P. aeruginosa goes through significant morphological changes turning into the mucoid form after which its eradication becomes almost impossible. Within this chapter, we explore the bioenergetics changes produced within P. aeruginosa during infections in humans and the metabolic pathways that are involved in those changes that lead to chronic infection.
Keywords
- P. aeruginosa
- host
- bioenergetics
- phosphate
- choline
1. Introduction
There are many lung pathogens but one of the most studied is
The
It is often said that
Colonization with
2. Host-bacteria interaction in acute infection
2.1 Lung changes upon bacterial invasion
The flagella and lipopolysaccharide (LPS) from
When LPS binds to the host cells, where CFTR is also a receptor [42], it upregulates NF-κB at the gene level (Table 1), promoting inflammation [43] by secretion of IL1, IL6, IL8, ICAM-1, and also CXCL1 [44, 45, 46, 47], although in different degrees of regulation. For example, CXCL1 expression is orchestrated by a fatty acid-binding protein (FABP4) that delivers fatty acids from the cytoplasm to the nuclear receptor PPAR. These prompt macrophage signaling through the myeloid differentiation protein-88 (MyD88) to induce cytokine production following engagement of TLRs with LPS [48, 49, 50, 51]. Macrophages require MyD88 to produce CXCL1 but also eicosapentaenoic acid and docosahexaenoic acid, both substrates of FABP4. This demonstrates the importance of fatty acid metabolism to promote host resistance to
Lung | |||||
---|---|---|---|---|---|
Gene ID | FC | Name | Gene ID | FC | Name |
hemE | 16.1a | Uroporphyrinogen decarboxylase | 4502 | Dioxin-inducible cytochrome P | |
pyrC | 12.1 | Dihydroorotase (biofilm development) | 252 | ppGpp | |
pyrH | 6.4 | Uridylate kinase (biofilm development) | 206.7 | Tumor necrosis factor-α-inducible DNA-binding protein A | |
adhA | 5.5 | Alcohol dehydrogenase | 133.1 | Proteasome subunit C | |
pelB, pelE | 5.6, 3.7 | Extracellular polysaccharide (competitive disruption of | hORC2L | 13.4b | Human origin recognition complex protein 2 |
cls | 7.0 | Cardiolipin synthase | MCP-1 | 13.3 | Monocyte chemotactic protein 1 |
pscD | 3.2 | T3SS export protein | 3.5 | c-Jun | |
plcN | 3.2 | Phospholipase C precursor | 3 | GTP-binding protein rhoB4. | |
algD,E,F,8,amrZ | 1.9–10.7 | Alginate biosynthesis | 2.9 | Urokinase-type plasminogen activator | |
ppiA | 2.5 | Peptidyl-prolyl cis-trans isomerase | PKC | 2.8 | Protein kinase C, ETA type |
hmgA | −7.2 | Homogentisate 1–2-dioxygenase | 2.7 | Folylpolyglutamate synthetase | |
algC | −9.3 | Phosphomannomutase | TTP | 5.7 | Tristetraproline |
hemE | 16.1 | Uroporphyrinogen decarboxylase | 2.4 | Anti-oncogene | |
pyrC | 12.1 | Dihydroorotase (biofilm development) | MAD3 | 5.1 | IκB-α |
pyrH | 6.4 | Uridylate kinase (biofilm development) | hENT1 | 4.2 | Placental equilibrative nucleoside transporter 1 |
adhA | 5.5 | Alcohol dehydrogenase | TEL | 2.8 | Transcription factor |
pelB, pelE | 5.6, 3.7 | Extracellular polysaccharide (competitive disruption of | DPH2L | 2.6 | Diphtheria toxin resistance protein |
cls | 7.0 | Cardiolipin synthase | TFPI2 | 2.3 | Tissue factor pathway inhibitor 2 |
2.1 | Ankyrin motif | ||||
ESE-1 | 2.1 | Epithelial-specific transcription factor | |||
−12.5 | 8IRF | ||||
−11.9 | JAK-1 | ||||
EPB49 | −2.0 | Erythrocyte membrane protein band 4.9. (Dematin) | |||
−2.3 |
The T cells also play an important role in acute infection. IL17 producing T cells are expanded [54], via expression of STAT3 and retinoid orphan receptor [55]; these steps are crucial for B cell activation and immunoglobulin release for bacterial clearance [56]. On the contrary, excess of T regulatory cells (Treg) are associated with secondary
Death of CF patients chronically infected with
2.2 Bacterial metabolic changes for invasion
Simultaneously, the contact of
Composition | Succinatea + NH4Cl | Cholinea | ||||
---|---|---|---|---|---|---|
μg/mg of protein | μmol/mg of protein | μg/mg of protein | μmol/mg of protein | % | pb | |
Phosphate | 1400 ± 100 | 14.7 ± 0.7 | 460 ± 90 | 4.8 ± 0.7 | 33 | 0.001 |
ATP | 1650 ± 330 | 3.0 ± 0.6 | 1270 ± 165 | 2.3 ± 0.3 | −23 | 0.32 |
Polyphosphates | 4.0 ± 1.8 | 0.042 ± 0.01 | 6.3 ± 1.4 | 0.066 ± 0.008 | 57 | 0.004 |
Carbohydratesc | 210 ± 40 | 1.2 ± 0.2 | 330 ± 50 | 1.8 ± 0.2 | 50 | 0.03 |
LPSd | 19 ± 4 | 0.08 ± 0.02 | 41 ± 9 | 0.16 ± 0.03 | 100 | 0.02 |
Phospholipidse | 114 ± 7 | 0.65 ± 0.04 | 71 ± 4 | 0.1 ± 0.02 | −85 | |
Biosynthetic energy (ATP)f | — | 1675 | — | 924 | 45 |
After the invasion, the bacteria attach to the lung epithelium producing profound metabolic changes, which correlates with morphological changes to the rugose small-colony variant (RSCV) [65, 66, 67]. The transition to the RSCV precedes inactivation of serine hydroxymethyltransferase; this produces accumulation of cyclic diguanylate [68] and nucleotide ppGpp that leads to polyPi accumulation [69] and to alginate production [68, 70, 71, 72].
Table 2 shows that the total content of phosphate is reduced 3 times in choline feed bacteria, although it accumulates Pi in polyPi. The polyPi may be thought as the energetic savings of the bacteria which is done at expenses of phospholipid biosynthesis. This is possible reducing the size of the bacterium [73] and increasing the area/volume ratio that facilitates O2 exchange for which the bacteria have to compete with the host [74]. The overall bacterial changes save energy accumulating ppGpp, the substrate for polyPi synthesis by polyphosphate kinase, which is also increased [75]. Some of these polyPi are located in the outer membrane where this highly energetic polymer has Pi bonds similar to the ATP and a highly negative charge neutralized by cations such as Ca2+ and Mg2+. Thus, polyPi function as an energy storage, buffer, and ion chelator that may shield the bacterium from environmental changes.
After adhering to the host ciliated epithelial cells, through mucin, the bacterium is enabled to form aggregates, secrete alginate, and modify its LPS [76]; this is a process regulated by 3,5-cyclic diguanylic acid [68]. The LPS is a macromolecule (C205H366N3O117P5) of 4899.956 g/mol that covers the outer membrane extending 40 nm outward. It is released with vesicle-containing enzymes and outer membrane (OM). Its extended formula was determined in 2003 (Figure 1); it is anchored to the OM through the lipid A which binds to the 3-deoxy-d-manno-2-octulosonic acid (KDO), the first glycoside of the core oligosaccharide, bound to the distal O antigen, a highly variable region [77, 78]. A metabolic crossroad between the LPS and alginate biosynthesis (Figure 2) is mannose-6-phosphate isomerization to mannose-1-phosphate by phosphomannomutase (Alg C). The glucose-6 phosphate (G6P) can be transformed to G1P to produce LPS or to isomerize mannose-6-phosphate to G1P. Similarly, fructose-6-phosphate (F6P) can be converted to mannose-6-phosphate and then isomerized to mannose-1-phosphate that becomes alginate by d-mannuronate linkage to l-guluronate via a P-1,4 glycosidic bond. Thus, isomerization of mannose 6-phosphate to mannose 1-phosphate by phosphomannomutase, encoded as algC, is common to the biosynthesis of LPS and alginate since mutants in this phosphomannomutase are hindered in their ability to infect
2.3 Interaction between lung and bacteria
The host-pathogen interaction studied
Further validation of this host-pathogen interaction is verified by the metabolite variations in a mouse model that uses live bacteria, instead of LPS. Figure 4A shows that phosphatidylcholine and glycine are significantly reduced in the lung upon infection, due to their consumption, while succinate and lactate are significantly accumulated [85]. Variations of choline concentration in the lung are not significant although glycerophosphocholine and glycine are [86, 87], which are the degradation products of choline. This is because
The succinate accumulated in the lung after infection [85], as Krebs cycle metabolite, inhibits histone demethylases, collagen hydrolases, α-ketoglutarate dioxygenases, and the 5-methylcytosine hydroxylase family [96].
The LPS of
3. Chronic infection of P. aeruginosa
Upon infection, the host decreases iron levels in the blood [99]; this iron deficiency regulates a great number of bacterial virulent genes like alginate, the most relevant virulence factor, for
The first gene described for the biosynthesis of alginate was the phosphomannose isomerase and GDP-mannose dehydrogenase (AlgD) that catalyze the conversion of GDP-mannose to GDP-mannuronic acid [105]. Upon oxygen limitation,
Several authors have studied the AlgD regulation, Figure 6 shows a 20-years breach in the finding of AlgD regulators. More positive regulators have been identified, such as AlgR that is upregulated by NaCl and also by the nitrogen source [108]. AlgD is also under the same promoter than PLC, which is sensitive to the nitrogen source [109] that regulates the anaerobiosis genes. These genes detect the ratio of glutamine to 2-ketoglutarate, which is dependent on O2 availability [108, 110]. Another positive regulator of AlgD is AlgU [111], but the only negative regulator known is the RpoN, a sigma factor, that regulates nitrogen metabolism. RpoN is increased by disruption of pyrimidine synthesis and decreased by the supplementation with uracil, showing that a high level of RpoN, in the RSCV form, may block the alginate biosynthesis [110, 112].
Studies on the biosynthetic pathway of biofilms show that chelation of iron by lactoferrin destabilizes the bacterial membrane [113], which combined with xylitol hinders the ability of the bacteria to respond to iron deficiency [101], showing some promise for CF treatment.
4. Conclusions
Scientists agree that suppression of alginate production is vital to treat CF patients, but in 40 years of research, little has been achieved in suppressing its production
5. Perspectives
The advancement of techniques with high output data like microarrays, proteomes, and mass spectrometry are closing the breach among the different approaches that have been used to tackle
References
- 1.
Dean HF, Royle P, Morgan AF. Detection of FP plasmids in hospital isolates of Pseudomonas aeruginosa . Journal of Bacteriology. 1979;138 (1):249-250 - 2.
Hoadley AW, Knight DE. External otitis among swimmers and nonswimmers. Archives of Environmental Health. 1975; 30 (9):445-448 - 3.
Crull MR, Ramos KJ, Caldwell E, Mayer-Hamblett N, Aitken ML, Goss CH. Change in Pseudomonas aeruginosa prevalence in cystic fibrosis adults over time. BMC Pulmonary Medicine. 2016;16 (1):176 - 4.
MacKenzie T, Gifford AH, Sabadosa KA, Quinton HB, Knapp EA, Goss CH, et al. Longevity of patients with cystic fibrosis in 2000 to 2010 and beyond: Survival analysis of the cystic fibrosis foundation patient registry. Annals of Internal Medicine. 2014; 161 (4):233-241. DOI: 10.7326/M13-0636 - 5.
Knudsen PK, Olesen HV, Høiby N, Johannesson M, Karpati F, Laerum BN, et al. Differences in prevalence and treatment of Pseudomonas aeruginosa in cystic fibrosis centres in Denmark, Norway and Sweden. Journal of Cystic Fibrosis. 2009;8 (2):135-142. DOI: 10.1016/j.jcf.2008.11.001. Epub 2009 Jan 20 - 6.
Varaiya A, Kulkarni M, Bhalekar P, Dogra J. Incidence of metallo-beta-lactamase-producing Pseudomonas aeruginosa in diabetes and cancer patients. Indian Journal of Pathology and Microbiology. 2008;51 (2):200-203 - 7.
Trecarichi EM, Tumbarello M. Antimicrobial-resistant Gram-negative bacteria in febrile neutropenic patients with cancer: Current epidemiology and clinical impact. Current Opinion in Infectious Diseases. 2014; 27 (2):200-210 - 8.
Rolston KV, Bodey GP. Pseudomonas aeruginosa infection in cancer patients. Cancer Investigation. 1992;10 (1):43-59 - 9.
Corredoira JM, Ariza J, Pallarés R, Carratalá J, Viladrich PF, Rufí G, et al. Gram-negative bacillary cellulitis in patients with hepatic cirrhosis. European Journal of Clinical Microbiology & Infectious Diseases. 1994; 13 (1):19-24 - 10.
Ormerod LD, Smith RE. Contact lens-associated microbial keratitis. Archives of Ophthalmology. 1986; 104 (1):79-83 - 11.
Huber-Spitzy V, Baumgartner I, Arocker-Mettinger E, Schiffbänker M, Georgiew L, Grabner G. Corneal ulcer. Current analysis from specialized ambulatory care of a clinic. Klinische Monatsblätter für Augenheilkunde. 1992; 200 (4):251-256 - 12.
Singh G, Palanisamy M, Madhavan B, Rajaraman R, Narendran K, Kour A, et al. Multivariate analysis of childhood microbial keratitis in South India. Annals of the Academy of Medicine, Singapore. 2006; 35 (3):185-189 - 13.
Watt KG, Swarbrick HA. Trends in microbial keratitis associated with orthokeratology. Eye & Contact Lens. 2007; 33 (6 Pt 2):373-377; discussion 382 - 14.
Menon KV, Sorour TM. Epidemiologic and demographic attributes of primary spondylodiscitis in a middle eastern population sample. World Neurosurgery. 2016; 95 :31-39. DOI: 10.1016/j.wneu.2016.07.088. Epub 2016 Aug 2 - 15.
Lee MK, Chiu CS, Chow VC, Lam RK, Lai RW. Prevalence of hospital infection and antibiotic use at a university medical center in Hong Kong. Journal of Hospital Infection. 2007; 65 (4):341-347. Epub 2007 Feb 2 - 16.
Boucher HW, Talbot GH, Bradley JS, Edwards JE, Gilbert D, Rice LB, et al. Bad bugs, no drugs: No ESKAPE! An update from the Infectious Diseases Society of America. Clinical Infectious Diseases. 2009; 48 (1):1-12. DOI: 10.1086/595011 - 17.
Engler K, Mühlemann K, Garzoni C, Pfahler H, Geiser T, von Garnier C. Colonisation with Pseudomonas aeruginosa and antibiotic resistance patterns in COPD patients. Swiss Medical Weekly. 2012;142 :w13509. DOI: 10.4414/smw.2012.13509. eCollection 2012 - 18.
Gallego M, Pomares X, Espasa M, Castañer E, Solé M, Suárez D, et al. Pseudomonas aeruginosa isolates in severe chronic obstructive pulmonary disease: Characterization and risk factors. BMC Pulmonary Medicine. 2014;14 :103. DOI: 10.1186/1471-2466-14-103 - 19.
Lieberman D, Lieberman D. Pseudomonal infections in patients with COPD: Epidemiology and management. American Journal of Respiratory Medicine. 2003; 2 (6):459-468 - 20.
Huerta A, Soler N, Esperatti M, Guerrero M, Menendez R, Gimeno A, et al. Importance of Aspergillus spp. isolation in acute exacerbations of severe COPD: Prevalence, factors and follow-up: The FUNGI-COPD study. Respiratory Research. 2014;15 :17. DOI: 10.1186/1465-9921-15-17 - 21.
Planquette B, Péron J, Dubuisson E, Roujansky A, Laurent V, Le Monnier A, et al. Antibiotics against Pseudomonas aeruginosa for COPD exacerbation in ICU: A 10-year retrospective study. International Journal of Chronic Obstructive Pulmonary Disease. 2015;10 :379-388. DOI: 10.2147/COPD.S71413. eCollection 2015 - 22.
Emerson J, Rosenfeld M, McNamara S, Ramsey B, Gibson RL. Pseudomonas aeruginosa and other predictors of mortality and morbidity in young children with cystic fibrosis. Pediatric Pulmonology. 2002;34 :91-100. DOI: 10.1002/ppul.10127 - 23.
Gibson RL, Burns JL, Ramsey BW. Pathophysiology and management of pulmonary infections in cystic fibrosis. American Journal of Respiratory and Critical Care Medicine. 2003; 168 :918-951. DOI: 10.1164/rccm.200304-505SO - 24.
Perez MM, Luna MC, Pivetta OH, Keyeux G. CFTR gene analysis in Latin American CF patients: Heterogeneous origin and distribution of mutations across the continent. Journal of Cystic Fibrosis. 2007; 6 :194-208 - 25.
Perone C, Medeiros GS, del Castillo DM, de Aguiar MJB, Januário JN. Frequency of 8 CFTR gene mutations in cystic fibrosis patients in Minas Gerais, Brazil, diagnosed by neonatal screening. Brazilian Journal of Medical and Biological Research. 2010; 43 (2):134-138 - 26.
Drzymała-Czyż S, Szczepanik M, Krzyżanowska P, Duś-Żuchowska M, Pogorzelski A, Sapiejka E, et al. Serum phospholipid fatty acid composition in cystic fibrosis patients with and without liver cirrhosis. Annals of Nutrition & Metabolism. 2017; 71 (1-2):91-98. DOI: 10.1159/000477913. Epub 2017 Jul 22 - 27.
Chen WC, Huang JW, Chen KY, Hsueh PR, Yang PC. Spontaneous bilateral bacterial empyema in a patient with nephrotic syndrome. The Journal of Infection. 2006; 53 (3):e131-e134. Epub 2006 Feb 7 - 28.
Fernández J, Acevedo J, Castro M, Garcia O, de Lope CR, Roca D, et al. Prevalence and risk factors of infections by multiresistant bacteria in cirrhosis: A prospective study. Hepatology. 2012; 55 (5):1551-1561. DOI: 10.1002/hep.25532. Epub 2012 Apr 4 - 29.
Widdicombe J. In: Stockley RA, editor. Pulmonary Defences. Chichester: Wiley; 1997. pp. 1-15 - 30.
Joris L, Dab I, Quinton PM. Elemental composition of human airway surface fluid in healthy and diseased airways. American Review of Respiratory Disease. 1993; 148 (6 Pt 1):1633-1637 - 31.
Veldhuizen RAW, Nag K, Orgeig S, Possmayer F. The role of lipids in pulmonary surfactant. Biochimica et Biophysica Acta—Molecular Basis of Disease. 1998; 1408 :90-108 - 32.
Bufler P, Schmidt B, Schikor D, Bauernfeind A, Crouch EC, Griese M. Surfactant protein A and D differently regulate the immune response to nonmucoid Pseudomonas aeruginosa and its lipopolysaccharide. American Journal of Respiratory Cell and Molecular Biology. 2003;28 (2):249-256 - 33.
Perez-Gil J, Weaver TE. Pulmonary surfactant pathophysiology: Current models and open questions. Cytokine stimulation by Pseudomonas aeruginosa —Strain variation and modulation by pulmonary surfactant. Physiology. 2010;25 :132-141 - 34.
Hickling TP, Sim RB, Malhotra R. Induction of TNF-alpha release from human buffy coat cells by Pseudomonas aeruginosa is reduced by lung surfactant protein A. FEBS Letters. 1998;437 (1-2):65-69 - 35.
Adamo R, Sokol S, Soong G, Gomez M, Prince A. P. aeruginosa flagella activate airway epithelial cells through asialo GM1 and TLR2 as well as TLR5. American Journal of Respiratory Cell and Molecular Biology. 2004;30 :627-634 - 36.
Zhang Z, Louboutin JP, Weiner DJ, Goldberg JB, Wilson JM. Human airway epithelial cells sense Pseudomonas aeruginosa infection via recognition of flagellin by Toll-like receptor 5. Infection and Immunity. 2005;73 :7151-7160 - 37.
Ramphal R, Balloy V, Huerre M, Si-Tahar M, Chignard M. TLRs 2 and 4 are not involved in hypersusceptibility to acute Pseudomonas aeruginosa lung infections. Journal of Immunology. 2005;175 :3927-3934 - 38.
Power MR, Peng Y, Maydanski E, Marshall JS, Lin TJ. The development of early host response to Pseudomonas aeruginosa lung infection is critically dependent on myeloid differentiation factor 88 in mice. The Journal of Biological Chemistry. 2004;279 :49315-49322 - 39.
Flo TH, Ryan L, Latz E, Takeuchi O, Monks BG, Lien E, et al. Involvement of Toll-like receptor (TLR) 2 and TLR4 in cell activation by mannuronic acid polymers. The Journal of Biological Chemistry. 2002; 277 :35489-35495 - 40.
Epelman S, Stack D, Bell C, Wong E, Neely GG, Krutzik S, et al. Different domains of Pseudomonas aeruginosa exoenzyme S activate distinct TLRs. Journal of Immunology. 2004;173 :2031-2040 - 41.
Parker D, Prince A. Epithelial uptake of flagella initiates proinflammatory signaling. PLoS One. 2013; 8 (3):e59932. DOI: 10.1371/journal.pone.0059932. Epub 2013 Mar 20 - 42.
Schroeder TH, Lee MM, Yacono PW, Cannon CL, Gerçeker AA, Golan DE, et al. CFTR is a pattern recognition molecule that extracts Pseudomonas aeruginosa LPS from the outer membrane into epithelial cells and activates NF-kappa B translocation. Proceedings of the National Academy of Sciences of the United States of America. 2002;99 (10):6907-6912 - 43.
Ichikawa JK, Norris A, Bangera MG, Geiss GK, van ’t Wout AB, Bumgarner RE, et al. Interaction of Pseudomonas aeruginosa with epithelial cells: Identification of differentially regulated genes by expression microarray analysis of human cDNAs. Proceedings of the National Academy of Sciences of the United States of America. 2000;97 (17):9659-9664 - 44.
Reiniger N, Ichikawa JK, Pier GB. Influence of cystic fibrosis transmembrane conductance regulator on gene expression in response to Pseudomonas aeruginosa infection of human bronchial epithelial cells. Infection and Immunity. 2005;73 (10):6822-6830 - 45.
Joseph T, Look D, Ferkol T. NF-kappaB activation and sustained IL-8 gene expression in primary cultures of cystic fibrosis airway epithelial cells stimulated with Pseudomonas aeruginosa . American Journal of Physiology. Lung Cellular and Molecular Physiology. 2005;288 (3):L471-L479 - 46.
Ribeiro CM, Paradiso AM, Schwab U, Perez-Vilar J, Jones L, O’neal W, et al. Chronic airway infection/inflammation induces a Ca2+i-dependent hyperinflammatory response in human cystic fibrosis airway epithelia. The Journal of Biological Chemistry. 2005; 280 (18):17798-17806 - 47.
Véliz Rodriguez T, Moalli F, Polentarutti N, Paroni M, Bonavita E, Anselmo A, et al. Role of Toll interleukin-1 receptor (IL-1R) 8, a negative regulator of IL-1R/Toll-like receptor signaling, in resistance to acute Pseudomonas aeruginosa lung infection. Infection and Immunity. 2012;80 (1):100-109. DOI: 10.1128/IAI.05695-11. Epub 2011 Oct 24 - 48.
Björkbacka H, Fitzgerald KA, Huet F, Li X, Gregory JA, Lee MA, et al. The induction of macrophage gene expression by LPS predominantly utilizes Myd88-independent signaling cascades. Physiological Genomics. 2004; 19 :319-330 - 49.
Weighardt H, Kaiser-Moore S, Vabulas RM, Kirschning CJ, Wagner H, Holzmann B. Cutting edge: Myeloid differentiation factor 88 deficiency improves resistance against sepsis caused by polymicrobial infection. Journal of Immunology. 2002; 169 :2823-2827 - 50.
Shi S, Nathan C, Schnappinger D, Drenkow J, Fuortes M, Block E, et al. MyD88 primes macrophages for full-scale activation by interferon-γ yet mediates few responses to Mycobacterium tuberculosis . The Journal of Experimental Medicine. 2003;198 :987-997 - 51.
Skerrett SJ, Liggitt HD, Hajjar AM, Wilson CB. Cutting edge: Myeloid differentiation factor 88 is essential for pulmonary host defense against Pseudomonas aeruginosa but notStaphylococcus aureus . Journal of Immunology. 2004;172 :3377-3381 - 52.
Liang X, Gupta K, Quintero JR, Cernadas M, Kobzik L, Christou H, et al. Macrophage FABP4 is required for neutrophil recruitment and bacterial clearance in Pseudomonas aeruginosa pneumonia. FASEB Journal. 2018:fj201802002R. DOI: 10.1096/fj.201802002R - 53.
Tiesset H, Pierre M, Desseyn JL, Guéry B, Beermann C, Galabert C, et al. Dietary (n-3) polyunsaturated fatty acids affect the kinetics of pro- and antiinflammatory responses in mice with Pseudomonas aeruginosa lung infection. The Journal of Nutrition. 2009;139 (1):82-89. DOI: 10.3945/jn.108.096115. Epub 2008 Dec 3 - 54.
Bayes HK, Ritchie ND, Evans TJ. Interleukin-17 is required for control of chronic lung infection caused by Pseudomonas aeruginosa . Infection and Immunity. 2016;84 (12):3507-3516 - 55.
Ding FM, Zhang XY, Chen YQ , Liao RM, Xie GG, Zhang PY, et al. Lentivirus-mediated overexpression of suppressor of cytokine signaling-3 reduces neutrophilic airway inflammation by suppressing T-helper 17 responses in mice with chronic Pseudomonas aeruginosa lung infections. International Journal of Molecular Medicine. 2018;41 (4):2193-2200. DOI: 10.3892/ijmm.2018.3417. Epub 2018 Jan 23 - 56.
Pan T, Tan R, Li M, Liu Z, Wang X, Tian L, et al. IL17-producing γδ T cells may enhance humoral immunity during pulmonary Pseudomonas aeruginosa infection in mice. Frontiers in Cellular and Infection Microbiology. 2016;6 :170. DOI: 10.3389/fcimb.2016.00170. eCollection 2016 - 57.
Li JL, Chen TS, Yuan CC, Zhao GQ , Xu M, Li XY, et al. Regulatory T cell activity in immunosuppresive mice model of Pseudomonas aeruginosa pneumonia . Journal of Huazhong University of Science and Technology. Medical Sciences. 2017;37 (4):505-509. DOI: 10.1007/s11596-017-1764-2. Epub 2017 Aug 8 - 58.
Hu ZQ , Yao YM, Chen W, Bian JL, Zhao LJ, Chen LW, et al. Partial depletion of regulatory T cells enhances host inflammatory response against acute Pseudomonas aeruginosa infection after sepsis. Inflammation. 2018;41 (5):1780-1790. DOI: 10.1007/s10753-018-0821-8 - 59.
Shindo Y, Fuchs AG, Davis CG, Eitas T, Unsinger J, Burnham CD, et al. Interleukin 7 immunotherapy improves host immunity and survival in a two-hit model of Pseudomonas aeruginosa pneumonia. Journal of Leukocyte Biology. 2017;101 (2):543-554. DOI: 10.1189/jlb.4A1215-581R. Epub 2016 Sep 14 - 60.
Chen W, Lian J, Ye JJ, Mo QF, Qin J, Hong GL, et al. Ethyl pyruvate reverses development of Pseudomonas aeruginosa pneumonia during sepsis-induced immunosuppression. International Immunopharmacology. 2017;52 :61-69. DOI: 10.1016/j.intimp.2017.08.024. Epub 2017 Aug 31 - 61.
Pugh AM, Auteri NJ, Goetzman HS, Caldwell CC, Nomellini V. A murine model of persistent inflammation, immune suppression, and catabolism syndrome. International Journal of Molecular Sciences. 2017; 18 (8);pii: E1741. DOI: 10.3390/ijms18081741 - 62.
Naughton S, Parker D, Seemann T, Thomas T, Turnbull L, Rose B, et al. Pseudomonas aeruginosa AES-1 exhibits increased virulence gene expression during chronic infection of cystic fibrosis lung. PLoS One. 2011;6 (9):e24526. DOI: 10.1371/journal.pone.0024526. Epub 2011 Sep 15 - 63.
Bricio-Moreno L, Sheridan VH, Goodhead I, Armstrong S, Wong JKL, Waters EM, et al. Evolutionary trade-offs associated with loss of PmrB function in host-adapted Pseudomonas aeruginosa . Nature Communications. 2018;9 (1):2635. DOI: 10.1038/s41467-018-04996-x - 64.
Grumelli S. Choline triggers exacerbations of chronic obstructive pulmonary disease in patients infected with Pseudomonas aeruginosa . Current Respiratory Medicine Reviews. 2016;12 (2):167-174. DOI: 10.2174/1573398X12999160506104327 - 65.
Déziel E, Comeau Y, Villemur R. Initiation of biofilm formation by Pseudomonas aeruginosa 57RP correlates with emergence of hyperpiliated and highly adherent phenotypic variants deficient in swimming, swarming, and twitching motilities. Journal of Bacteriology. 2001;183 :1195-1204 - 66.
Drenkard E, Ausubel FM. Pseudomonas biofilm formation and antibiotic resistance are linked to phenotypic variation. Nature. 2002; 416 :740-743 - 67.
von Götz F, Häussler S, Jordan D, Saravanamuthu SS, Wehmhöner D, Strüssmann A, 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. Journal of Bacteriology. 2004;186 (12):3837-3847 - 68.
Pu M, Sheng L, Song S, Gong T, Wood TK. Serine hydroxymethyltransferase ShrA (PA2444) controls rugose small-colony variant formation in Pseudomonas aeruginosa . Frontiers in Microbiology. 2018;9 :315. DOI: 10.3389/fmicb.2018.00315. eCollection 2018 - 69.
Rao NN, Liu S, Kornberg A. Inorganic polyphosphate in Escherichia coli : The phosphate regulon and the stringent response. Journal of Bacteriology. 1998;180 (8):2186-2193 - 70.
Malone JG, Jaeger T, Spangler C, Ritz D, Spang A, Arrieumerlou C, et al. YfiBNR mediates cyclic di-GMP dependent small colony variant formation and persistence in Pseudomonas aeruginosa . PLoS Pathogens. 2010;6 (3):e1000804. DOI: 10.1371/journal.ppat.1000804 - 71.
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. DOI: 10.2217/fmb.14.107 - 72.
Malone JG, Jaeger T, Manfredi P, Dötsch A, Blanka A, Bos R, et al. The YfiBNR signal transduction mechanism reveals novel targets for the evolution of persistent Pseudomonas aeruginosa in cystic fibrosis airways. PLOS Pathogens. 2012;8 (6):e1002760. DOI: 10.1371/journal.ppat.1002760. Epub 2012 Jun 14 - 73.
Grumelli SM. Bioenergetics of phosphate incorporation and polyphosphate accumulation by choline in Pseudomonas aeruginosa [doctoral thesis]. 2000. Ejemplares 59118 - 74.
Lim WS, Phang KK, Tan AH, Li SF, Ow DS. Small colony variants and single nucleotide variations in Pf1 region of PB1 phage-resistant Pseudomonas aeruginosa . Frontiers in Microbiology. 2016;7 :282. DOI: 10.3389/fmicb.2016.00282. eCollection 2016 - 75.
Nikel PI, Chavarría M, Martínez-García E, Taylor AC, de Lorenzo V. Accumulation of inorganic polyphosphate enables stress endurance and catalytic vigour in Pseudomonas putida KT2440. Microbial Cell Factories. 2013;12 :50. DOI: 10.1186/1475-2859-12-50 - 76.
Landry RM, An D, Hupp JT, Singh PK, Parsek MR. Mucin- Pseudomonas aeruginosa interactions promote biofilm formation and antibiotic resistance. Molecular Microbiology. 2006;59 (1):142-151 - 77.
Zdorovenko EL, Zatonskii GV, Kocharova NA, Shashkov AS, Knirel YA, Ovod VV. Structure of the O polysaccharides and serological classification of Pseudomonas syringae pv.porri from genomospecies 4. European Journal of Biochemistry. 2003;270 (1):20-27 - 78.
Bystrova OV, Shashkov AS, Kocharova NA, Knirel YA, Zähringer U, Pier GB. Elucidation of the structure of the lipopolysaccharide core and the linkage between the core and the O-antigen in Pseudomonas aeruginosa immunotype 5 using strong alkaline degradation of the lipopolysaccharide. Biochemistry (Mosc). 2003;68 (8):918-925 - 79.
Olvera C, Goldberg JB, Sánchez R, Soberón-Chávez G. The Pseudomonas aeruginosa algC gene product participates in rhamnolipid biosynthesis. FEMS Microbiology Letters. 1999;179 (1):85-90 - 80.
Wargo MJ, Gross MJ, Rajamani S, et al. Hemolytic phospholipase c inhibition protects lung function during Pseudomonas aeruginosa . American Journal of Respiratory and Critical Care Medicine. 2011;184 :345-354 - 81.
Salvano MA, Domenech CE. Kinetic properties of purified Pseudomonas aeruginosa phosphorylcholine phosphatase indicated that this enzyme may be utilized by the bacteria to colonize in different environments. Current Microbiology. 1999;39 :1-8 - 82.
Kadurugamuwa JL, Beveridge TJ. Virulence factors are released from Pseudomonas aeruginosa in association with membrane vesicles during normal growth and exposure to gentamicin: A novel mechanism of enzyme secretion. Journal of Bacteriology. 1995;177 (14):3998-4008 - 83.
Fuchs B, Rupp M, Ghofrani HA, et al. Diacylglycerol regulates acute hypoxic pulmonary vasoconstriction via TRPC6. Respiratory Research. 2011; 12 :20 - 84.
Drake J, Glavinović MI, Trifaro JM. Choline blockage of currents through Ca2+ activated K+ channels in bovine chromaffin cells. Neuroscience. 1992; 49 :945-950 - 85.
LeGouëllec A, Moyne O, Meynet E, Toussaint B, Fauvelle F. High-resolution magic angle spinning NMR-based metabolomics revealing metabolic changes in lung of mice infected with P. aeruginosa consistent with the degree of disease severity. Journal of Proteome Research. 2018;17 (10):3409-3417. DOI: 10.1021/acs.jproteome.8b00306. Epub 2018 Sep 14 - 86.
Salvano MA, Lisa TA, Domenech CE. Choline transport in Pseudomonas aeruginosa . Molecular and Cellular Biochemistry. 1989;85 :81-89 - 87.
Malek AA, Chen C, Wargo MJ, Beattie GA, Hogan DA. Roles of three transporters, CbcXWV, BetT1, and BetT3, in Pseudomonas aeruginosa choline uptake for catabolism. Journal of Bacteriology. 2011;193 (12):3033-3041 - 88.
Sage AE, Vasil AI, Vasil ML. Molecular characterization of mutants affected in the osmoprotectant-dependent induction of phospholipase C in Pseudomonas aeruginosa PAO1. Molecular Microbiology. 1997;23 (1):43-56 - 89.
Diab F, Bernard T, Bazire A, Haras D, Blanco C, Jebbar M. Succinate-mediated catabolite repression control on the production of glycine betaine catabolic enzymes in Pseudomonas aeruginosa PAO1 under low and elevated salinities. Microbiology. 2006;152 (Pt 5):1395-1406 - 90.
Wargo MJ, Szwergold BS, Hogan DA. Identification of two gene clusters and a transcriptional regulator required for Pseudomonas aeruginosa glycine betaine catabolism. Journal of Bacteriology. 2008;190 (8):2690-2699. Epub 2007 Oct 19 - 91.
Wargo MJ. Choline catabolism to glycine betaine contributes to Pseudomonas aeruginosa survival during murine lung infection. PLoS One. 2013;8 (2):e56850. DOI: 10.1371/journal.pone.0056850. Epub 2013 Feb 14 - 92.
Le Rudulier D, Strøm AR, Dandekar AM, Smith LT, Valentine RC. Molecular biology of osmoregulation. Science. 1984; 224 :1064-1068 - 93.
Lisa TA, Garrido MN, Domenech CE. Induction of acid phosphatase and cholinesterase activities in Ps. aeruginosa and their in-vitro control by choline, acetylcholine and betaine. Molecular and Cellular Biochemistry. 1983;50 :149-155 - 94.
Bray C, Son JH, Kumar P, Harris JD, Meizel S. A role for the human sperm glycine receptor/Cl(−) channel in the acrosome reaction initiated by recombinant ZP3. Biology of Reproduction. 2002; 66 (1):91-97 - 95.
Wheeler MD, Thurman RG. Production of superoxide and TNF-alpha from alveolar macrophages is blunted by glycine. American Journal of Physiology. 1999; 277 (5):L952-L959. DOI: 10.1152/ajplung.1999.277.5.L952 - 96.
Pavliakova D, Chu C, Bystricky S, et al. Treatment with succinic anhydride improves the immunogenicity of Shigella flexneri type 2a O-specific polysaccharide-protein conjugates in mice. Infection and Immunity. 1999;67 (10):5526-5529 - 97.
Greer GG, Milazzo FH. Pseudomonas aeruginosa lipopolysaccharide: An uncoupler of mitochondrial oxidative phosphorylation. Canadian Journal of Microbiology. 1975;21 (6):877-883 - 98.
Joo SH, Chung HS, Raetz CR, Garrett TA. Activity and crystal structure of Arabidopsis thaliana UDP-N-acetylglucosamine acyltransferase. Biochemistry. 2012;51 (21):4322-4330. DOI: 10.1021/bi3002242. Epub 2012 May 14 - 99.
Al-Hasan MN, Juhn YJ, Bang DW, Yang HJ, Baddour LM. External validation of bloodstream infection mortality risk score in a population-based cohort. Clinical Microbiology and Infection. 2014; 20 (9):886-891. DOI: 10.1111/1469-0691.12607. Epub 2014 Mar 26 - 100.
Litwin CM, Calderwood SB. Role of iron in regulation of virulence genes. Clinical Microbiology Reviews. 1993; 6 :137-149 - 101.
Wittgens A, Kovacic F, Müller MM, Gerlitzki M, Santiago-Schübel B, Hofmann D, et al. Novel insights into biosynthesis and uptake of rhamnolipids and their precursors. Applied Microbiology and Biotechnology. 2017; 101 (7):2865-2878. DOI: 10.1007/s00253-016-8041-3. Epub 2016 Dec 17 - 102.
Venturi V, Ottevanger C, Leong J, Weisbeek PJ. Identification and characterization of a siderophore regulatory gene (pfrA) of Pseudomonas putida WCS358: Homology to the alginate regulatory gene algQ ofPseudomonas aeruginosa . Molecular Microbiology. 1993;10 (1):63-73 - 103.
Bereswill S, Waidner U, Odenbreit S, Lichte F, Fassbinder F, Bode G, et al. Structural, functional and mutational analysis of the pfr gene encoding a ferritin from Helicobacter pylori . Microbiology. 1998;144 (Pt 9):2505-2516 - 104.
Linker A, Jones RS. A new polysaccharide resembling alginic acid isolated from pseudomonads. Journal of Biological Chemistry. 1966; 241 :3845-3851 - 105.
Deretic V, Gill JF, Chakrabarty AM. Gene algD coding for GDPmannose dehydrogenase is transcriptionally activated in mucoid Pseudomonas aeruginosa . Journal of Bacteriology. 1987;169 (1):351-358 - 106.
Cunin R, Glansdorff N, Pierard A, Stalon V. Biosynthesis and metabolism of arginine in bacteria. Microbiological Review. 1986; 50 :314-352 - 107.
Park SM, Lu CD, Abdelal AT. Cloning and characterization of argR, a gene that participates in regulation of arginine biosynthesis and catabolism in Pseudomonas aeruginosa PAO1. Journal of Bacteriology. 1997;179 (17):5300-5308 - 108.
Deretic V, Govan JR, Konyecsni WM, Martin DW. Mucoid Pseudomonas aeruginosa in cystic fibrosis: Mutations in the muc loci affect transcription of the algR and algD genes in response to environmental stimuli. Molecular Microbiology. 1990;4 (2):189-196 - 109.
Wang Y, Hay ID, Rehman ZU, Rehm BH. Membrane-anchored MucR mediates nitrate-dependent regulation of alginate production in Pseudomonas aeruginosa . Applied Microbiology and Biotechnology. 2015;99 (17):7253-7265. DOI: 10.1007/s00253-015-6591-4. Epub 2015 Apr 29 - 110.
Savioz A, Zimmermann A, Haas D. Pseudomonas aeruginosa promoters which contain a conserved GG-N10-GC motif but appear to be RpoN-independent. Molecular Genetics and Genomics. 1993;238 (1-2):74-80 - 111.
Yin Y, Withers TR, Wang X, Yu HD. Evidence for sigma factor competition in the regulation of alginate production by Pseudomonas aeruginosa . PLoS One. 2013;8 (8):e72329. DOI: 10.1371/journal.pone.0072329. eCollection 2013 - 112.
Al Ahmar R, Kirby BD, Yu HD. Pyrimidine biosynthesis regulates small colony variant and mucoidy in Pseudomonas aeruginosa through sigma factor competition. Journal of Bacteriology. 2018. pii: JB.00575-18. DOI: 10.1128/JB.00575-18 - 113.
Ammons CM, Ward LS, Fisher ST, Wolcott RD, James GA. In vitro susceptibility of established biofilms composed of a clinical wound isolate of Pseudomonas aeruginosa treated with lactoferrin and xylitol. International Journal of Antimicrobial Agents. 2009;33 (3):230-236