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Host-Pathogen Interaction in the Lung of Patients Infected with Pseudomonas aeruginosa

Written By

Sandra Grumelli

Submitted: September 11th, 2018 Reviewed: January 23rd, 2019 Published: August 16th, 2019

DOI: 10.5772/intechopen.84657

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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 Pseudomonas aeruginosabecause it cannot be eradicated under certain conditions. As an opportunistic pathogen, its interaction with the host has some particularities that we will explore in this chapter.

The Pseudomonadaceaecomprise Gram-negative microorganism, nonsporulated, aerobic strict of wide distribution in the environment from the soil, water, and plants to humans; this is due to their nutritional versatility. Of this vast group, only Pseudomonas cepacia, mallei, and aeruginosainfect humans, of which aeruginosais the more relevant because it is the most frequent cause of nosocomial infections [1].

It is often said that Pseudomonas aeruginosadoes not infect healthy individuals but there are reports on the contrary, as swimmers otitis [2]. Because it is an opportunist pathogen, it does not need the host for its survival, and it may be lethal after becoming a chronic infection in susceptible patients with cystic fibrosis (CF) [3, 4, 5], cancer [6, 7, 8], hepatic cirrhosis [9], keratitis [10, 11, 12, 13], or spondylodiscitis [14]. This bacterium is most feared by pulmonologist because when acquired by nosocomial patients [15, 16], it complicates any existing conditions, and when it invades immune-compromised patients, its eradication may become impossible.

Colonization with P. aeruginosais observed in all stages of chronic obstructive pulmonary disease (COPD), but the prevalence significantly increases with disease severity from 0.7%, in stage 1 of the Global Initiative for Obstructive Lung Disease, to 1.5% for stages 2 and 3 up to 2.6% for stage 4 [17, 18]. This prevalence rises to 8–13% in acute exacerbations of COPD [19, 20, 21]. But still, the main susceptibility for the infection and death by P. aeruginosa[22, 23] are the mutations of the CF transmembrane conductance regulator (CFTR) identified as F508, G542X, G551D, W1282X, R1162X, and N1303K [24, 25]. CF also has co-morbidity such as liver cirrhosis [26] with 18% prevalence [27, 28] of P. aeruginosainfection in this subset.

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2. Host-bacteria interaction in acute infection

2.1 Lung changes upon bacterial invasion

The flagella and lipopolysaccharide (LPS) from P. aeruginosaare the first to contact the ciliated epithelial cells [29]. In the airways, these cells are covered by the surfactants containing 45% less NaCl and 600 more K+ than in plasma [30], while the alveolar epithelial cells are covered by a surfactant layer that contains mostly phosphatidylcholine (80%) [31] and surfactant proteins A, B, C, and D [32, 33] that bind LPS in a calcium-dependent manner [34]. After the surfactant layer is crossed, the flagellum binds to the epithelial cells through toll-like receptors (TLR) 2, 3, 4 and 5 [35, 36, 37, 38, 39, 40] that are quickly endocytosed to be degraded in the proteasome. The activated TLR5 induces the macrophages chemoattractants CXCL1, CXCL2, and neutrophil chemokine CCL20, which are inhibited by TLR5 inhibitors [41]. The peptides digested are then presented to macrophages and dendritic cells.

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 P. aeruginosa, facilitating macrophage-neutrophil cross-talk during the infection [52, 53].

P. aeruginosaLung
Gene IDFCNameGene IDFCName
hemE16.1aUroporphyrinogen decarboxylase4502Dioxin-inducible cytochrome P
pyrC12.1Dihydroorotase (biofilm development)252ppGpp
pyrH6.4Uridylate kinase (biofilm development)206.7Tumor necrosis factor-α-inducible DNA-binding protein A
adhA5.5Alcohol dehydrogenase133.1Proteasome subunit C
pelB, pelE5.6, 3.7Extracellular polysaccharide (competitive disruption of S. aureusbiofilms)hORC2L13.4bHuman origin recognition complex protein 2
cls7.0Cardiolipin synthaseMCP-113.3Monocyte chemotactic protein 1
pscD3.2T3SS export protein3.5c-Jun
plcN3.2Phospholipase C precursor3GTP-binding protein rhoB4.
algD,E,F,8,amrZ1.9–10.7Alginate biosynthesis2.9Urokinase-type plasminogen activator
ppiA2.5Peptidyl-prolyl cis-trans isomerasePKC2.8Protein kinase C, ETA type
hmgA−7.2Homogentisate 1–2-dioxygenase2.7Folylpolyglutamate synthetase
algC−9.3PhosphomannomutaseTTP5.7Tristetraproline
hemE16.1Uroporphyrinogen decarboxylase2.4Anti-oncogene
pyrC12.1Dihydroorotase (biofilm development)MAD35.1IκB-α
pyrH6.4Uridylate kinase (biofilm development)hENT14.2Placental equilibrative nucleoside transporter 1
adhA5.5Alcohol dehydrogenaseTEL2.8Transcription factor
pelB, pelE5.6, 3.7Extracellular polysaccharide (competitive disruption of S. aureusbiofilms)DPH2L2.6Diphtheria toxin resistance protein
cls7.0Cardiolipin synthaseTFPI22.3Tissue factor pathway inhibitor 2
2.1Ankyrin motif
ESE-12.1Epithelial-specific transcription factor
−12.58IRF
−11.9JAK-1
EPB49−2.0Erythrocyte membrane protein band 4.9. (Dematin)
−2.3Alurepeat-containing sequence

Table 1.

Genetic changes due to host-pathogen interaction quantified by microarrays of mRNA.

Change relative to P. aeruginosaacute infection/chronic contact to host cell [62].


Relative change of lung cell gene profile after 3 h contact with P. aeruginosa[43]. Data reported by Naughton [62] and Ichikawa et al. [43].


FC, fold changes; NC, no change.

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 P. aeruginosainfections, because depletion of Tregs decreases IL-10 levels and elevates IL-17A, IL-1β, and IL-6 [57, 58]. Therefore, the underlying immune suppression, by Treg accumulation, and Th17 depletion are the cause of chronic infection [57]. This may be reversed by treatment with IL7 or ethyl pyruvate increasing IL17, INFγ, and CD8+ T cells [59, 60].

Death of CF patients chronically infected with P. aeruginosaoccurs due to the depletion of neutrophils, IL6, and granulocyte-colony stimulating factor which causes dysfunctional neutrophil burst. This reduces the secretion of reactive oxygen species, which are essential for bacterial killing and clearance [61].

2.2 Bacterial metabolic changes for invasion

Simultaneously, the contact of P. aeruginosawith the lung upregulates in the bacteria genes involved mainly in biofilm synthesis [62] (Table 1). These changes in gene expression result in downregulation of proteins involved in LPS biosynthesis, antimicrobial resistance, and phenazine production concomitant with the upregulation of proteins involved in adherence, lysozyme resistance, and inhibition of the chloride ion channel, and CFTR [63]. P. aeruginosareleases choline from surfactants [81]. In vitrostudies utilizing choline, as a carbon and nitrogen source, shows that it produces accumulation of polyphosphates (polyPi), carbohydrates, and LPS accompanied by depletion of phosphate (Pi) and phospholipids (PL); deeply modifying its energetic metabolism, the bacteria save 45% of energy in polyPi [64] (Table 2).

CompositionSuccinatea + NH4ClCholinea
μg/mg of proteinμmol/mg of proteinμg/mg of proteinμmol/mg of protein%pb
Phosphate1400 ± 10014.7 ± 0.7460 ± 904.8 ± 0.7330.001
ATP1650 ± 3303.0 ± 0.61270 ± 1652.3 ± 0.3−230.32
Polyphosphates4.0 ± 1.80.042 ± 0.016.3 ± 1.40.066 ± 0.008570.004
Carbohydratesc210 ± 401.2 ± 0.2330 ± 501.8 ± 0.2500.03
LPSd19 ± 40.08 ± 0.0241 ± 90.16 ± 0.031000.02
Phospholipidse114 ± 70.65 ± 0.0471 ± 40.1 ± 0.02−85
Biosynthetic energy (ATP)f167592445

Table 2.

Metabolic changes in the bacteria upon infection.

Bacteria were grown in a high phosphate basal salt medium. All chemical determinations were done on 1.05 ± 0.16 and 1.00 ± 0.20 mg ml −1 of culture from whole bacteria grown with 20 mM succinate plus 18.7 mM NH4C1 or 20 mM choline chloride, respectively. Results are the average of four independent experiments ± SD.


Values obtained by ANOVA analysis.


Total carbohydrates were measured by the phenol method.


Measured as the content of KDO according to the determination of formylpyruvic with thiobarbituric acid.


Total phospholipids from bacteria grown with succinate/NH4Cl or choline.


Value obtained by calculation of the biosynthetic cost of LPS 470 μmol ATP/gr of cells, 1 μmol ATP/g polyphosphate, 470 μmol ATP/g of glycoside, and 2578 μmol ATP/g of phospholipids. Table taken from Grumelli [64].


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 in vivo[79].

Figure 1.

LPS formula and structure set forth in PubChem (CID 11970143); and its parts KDO, (CID 49792052); and Lipid A (CID 9877306).

Figure 2.

The metabolic fork that derives glucose-6 phosphate (G6P) from biosynthesis of LPS to alginate. Tridimensional structure of phosphomannomutase; red and blue represent oppositely charged regions.

2.3 Interaction between lung and bacteria

The host-pathogen interaction studied in vivoutilizing LPS in the lung of mice exposed to cigarette smoke model exacerbations of COPD in patients chronically infected with P. aeruginosa. Figure 3 proposes that this extracellular pathogen releases to the medium phospholipase C (PLC) [80] and phosphoryl-choline phosphatase (PChP) [81] within vesicles [82]. These vesicles degrade the surfactant, from phosphatidylcholine [85] to phosphoryl-choline and diacylglycerol (DAG) [83], causing Ca2+ mediated vaso-constriction [84]. Choline and phosphate (Pi) released by PChP produce airway constriction and inflammation in the lung tissue.

Figure 3.

(A) Representative scheme of the host-pathogen interaction in mice lung during exacerbations of COPD. As an extracellular pathogen,P. aeruginosareleases to the medium phospholipase C (PLC) and phosphorylcholine phosphatase (PChP) within vesicles that degrades the membranes and surfactant of lung epithelial cells from phosphatidylcholine to phosphorylcholine and diacylglycerol (DAG) that cause Ca2+ mediated vaso-constriction. Choline and Pi released by PChP produces airway constriction in the lung tissue, and LPS and PolyPi accumulation inP. aeruginosa. (B) Representative experiment of inflammatory cells present in BAL of naïve mice (n = 5), mice treated with of LPS (n = 4), smoke exposed (n = 8) and smoke plus 100 ng/weekly of LPS (n = 3) fromP. aeruginosa. *P = 0.01 relative to naïve mice, **P = 0.04 relative to naïve mice, ***P = 0.01 relative to smoke exposed, §P = 0.01 relative to naïve mice, †P = 0.05 relative to smoke exposed, ∫P = 0.05 relative to naïve mice, and ‡P = 0.01 relative to smoke exposed. The figure is taken from Grumelli et al. [64].

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 P. aeruginosais capable of releasing choline and converting it to betaine and then to glycine (Figure 4B) [88, 89, 90, 91], for osmoprotection [92, 93] from the hyperosmolarity in the CF lung. Glycine also triggers chloride influx, inhibiting the Ca2+ mobilized by LPS [94]. This is a mechanism of self-preservation because macrophages are activated by LPS but suppressed by free glycine [95].

Figure 4.

(A) Lung alterations due to host-pathogen interaction upon infection. Gluc, glucose; Asc, ascorbate; GPC, glycerophosphocholine; Gly, glycine; Succ, succinate; bHB, beta-hydroxybutyrate; Val, valine; Leu/iso, leucine/isoleucine; Lac, lactate; and Gsh, glutathione reduced; figure taken from [85] and (B) choline conversion byP. aeruginosa.

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]. In vitrosuccinate is the favorite carbon source for P. aeruginosa. Its consumption reduces the length of the LPS (Table 3), increasing the PL and Pi content and preventing the polyPi accumulation (Table 2), which is essential to the stress response [64]. The LPS and PL biosynthesis has a common metabolite, the R-3-hydroxyacyl-ACP that is the substrate for R-3-hydroxyacyl-ACP dehydrase (FabZ) [98], to synthesize PL, and for LpxA, for LPS synthesis. Thus, the increased content of PL is at the expense of Lipid A from LPS (Figure 5), as shown in Table 2.

CompositionSuccinatea + NH4
(μmol/μmol KDO)
Cholinea
(μmol/μmol KDO)
%p
LPSb
Total Pi27 ± 533 ± 822NS
Carbohydratesc0.09 ± 0.010.15 ± 0.0267≤0.05
Lipid A
Palmitic ac.d34 ± 239 ± 515NSe
12 carbon-hydroxyl ac.32 ± 1445 ± 2041NS

Table 3.

Variation in LPS composition according to the lung environmental changes.

Bacteria were grown in a high phosphate basal salt medium with 20 mM succinate plus 18.7 mM NH4C1 or 20 mM choline chloride. All chemical determinations were carried out on LPS isolated with Triton X-100 from whole bacteria harvested at absorbance at 660 nm of 0.7. Total cellular contents were 1.05 + 0.16 and 1.00 + 0.20 mg/ml for succinate and choline, respectively. Results are the average of four independent experiments ± SD. P values were obtained by ANOVA analysis.


KDO quantified.


Carbohydrates quantified by the phenol method.


Lipids were hydrolyzed from lipid A, identified by mass spectrometry. Results are expressed relative to stearic acid and averaged of three independent experiments ± SD.


No significative. Data taken from Grumelli [64].


Figure 5.

R-3-hydroxyacyl-ACP, metabolite common to the biosynthesis of LPS and PL for whichR-3-hydroxyacyl-ACP dehydrase (FabZ) and LpxA compete [98].

The LPS of P. aeruginosastimulates the O2 uptake from mitochondria [97] producing decoupling of the oxidative phosphorylation, reducing the respiratory rate, which generates stress in the host lung triggering exacerbations [44, 64, 97]. Therefore, succinate accumulation signifies that choline consumption is increasing the adaptation of the bacteria to the lung environment and the transition to the RSVC form, for chronic infection.

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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 P. aeruginosasurvival [100]. In the lung, iron deficiency turns on AlgQ, the bacterial biofilm production gene, also known as AlgR2 [101, 102], under the Pfr A regulation that assists to the formation of two kinds of cytoplasmic aggregates: large vacuole-like bodies and smaller granules containing iron in association with oxygen or phosphate, very likely polyPi [103]. This leads to the RSCV type of P. aeruginosa.Under these conditions, the bacteria secrete alginate, a linear polysaccharide of d-mannuronic acid linked to l-guluronic acid [104].

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, P. aeruginosautilizes nitrate or arginine as electron acceptors, via the succinylarginine pathway [106, 107]. The AlgD expression is tightly regulated by several environmental sources including nitrogen, O2, Pi, NaCl, etc. Although the regulation of AlgD has been extensively studied, it is not completely understood, and eradication of chronic infection greatly depends on control of alginate production.

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].

Figure 6.

Regulators of AlgD in alginate production. Negative and positive regulators found up-today.

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.

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4. Conclusions

P. aeruginosais a relevant pathogen given its widespread prevalence across different organs. The latent menace it poses for inpatients is a liability for institutions. For this, and the negative prognosis that P. aeruginosainfections in CF patients has, it is one of the subjects more researched for the last 40 years. The efforts have resulted in understanding the process of invasion, immune response, and bacterial tactics to achieve chronic infection. The complexity of the metabolic changes caused by the contact between the host and the bacteria is so extensive that the selection of variables for in vitro studies is difficult since the production of biofilm by P. aeruginosaseems to be regulated by everything, O2, N2, Fe2+, Pi, and NaCl. This multiregulatory network is still a puzzle to be resolved.

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 in vivo.

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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 P. aeruginosainfections. For example, mass-spectrometry has verified through metabolite detection the metabolic pathways studied by molecular biologists and enzymologists. The integration of these studies with the physicians is needed to assess the areas that show more promises to control alginate production and P. aeruginosaeradication after it became a chronic infection.

References

  1. 1. Dean HF, Royle P, Morgan AF. Detection of FP plasmids in hospital isolates ofPseudomonas aeruginosa. Journal of Bacteriology. 1979;138(1):249-250
  2. 2. Hoadley AW, Knight DE. External otitis among swimmers and nonswimmers. Archives of Environmental Health. 1975;30(9):445-448
  3. 3. Crull MR, Ramos KJ, Caldwell E, Mayer-Hamblett N, Aitken ML, Goss CH. Change inPseudomonas aeruginosaprevalence in cystic fibrosis adults over time. BMC Pulmonary Medicine. 2016;16(1):176
  4. 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. 5. Knudsen PK, Olesen HV, Høiby N, Johannesson M, Karpati F, Laerum BN, et al. Differences in prevalence and treatment ofPseudomonas aeruginosain 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. 6. Varaiya A, Kulkarni M, Bhalekar P, Dogra J. Incidence of metallo-beta-lactamase-producingPseudomonas aeruginosain diabetes and cancer patients. Indian Journal of Pathology and Microbiology. 2008;51(2):200-203
  7. 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. 8. Rolston KV, Bodey GP.Pseudomonas aeruginosainfection in cancer patients. Cancer Investigation. 1992;10(1):43-59
  9. 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. 10. Ormerod LD, Smith RE. Contact lens-associated microbial keratitis. Archives of Ophthalmology. 1986;104(1):79-83
  11. 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. 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. 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. 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. 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. 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. 17. Engler K, Mühlemann K, Garzoni C, Pfahler H, Geiser T, von Garnier C. Colonisation withPseudomonas aeruginosaand antibiotic resistance patterns in COPD patients. Swiss Medical Weekly. 2012;142:w13509. DOI: 10.4414/smw.2012.13509. eCollection 2012
  18. 18. Gallego M, Pomares X, Espasa M, Castañer E, Solé M, Suárez D, et al.Pseudomonas aeruginosaisolates in severe chronic obstructive pulmonary disease: Characterization and risk factors. BMC Pulmonary Medicine. 2014;14:103. DOI: 10.1186/1471-2466-14-103
  19. 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. 20. Huerta A, Soler N, Esperatti M, Guerrero M, Menendez R, Gimeno A, et al. Importance ofAspergillusspp. 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. 21. Planquette B, Péron J, Dubuisson E, Roujansky A, Laurent V, Le Monnier A, et al. Antibiotics againstPseudomonas aeruginosafor 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. 22. Emerson J, Rosenfeld M, McNamara S, Ramsey B, Gibson RL.Pseudomonas aeruginosaand other predictors of mortality and morbidity in young children with cystic fibrosis. Pediatric Pulmonology. 2002;34:91-100. DOI: 10.1002/ppul.10127
  23. 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. 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. 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. 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. 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. 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. 29. Widdicombe J. In: Stockley RA, editor. Pulmonary Defences. Chichester: Wiley; 1997. pp. 1-15
  30. 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. 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. 32. Bufler P, Schmidt B, Schikor D, Bauernfeind A, Crouch EC, Griese M. Surfactant protein A and D differently regulate the immune response to nonmucoidPseudomonas aeruginosaand its lipopolysaccharide. American Journal of Respiratory Cell and Molecular Biology. 2003;28(2):249-256
  33. 33. Perez-Gil J, Weaver TE. Pulmonary surfactant pathophysiology: Current models and open questions. Cytokine stimulation byPseudomonas aeruginosa—Strain variation and modulation by pulmonary surfactant. Physiology. 2010;25:132-141
  34. 34. Hickling TP, Sim RB, Malhotra R. Induction of TNF-alpha release from human buffy coat cells byPseudomonas aeruginosais reduced by lung surfactant protein A. FEBS Letters. 1998;437(1-2):65-69
  35. 35. Adamo R, Sokol S, Soong G, Gomez M, Prince A.P. aeruginosaflagella 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. 36. Zhang Z, Louboutin JP, Weiner DJ, Goldberg JB, Wilson JM. Human airway epithelial cells sensePseudomonas aeruginosainfection via recognition of flagellin by Toll-like receptor 5. Infection and Immunity. 2005;73:7151-7160
  37. 37. Ramphal R, Balloy V, Huerre M, Si-Tahar M, Chignard M. TLRs 2 and 4 are not involved in hypersusceptibility to acutePseudomonas aeruginosalung infections. Journal of Immunology. 2005;175:3927-3934
  38. 38. Power MR, Peng Y, Maydanski E, Marshall JS, Lin TJ. The development of early host response toPseudomonas aeruginosalung infection is critically dependent on myeloid differentiation factor 88 in mice. The Journal of Biological Chemistry. 2004;279:49315-49322
  39. 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. 40. Epelman S, Stack D, Bell C, Wong E, Neely GG, Krutzik S, et al. Different domains ofPseudomonas aeruginosaexoenzyme S activate distinct TLRs. Journal of Immunology. 2004;173:2031-2040
  41. 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. 42. Schroeder TH, Lee MM, Yacono PW, Cannon CL, Gerçeker AA, Golan DE, et al. CFTR is a pattern recognition molecule that extractsPseudomonas aeruginosaLPS 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. 43. Ichikawa JK, Norris A, Bangera MG, Geiss GK, van ’t Wout AB, Bumgarner RE, et al. Interaction ofPseudomonas aeruginosawith 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. 44. Reiniger N, Ichikawa JK, Pier GB. Influence of cystic fibrosis transmembrane conductance regulator on gene expression in response toPseudomonas aeruginosainfection of human bronchial epithelial cells. Infection and Immunity. 2005;73(10):6822-6830
  45. 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 withPseudomonas aeruginosa. American Journal of Physiology. Lung Cellular and Molecular Physiology. 2005;288(3):L471-L479
  46. 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. 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 acutePseudomonas aeruginosalung infection. Infection and Immunity. 2012;80(1):100-109. DOI: 10.1128/IAI.05695-11. Epub 2011 Oct 24
  48. 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. 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. 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 toMycobacterium tuberculosis. The Journal of Experimental Medicine. 2003;198:987-997
  51. 51. Skerrett SJ, Liggitt HD, Hajjar AM, Wilson CB. Cutting edge: Myeloid differentiation factor 88 is essential for pulmonary host defense againstPseudomonas aeruginosabut notStaphylococcus aureus. Journal of Immunology. 2004;172:3377-3381
  52. 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 inPseudomonas aeruginosapneumonia. FASEB Journal. 2018:fj201802002R. DOI: 10.1096/fj.201802002R
  53. 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 withPseudomonas aeruginosalung infection. The Journal of Nutrition. 2009;139(1):82-89. DOI: 10.3945/jn.108.096115. Epub 2008 Dec 3
  54. 54. Bayes HK, Ritchie ND, Evans TJ. Interleukin-17 is required for control of chronic lung infection caused byPseudomonas aeruginosa. Infection and Immunity. 2016;84(12):3507-3516
  55. 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 chronicPseudomonas aeruginosalung infections. International Journal of Molecular Medicine. 2018;41(4):2193-2200. DOI: 10.3892/ijmm.2018.3417. Epub 2018 Jan 23
  56. 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 pulmonaryPseudomonas aeruginosainfection in mice. Frontiers in Cellular and Infection Microbiology. 2016;6:170. DOI: 10.3389/fcimb.2016.00170. eCollection 2016
  57. 57. Li JL, Chen TS, Yuan CC, Zhao GQ , Xu M, Li XY, et al. Regulatory T cell activity in immunosuppresive mice model ofPseudomonas 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. 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 acutePseudomonas aeruginosainfection after sepsis. Inflammation. 2018;41(5):1780-1790. DOI: 10.1007/s10753-018-0821-8
  59. 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 ofPseudomonas aeruginosapneumonia. Journal of Leukocyte Biology. 2017;101(2):543-554. DOI: 10.1189/jlb.4A1215-581R. Epub 2016 Sep 14
  60. 60. Chen W, Lian J, Ye JJ, Mo QF, Qin J, Hong GL, et al. Ethyl pyruvate reverses development ofPseudomonas aeruginosapneumonia during sepsis-induced immunosuppression. International Immunopharmacology. 2017;52:61-69. DOI: 10.1016/j.intimp.2017.08.024. Epub 2017 Aug 31
  61. 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. 62. Naughton S, Parker D, Seemann T, Thomas T, Turnbull L, Rose B, et al.Pseudomonas aeruginosaAES-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. 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-adaptedPseudomonas aeruginosa. Nature Communications. 2018;9(1):2635. DOI: 10.1038/s41467-018-04996-x
  64. 64. Grumelli S. Choline triggers exacerbations of chronic obstructive pulmonary disease in patients infected withPseudomonas aeruginosa. Current Respiratory Medicine Reviews. 2016;12(2):167-174. DOI: 10.2174/1573398X12999160506104327
  65. 65. Déziel E, Comeau Y, Villemur R. Initiation of biofilm formation byPseudomonas aeruginosa57RP 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. 66. Drenkard E, Ausubel FM. Pseudomonas biofilm formation and antibiotic resistance are linked to phenotypic variation. Nature. 2002;416:740-743
  67. 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 ofPseudomonas aeruginosaisolated from a lung of a patient with cystic fibrosis. Journal of Bacteriology. 2004;186(12):3837-3847
  68. 68. Pu M, Sheng L, Song S, Gong T, Wood TK. Serine hydroxymethyltransferase ShrA (PA2444) controls rugose small-colony variant formation inPseudomonas aeruginosa. Frontiers in Microbiology. 2018;9:315. DOI: 10.3389/fmicb.2018.00315. eCollection 2018
  69. 69. Rao NN, Liu S, Kornberg A. Inorganic polyphosphate inEscherichia coli: The phosphate regulon and the stringent response. Journal of Bacteriology. 1998;180(8):2186-2193
  70. 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 inPseudomonas aeruginosa. PLoS Pathogens. 2010;6(3):e1000804. DOI: 10.1371/journal.ppat.1000804
  71. 71. Evans TJ. Small colony variants ofPseudomonas aeruginosain chronic bacterial infection of the lung in cystic fibrosis. Future Microbiology. 2015;10(2):231-239. DOI: 10.2217/fmb.14.107
  72. 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 persistentPseudomonas aeruginosain cystic fibrosis airways. PLOS Pathogens. 2012;8(6):e1002760. DOI: 10.1371/journal.ppat.1002760. Epub 2012 Jun 14
  73. 73. Grumelli SM. Bioenergetics of phosphate incorporation and polyphosphate accumulation by choline in Pseudomonas aeruginosa [doctoral thesis]. 2000. Ejemplares 59118
  74. 74. Lim WS, Phang KK, Tan AH, Li SF, Ow DS. Small colony variants and single nucleotide variations in Pf1 region of PB1 phage-resistantPseudomonas aeruginosa. Frontiers in Microbiology. 2016;7:282. DOI: 10.3389/fmicb.2016.00282. eCollection 2016
  75. 75. Nikel PI, Chavarría M, Martínez-García E, Taylor AC, de Lorenzo V. Accumulation of inorganic polyphosphate enables stress endurance and catalytic vigour inPseudomonas putidaKT2440. Microbial Cell Factories. 2013;12:50. DOI: 10.1186/1475-2859-12-50
  76. 76. Landry RM, An D, Hupp JT, Singh PK, Parsek MR. Mucin-Pseudomonas aeruginosainteractions promote biofilm formation and antibiotic resistance. Molecular Microbiology. 2006;59(1):142-151
  77. 77. Zdorovenko EL, Zatonskii GV, Kocharova NA, Shashkov AS, Knirel YA, Ovod VV. Structure of the O polysaccharides and serological classification ofPseudomonas syringaepv.porrifrom genomospecies 4. European Journal of Biochemistry. 2003;270(1):20-27
  78. 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 inPseudomonas aeruginosaimmunotype 5 using strong alkaline degradation of the lipopolysaccharide. Biochemistry (Mosc). 2003;68(8):918-925
  79. 79. Olvera C, Goldberg JB, Sánchez R, Soberón-Chávez G. ThePseudomonas aeruginosaalgC gene product participates in rhamnolipid biosynthesis. FEMS Microbiology Letters. 1999;179(1):85-90
  80. 80. Wargo MJ, Gross MJ, Rajamani S, et al. Hemolytic phospholipase c inhibition protects lung function duringPseudomonas aeruginosa. American Journal of Respiratory and Critical Care Medicine. 2011;184:345-354
  81. 81. Salvano MA, Domenech CE. Kinetic properties of purifiedPseudomonas aeruginosaphosphorylcholine phosphatase indicated that this enzyme may be utilized by the bacteria to colonize in different environments. Current Microbiology. 1999;39:1-8
  82. 82. Kadurugamuwa JL, Beveridge TJ. Virulence factors are released fromPseudomonas aeruginosain 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. 83. Fuchs B, Rupp M, Ghofrani HA, et al. Diacylglycerol regulates acute hypoxic pulmonary vasoconstriction via TRPC6. Respiratory Research. 2011;12:20
  84. 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. 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 withP. aeruginosaconsistent 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. 86. Salvano MA, Lisa TA, Domenech CE. Choline transport inPseudomonas aeruginosa. Molecular and Cellular Biochemistry. 1989;85:81-89
  87. 87. Malek AA, Chen C, Wargo MJ, Beattie GA, Hogan DA. Roles of three transporters, CbcXWV, BetT1, and BetT3, inPseudomonas aeruginosacholine uptake for catabolism. Journal of Bacteriology. 2011;193(12):3033-3041
  88. 88. Sage AE, Vasil AI, Vasil ML. Molecular characterization of mutants affected in the osmoprotectant-dependent induction of phospholipase C inPseudomonas aeruginosaPAO1. Molecular Microbiology. 1997;23(1):43-56
  89. 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 inPseudomonas aeruginosaPAO1 under low and elevated salinities. Microbiology. 2006;152(Pt 5):1395-1406
  90. 90. Wargo MJ, Szwergold BS, Hogan DA. Identification of two gene clusters and a transcriptional regulator required forPseudomonas aeruginosaglycine betaine catabolism. Journal of Bacteriology. 2008;190(8):2690-2699. Epub 2007 Oct 19
  91. 91. Wargo MJ. Choline catabolism to glycine betaine contributes toPseudomonas aeruginosasurvival during murine lung infection. PLoS One. 2013;8(2):e56850. DOI: 10.1371/journal.pone.0056850. Epub 2013 Feb 14
  92. 92. Le Rudulier D, Strøm AR, Dandekar AM, Smith LT, Valentine RC. Molecular biology of osmoregulation. Science. 1984;224:1064-1068
  93. 93. Lisa TA, Garrido MN, Domenech CE. Induction of acid phosphatase and cholinesterase activities inPs. aeruginosaand their in-vitro control by choline, acetylcholine and betaine. Molecular and Cellular Biochemistry. 1983;50:149-155
  94. 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. 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. 96. Pavliakova D, Chu C, Bystricky S, et al. Treatment with succinic anhydride improves the immunogenicity ofShigella flexneritype 2a O-specific polysaccharide-protein conjugates in mice. Infection and Immunity. 1999;67(10):5526-5529
  97. 97. Greer GG, Milazzo FH.Pseudomonas aeruginosalipopolysaccharide: An uncoupler of mitochondrial oxidative phosphorylation. Canadian Journal of Microbiology. 1975;21(6):877-883
  98. 98. Joo SH, Chung HS, Raetz CR, Garrett TA. Activity and crystal structure ofArabidopsis thalianaUDP-N-acetylglucosamine acyltransferase. Biochemistry. 2012;51(21):4322-4330. DOI: 10.1021/bi3002242. Epub 2012 May 14
  99. 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. 100. Litwin CM, Calderwood SB. Role of iron in regulation of virulence genes. Clinical Microbiology Reviews. 1993;6:137-149
  101. 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. 102. Venturi V, Ottevanger C, Leong J, Weisbeek PJ. Identification and characterization of a siderophore regulatory gene (pfrA) ofPseudomonas putidaWCS358: Homology to the alginate regulatory gene algQ ofPseudomonas aeruginosa. Molecular Microbiology. 1993;10(1):63-73
  103. 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 fromHelicobacter pylori. Microbiology. 1998;144(Pt 9):2505-2516
  104. 104. Linker A, Jones RS. A new polysaccharide resembling alginic acid isolated from pseudomonads. Journal of Biological Chemistry. 1966;241:3845-3851
  105. 105. Deretic V, Gill JF, Chakrabarty AM. Gene algD coding for GDPmannose dehydrogenase is transcriptionally activated in mucoidPseudomonas aeruginosa. Journal of Bacteriology. 1987;169(1):351-358
  106. 106. Cunin R, Glansdorff N, Pierard A, Stalon V. Biosynthesis and metabolism of arginine in bacteria. Microbiological Review. 1986;50:314-352
  107. 107. Park SM, Lu CD, Abdelal AT. Cloning and characterization of argR, a gene that participates in regulation of arginine biosynthesis and catabolism inPseudomonas aeruginosaPAO1. Journal of Bacteriology. 1997;179(17):5300-5308
  108. 108. Deretic V, Govan JR, Konyecsni WM, Martin DW. MucoidPseudomonas aeruginosain 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. 109. Wang Y, Hay ID, Rehman ZU, Rehm BH. Membrane-anchored MucR mediates nitrate-dependent regulation of alginate production inPseudomonas aeruginosa. Applied Microbiology and Biotechnology. 2015;99(17):7253-7265. DOI: 10.1007/s00253-015-6591-4. Epub 2015 Apr 29
  110. 110. Savioz A, Zimmermann A, Haas D.Pseudomonas aeruginosapromoters 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. 111. Yin Y, Withers TR, Wang X, Yu HD. Evidence for sigma factor competition in the regulation of alginate production byPseudomonas aeruginosa. PLoS One. 2013;8(8):e72329. DOI: 10.1371/journal.pone.0072329. eCollection 2013
  112. 112. Al Ahmar R, Kirby BD, Yu HD. Pyrimidine biosynthesis regulates small colony variant and mucoidy inPseudomonas aeruginosathrough sigma factor competition. Journal of Bacteriology. 2018. pii: JB.00575-18. DOI: 10.1128/JB.00575-18
  113. 113. Ammons CM, Ward LS, Fisher ST, Wolcott RD, James GA. In vitro susceptibility of established biofilms composed of a clinical wound isolate ofPseudomonas aeruginosatreated with lactoferrin and xylitol. International Journal of Antimicrobial Agents. 2009;33(3):230-236

Written By

Sandra Grumelli

Submitted: September 11th, 2018 Reviewed: January 23rd, 2019 Published: August 16th, 2019