scholarly journals Syndecan 1 Shedding Contributes to Pseudomonas aeruginosa Sepsis

2005 ◽  
Vol 73 (12) ◽  
pp. 7914-7921 ◽  
Author(s):  
Allan Haynes ◽  
Frank Ruda ◽  
Jeffrey Oliver ◽  
Abdul N. Hamood ◽  
John A. Griswold ◽  
...  
Keyword(s):  
Pseudomonas Aeruginosa ◽  
Thermal Injury ◽  
Opportunistic Pathogen ◽  
Multiple Organ ◽  
Innate Immune ◽  
Host Cells ◽  
Ectodomain Shedding ◽  
Systemic Spread ◽  
Immunocompromised State ◽  
First Time

ABSTRACT The innate immune system is comprised of many components that function coordinately to prevent bacterial sepsis. However, thermal injury suppresses many of these factors, and the opportunistic pathogen Pseudomonas aeruginosa takes advantage of this condition, making it one of the leading causes of morbidity and mortality in the setting of thermal injury. P. aeruginosa is extremely efficient at colonizing burn wounds, spreading systemically, and causing sepsis, which often results in a systemic inflammatory response, multiple-organ failure, and death. The pathogenicity of P. aeruginosa is due to the arsenal of virulence factors produced by the pathogen and the immunocompromised state of the host. Syndecan 1 is a major heparan sulfate proteoglycan present on many host cells involved in thermal injury. Syndecan 1 anchored to the cell surface can be cleaved in a process termed ectodomain shedding. Syndecan 1 shedding results in the release of intact, soluble proteoglycan ectodomains that have diverse roles in innate immunity. Here we show for the first time that thermal injury results in shedding of syndecan 1 from host tissue. Our data show that syndecan 1 null mice are significantly less susceptible to P. aeruginosa infection than their wild-type counterparts, as demonstrated by (i) significantly lower mortality; (ii) absence of systemic spread of P. aeruginosa; and (iii) significant reductions in some proinflammatory cytokines. These results suggest that shed syndecan 1 plays an important role in the pathogenesis of P. aeruginosa infection of thermal injury and that syndecan 1-neutralizing agents may be effective supplements to current P. aeruginosa treatments.

scholarly journals PrtR Homeostasis Contributes to Pseudomonas aeruginosa Pathogenesis and Resistance against Ciprofloxacin

2014 ◽  
Vol 82 (4) ◽  
pp. 1638-1647 ◽  
Author(s):  
Ziyu Sun ◽  
Jing Shi ◽  
Chang Liu ◽  
Yongxin Jin ◽  
Kewei Li ◽  
...  
Keyword(s):  
Gene Expression ◽  
Pseudomonas Aeruginosa ◽  
Bacterial Colonization ◽  
Mrna Level ◽  
Sos Response ◽  
Opportunistic Pathogen ◽  
Host Cells ◽  
Chronic Infections ◽  
Mobility Shift ◽  
Content Type

ABSTRACTPseudomonas aeruginosais an opportunistic pathogen that causes acute and chronic infections in humans. Pyocins are bacteriocins produced byP. aeruginosathat are usually released through lysis of the producer strains. Expression of pyocin genes is negatively regulated by PrtR, which gets cleaved under SOS response, leading to upregulation of pyocin synthetic genes. Previously, we demonstrated that PrtR is required for the expression of type III secretion system (T3SS), which is an important virulence component ofP. aeruginosa. In this study, we demonstrate that mutation inprtRresults in reduced bacterial colonization in a mouse acute pneumonia model. Examination of bacterial and host cells in the bronchoalveolar lavage fluids from infected mice revealed that expression of PrtR is induced by reactive oxygen species (ROS) released by neutrophils. We further demonstrate that treatment with hydrogen peroxide or ciprofloxacin, known to induce the SOS response and pyocin production, resulted in an elevated PrtR mRNA level. Overexpression of PrtR by atacpromoter repressed the endogenousprtRpromoter activity, and electrophoretic mobility shift assay revealed that PrtR binds to its own promoter, suggesting an autorepressive mechanism of regulation. A high level of PrtR expressed from a plasmid resulted in increased T3SS gene expression during infection and higher resistance against ciprofloxacin. Overall, our results suggest that the autorepression of PrtR contributes to the maintenance of a relatively stable level of PrtR, which is permissive to T3SS gene expression in the presence of ROS while increasing bacterial tolerance to stresses, such as ciprofloxacin, by limiting pyocin production.

Significant differences in type IV pilin allele distribution among Pseudomonas aeruginosa isolates from cystic fibrosis (CF) versus non-CF patients

Microbiology ◽  
2004 ◽  
Vol 150 (5) ◽  
pp. 1315-1326 ◽  
Author(s):  
Julianne V. Kus ◽  
Elizabeth Tullis ◽  
Dennis G. Cvitkovitch ◽  
Lori L. Burrows
Keyword(s):  
Cystic Fibrosis ◽  
Pseudomonas Aeruginosa ◽  
Opportunistic Pathogen ◽  
Host Cells ◽  
Phylogenetic Groups ◽  
Allele Distribution ◽  
Specific Pcr ◽  
Type Iv ◽  
Accessory Genes ◽  
Group I

Type IV pili (TFP) are important colonization factors of the opportunistic pathogen Pseudomonas aeruginosa, involved in biofilm formation and attachment to host cells. This study undertook a comprehensive analysis of TFP alleles in more than 290 environmental, clinical, rectal and cystic fibrosis (CF) isolates of P. aeruginosa. Based on the results, a new system of nomenclature is proposed, in which P. aeruginosa TFP are divided into five distinct phylogenetic groups. Each pilin allele is stringently associated with characteristic, distinct accessory genes that allow the identification of the allele by specific PCR. The invariant association of the pilin and accessory genes implies horizontal transfer of the entire locus. Analysis of pilin allele distribution among isolates from various sources revealed a striking bias in the prevalence of isolates with group I pilin genes from CF compared with non-CF human sources (P<0·0001), suggesting this particular pilin type, which can be post-translationally modified by glycosylation via the action of TfpO (PilO), may confer a colonization or persistence advantage in the CF host. This allele was also predominant in paediatric CF isolates (29 of 43; 67·4 %), showing that this bias is apparent early in colonization. Group I pilins were also the most common type found in environmental isolates tested. To the authors' knowledge, this is the first example of a P. aeruginosa virulence factor allele that is strongly associated with CF isolates.

scholarly journals A new regulator of pathogenicity (bvlR) is required for full virulence and tight microcolony formation in Pseudomonas aeruginosa

Microbiology ◽  
2014 ◽  
Vol 160 (7) ◽  
pp. 1488-1500 ◽  
Author(s):  
Ronan R. McCarthy ◽  
Marlies J. Mooij ◽  
F. Jerry Reen ◽  
Olivier Lesouhaitier ◽  
Fergal O’Gara
Keyword(s):  
Pseudomonas Aeruginosa ◽  
Transcriptional Repression ◽  
Transcriptional Regulators ◽  
Opportunistic Pathogen ◽  
Host Cells ◽  
Cell Contact ◽  
Virulence Determinants ◽  
Surface Attachment ◽  
Global Regulators ◽  
Virulence Regulator

LysR-type transcriptional regulators (LTTRs) are the most common family of transcriptional regulators found in the opportunistic pathogen Pseudomonas aeruginosa. They are known to regulate a wide variety of virulence determinants and have emerged recently as positive global regulators of pathogenicity in a broad spectrum of important bacterial pathogens. However, in spite of their key role in modulating expression of key virulence determinants underpinning pathogenic traits associated with the process of infection, surprisingly few are found to be transcriptionally altered by contact with host cells. BvlR (PA14_26880) an LTTR of previously unknown function, has been shown to be induced in response to host cell contact, and was therefore investigated for its potential role in virulence. BvlR expression was found to play a pivotal role in the regulation of acute virulence determinants such as type III secretion system and exotoxin A production. BvlR also played a key role in P. aeruginosa pathogenicity within the Caenorhabditis elegans acute model of infection. Loss of BvlR led to an inability to form tight microcolonies, a key step in biofilm formation in the cystic fibrosis lung, although surface attachment was increased. Unusually for LTTRs, BvlR was shown to exert its influence through the transcriptional repression of many genes, including the virulence-associated cupA and alg genes. This highlights the importance of BvlR as a new virulence regulator in P. aeruginosa with a central role in modulating key events in the pathogen–host interactome.

scholarly journals Exoenzyme Y Contributes to End-Organ Dysfunction Caused by Pseudomonas aeruginosa Pneumonia in Critically Ill Patients: An Exploratory Study

Toxins ◽  
2020 ◽  
Vol 12 (6) ◽  
pp. 369
Author(s):  
Brant M. Wagener ◽  
Naseem Anjum ◽  
Sarah C. Christiaans ◽  
Morgan E. Banks ◽  
Jordan C. Parker ◽  
...  
Keyword(s):  
Pseudomonas Aeruginosa ◽  
Organ Dysfunction ◽  
Virulence Factors ◽  
Opportunistic Pathogen ◽  
Lavage Fluid ◽  
Host Cells ◽  
Clinical Isolates ◽  
Icu Patients ◽  
Edema Factor ◽  
Host Infection

Pseudomonas aeruginosa is an opportunistic pathogen that causes pneumonia in immunocompromised and intensive care unit (ICU) patients. During host infection, P. aeruginosa upregulates the type III secretion system (T3SS), which is used to intoxicate host cells with exoenzyme (Exo) virulence factors. Of the four known Exo virulence factors (U, S, T and Y), ExoU has been shown in prior studies to associate with high mortality rates. Preclinical studies have shown that ExoY is an important edema factor in lung infection caused by P. aeruginosa, although its importance in clinical isolates of P. aeruginosa is unknown. We hypothesized that expression of ExoY would be highly prevalent in clinical isolates and would significantly contribute to patient morbidity secondary to P. aeruginosa pneumonia. A single-center, prospective observational study was conducted at the University of Alabama at Birmingham Hospital. Mechanically ventilated ICU patients with a bronchoalveolar lavage fluid culture positive for P. aeruginosa were included. Enrolled patients were followed from ICU admission to discharge and clinical P. aeruginosa isolates were genotyped for the presence of exoenzyme genes. Ninety-nine patients were enrolled in the study. ExoY was present in 93% of P. aeruginosa clinical isolates. Moreover, ExoY alone (ExoY+/ExoU−) was present in 75% of P. aeruginosa isolates, compared to 2% ExoU alone (ExoY−/ExoU+). We found that bacteria isolated from human samples expressed active ExoY and ExoU, and the presence of ExoY in clinical isolates was associated with end-organ dysfunction. This is the first study we are aware of that demonstrates that ExoY is important in clinical outcomes secondary to nosocomial pneumonia.

scholarly journals Heterologous Expression, Purification, and Characterization of an l-Ornithine N5-Hydroxylase Involved in Pyoverdine Siderophore Biosynthesis in Pseudomonas aeruginosa

2006 ◽  
Vol 188 (20) ◽  
pp. 7205-7210 ◽  
Author(s):  
Li Ge ◽  
Stephen Y. K. Seah
Keyword(s):  
Pseudomonas Aeruginosa ◽  
Dissociation Constants ◽  
Opportunistic Pathogen ◽  
Maximum Activity ◽  
Flavin Mononucleotide ◽  
Steady State Kinetic ◽  
Tightly Coupled ◽  
Essential Nutrient ◽  
Nadph Oxidation ◽  
First Time

ABSTRACT Pseudomonas aeruginosa is an opportunistic pathogen that produces the siderophore pyoverdine, which enables it to acquire the essential nutrient iron from its host. Formation of the iron-chelating hydroxamate functional group in pyoverdine requires the enzyme PvdA, a flavin-dependent monooxygenase that catalyzes the N 5 hydroxylation of l-ornithine. pvdA from P. aeruginosa was successfully overexpressed in Escherichia coli, and the enzyme was purified for the first time. The enzyme possessed its maximum activity at pH 8.0. In the absence of l-ornithine, PvdA has an NADPH oxidase activity of 0.24 ± 0.02 μmol min−1 mg−1. The substrate l-ornithine stimulated this activity by a factor of 5, and the reaction was tightly coupled to the formation of hydroxylamine. The enzyme is specific for NADPH and flavin adenine dinucleotide (FAD+) as cofactors, as it cannot utilize NADH and flavin mononucleotide. By fluorescence titration, the dissociation constants for NADPH and FAD+ were determined to be 105.6 ± 6.0 μM and 9.9 ± 0.3 μM, respectively. Steady-state kinetic analysis showed that the l-ornithine-dependent NADPH oxidation obeyed Michaelis-Menten kinetics with apparent Km and V max values of 0.58 mM and 1.34 μmol min−1 mg−1. l-Lysine was a nonsubstrate effector that stimulated NADPH oxidation, but uncoupling occurred and hydrogen peroxide instead of hydroxylated l-lysine was produced. l-2,4-Diaminobutyrate, l-homoserine, and 5-aminopentanoic acid were not substrates or effectors, but they were competitive inhibitors of the l-ornithine-dependent NADPH oxidation reaction, with Kic s of 3 to 8 mM. The results indicate that the chemical nature of effectors is important for simulation of the NADPH oxidation rate in PvdA.

scholarly journals Neutron crystallography reveals novel mechanisms used by Pseudomonas aeruginosa for host-cell binding

2021 ◽  
Author(s):  
Lukas Gajdos ◽  
Matthew P Blakeley ◽  
Michael Haertlein ◽  
V Trevor Forsyth ◽  
Juliette M Devos ◽  
...  
Keyword(s):  
Pseudomonas Aeruginosa ◽  
Calcium Ions ◽  
Bacterial Infections ◽  
Opportunistic Pathogen ◽  
Host Cells ◽  
Carbohydrate Binding ◽  
Hydrogen Atoms ◽  
High Affinity ◽  
Structural Details ◽  
Neutron Crystallography

The opportunistic pathogen Pseudomonas aeruginosa, a major cause of nosocomial infections, uses carbohydrate-binding proteins (lectins) as part of its binding to host cells. The fucose-binding lectin, LecB, displays a unique carbohydrate-binding site that incorporates two closely located calcium ions bridging between the ligand and protein, providing specificity and unusually high affinity. Here, we investigate the mechanisms involved in binding based on neutron crystallography studies of a fully deuterated LecB/fucose/calcium complex. The neutron structure, which includes the positions of all the hydrogen atoms, reveals that the high affinity of binding may be related to the occurrence of a low barrier hydrogen bond induced by the proximity of the two calcium ions, the presence of coordination rings between the sugar, calcium and LecB, and the dynamic behaviour of bridging water molecules at room temperature. These key structural details may assist in the design of anti-adhesive compounds to combat multi-resistance bacterial infections.

scholarly journals Molecular Cloning, Expression and FPLC Purification of Lectin A from Pseudomonas aeruginosa

2014 ◽  
Vol 2 (4) ◽  
pp. 529-536
Author(s):  
Peyman Ghoraishizadeh ◽  
Shraddha Raikar ◽  
Mahsa Takhtechian
Keyword(s):  
Cystic Fibrosis ◽  
Pseudomonas Aeruginosa ◽  
Molecular Cloning ◽  
Opportunistic Pathogen ◽  
Host Cells ◽  
Related Protein ◽  
Burn Victims ◽  
Gene Coding ◽  
Lectin Protein

Pseudomonas aeruginosa (PA) as an opportunistic pathogen infects the pulmonary tract, bladder, cystic fibrosis patients and burn victims. PA infections treatment is challenging because of its ability to rapidly develop resistance to multiple classes of antibiotics. Lectin is protein that isexpressed in cell of PA and cause of infection by attaching to the host cells. Lectin A gene coding lectin protein so we cloned and expressedthis gene then purified of related protein, that can be used in preparation of vaccine to treat PA infections.DOI: http://dx.doi.org/10.3126/ijasbt.v2i4.11559 Int J Appl Sci Biotechnol, Vol. 2(4): 529-536 

scholarly journals Inflammation: A Double-Edged Sword in the Response to Pseudomonas aeruginosa Infection

2017 ◽  
Vol 9 (3) ◽  
pp. 250-261 ◽  
Author(s):  
Christina K. Lin ◽  
Barbara I. Kazmierczak
Keyword(s):  
Pseudomonas Aeruginosa ◽  
Defense Mechanisms ◽  
Opportunistic Pathogen ◽  
Innate Immune ◽  
Immune Recognition ◽  
Chronic Infections ◽  
Acute Infections ◽  
Pathogen Persistence ◽  
Pseudomonas Aeruginosa Infection ◽  
Pathogen Clearance

The Gram-negative opportunistic pathogen Pseudomonas aeruginosa exploits failures of barrier defense and innate immunity to cause acute infections at a range of anatomic sites. We review the defense mechanisms that normally protect against P. aeruginosa pulmonary infection, as well as the bacterial products and activities that trigger their activation. Innate immune recognition of P. aeruginosa is critical for pathogen clearance; nonetheless, inflammation is also associated with pathogen persistence and poor host outcomes. We describe P. aeruginosa adaptations that improve this pathogen's fitness in the inflamed airway, and briefly discuss strategies to manipulate inflammation to benefit the host. Such adjunct therapies may become increasingly important in the treatment of acute and chronic infections caused by this multi-drug-resistant pathogen.

Pseudomonas aeruginosa at the dawn of a post-antibiotic era: clinical significance, resistance mechanisms, novel antibiotics and alternative treatments

2020 ◽  
Vol 65 (2) ◽  
pp. 31-67
Author(s):  
Orsolya Kovács ◽  
Endre Jakab
Keyword(s):  
Pseudomonas Aeruginosa ◽  
Treatment Options ◽  
Opportunistic Pathogen ◽  
Resistance Mechanisms ◽  
Modern Medicine ◽  
Host Cells ◽  
Bacteriophage Therapy ◽  
Priority List ◽  
Resistant Strains ◽  
Novel Antibiotics

Since their discovery, antibiotics have helped treat diseases prior to which many were untreatable, saving millions of lives. However, due to the overuse of antibiotics in medicine and agriculture, the advent of resistant strains of bacteria followed shortly after. The current antibiotic resistance crisis is bringing humanity closer to a post-antibiotic era, when all the advancements made by modern medicine could easily be reversed. Pseudomonas aeruginosa is a Gram-negative, rod-shaped bacterium, ubiquitous owing to its minimal nutritional and growth requirements. P. aeruginosa is one of the pathogens included in the priority list of the WHO, being assessed as critical due to its high antimicrobial resistance, leaving only a few effective treatment options to combat it. As an opportunistic pathogen, P. aeruginosa establishes infection in immunocompromised patients, primarily in hospital settings. In order to initiate infection, it requires several virulence factors that mediate the invasion of the pathogen into host cells. Owing to the multiple resistance mechanisms of P. aeruginosa, it has developed resistance to most classes of antibiotics. Due to its increased resistance, treating P. aeruginosa infections is a great challenge for clinicians. Several β-lactam/β-lactamase combinations have been approved and are available as treatment options, which overall show high efficacy against P. aeruginosa. Moreover, novel antibiotics are currently in development as possible antipseudomonal agents, including a Pseudomonas-specific formulation. In addition, new strategies such as bacteriophage therapy, pyocins or the inhibition of the quorum sensing system are being investigated for the treatment of P. aeruginosa infections.

scholarly journals Heparinase Is Essential for Pseudomonas aeruginosa Virulence during Thermal Injury and Infection

2017 ◽  
Vol 86 (1) ◽  
Author(s):  
Nyaradzo Dzvova ◽  
Jane A. Colmer-Hamood ◽  
John A. Griswold ◽  
Abdul N. Hamood
Keyword(s):  
Pseudomonas Aeruginosa ◽  
Wound Infection ◽  
Thermal Injury ◽  
Multiorgan Failure ◽  
Opportunistic Pathogen ◽  
Burn Wound ◽  
Content Type ◽  
Infected Skin ◽  
Intraperitoneal Inoculation

ABSTRACTThe opportunistic pathogenPseudomonas aeruginosais a major cause of sepsis in severely burned patients. If it is not eradicated from the wound, it translocates to the bloodstream, causing sepsis, multiorgan failure, and death. We recently described theP. aeruginosaheparinase-encoding gene,hepP, whose expression was significantly enhanced whenP. aeruginosastrain UCBPP_PA14 (PA14) was grown in whole blood from severely burned patients. Further analysis demonstrated thathepPcontributed to thein vivovirulence of PA14 in theCaenorhabditis elegansmodel. In this study, we utilized the murine model of thermal injury to examine the contribution ofhepPto the pathogenesis ofP. aeruginosaduring burn wound infection. Mutation ofhepPreduced the rate of mortality from 100% for mice infected with PA14 to 7% for mice infected with PA14::hepP. While comparable numbers of PA14 and PA14::hepPbacteria were recovered from infected skin, only PA14 was recovered from the livers and spleens of infected mice. Despite its inability to spread systemically, PA14::hepPformed perivascular cuffs around the blood vessels within the skin of the thermally injured/infected mice. Intraperitoneal inoculation of the thermally injured mice, bypassing the need for translocation, produced similar results. The rate of mortality for mice infected with PA14::hepPwas 0%, whereas it was 66% for mice infected with PA14. As before, only PA14 was recovered from the livers and spleens of infected mice. These results suggest thathepPplays a crucial role in the pathogenesis of PA14 during burn wound infection, most likely by contributing to PA14 survival in the bloodstream of the thermally injured mouse during sepsis.

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