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

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.

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Pseudomonas aeruginosa las and rhl quorum-sensing systems are important for infection and inflammation in a rat prostatitis model

Microbiology ◽

10.1099/mic.0.028464-0 ◽

2009 ◽

Vol 155 (8) ◽

pp. 2612-2619 ◽

Cited By ~ 21

Author(s):

Lisa K. Nelson ◽

Genevieve H. D'Amours ◽

Kimberley M. Sproule-Willoughby ◽

Douglas W. Morck ◽

Howard Ceri

Keyword(s):

Pseudomonas Aeruginosa ◽

Quorum Sensing ◽

Tissue Damage ◽

Inflammatory Markers ◽

Bacterial Colonization ◽

Opportunistic Pathogen ◽

Infection Model ◽

Chronic Infections ◽

Strain Pao1 ◽

Rat Prostate

Pseudomonas aeruginosa frequently acts as an opportunistic pathogen of mucosal surfaces; yet, despite causing aggressive prostatitis in some men, its role as a pathogen in the prostate has not been investigated. Consequently, we developed a Ps. aeruginosa infection model in the rat prostate by instilling wild-type (WT) Ps. aeruginosa strain PAO1 into the rat prostate. It was found that Ps. aeruginosa produced acute and chronic infections in this mucosal tissue as determined by bacterial colonization, gross morphology, tissue damage and inflammatory markers. WT strain PAO1 and its isogenic mutant PAO-JP2, in which both the lasI and rhlI quorum-sensing signal systems have been silenced, were compared during both acute and chronic prostate infections. In acute infections, bacterial numbers and inflammatory markers were comparable between WT PA01 and PAO-JP2; however, considerably less tissue damage occurred in infections with PAO-JP2. Chronic infections with PAO-JP2 resulted in reduced bacterial colonization, tissue damage and inflammation as compared to WT PAO1 infections. Therefore, the quorum-sensing lasI and rhlI genes in Ps. aeruginosa affect acute prostate infections, but play a considerably more important role in maintaining chronic infections. We have thus developed a highly reproducible model for the study of Ps. aeruginosa virulence in the prostate.

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Effect of Lactobacillus casei and Yogurt Administration on Prevention of Pseudomonas aeruginosa Infection in Young Mice

Journal of Food Protection ◽

10.4315/0362-028x-64.11.1768 ◽

2001 ◽

Vol 64 (11) ◽

pp. 1768-1774 ◽

Cited By ~ 52

Author(s):

SUSANA ALVAREZ ◽

CLAUDIA HERRERO ◽

ELENA BRU ◽

GABRIELA PERDIGON

Keyword(s):

Pseudomonas Aeruginosa ◽

Oral Administration ◽

Lactobacillus Casei ◽

Opportunistic Pathogen ◽

Lung Infection ◽

Pseudomonas Aeruginosa Infection ◽

Dose Dependent ◽

Chronic Pneumonia ◽

Dose Dependent Effect ◽

Young Mice

Pseudomonas aeruginosa is an opportunistic pathogen that rarely causes pulmonary disease in normal hosts but one that is an important cause of acute pneumonia in immunocompromised patients, including neonates, and of chronic pneumonia in patients with cystic fibrosis. The aim of this work was to study the effect of oral administration of Lactobacillus casei and yogurt on prevention of P. aeruginosa lung infection in young mice (3 weeks old). This study demonstrates that oral administration of L. casei or yogurt to young mice enhanced lung clearance of P. aeruginosa and phagocytic activity of alveolar macrophages through a dose-dependent effect. There were, however, no significant differences in white blood cell (WBC) differential counts. Furthermore, it was observed that previous administration of L. casei or yogurt induced a significant increase in IgA and IgM levels in bronchoalveolar lavages (BALs) after a P. aeruginosa infection, although there was no relationship with the serum values.

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Heterogenous response to R-pyocin killing in populations of Pseudomonas aeruginosa sourced from cystic fibrosis lungs

10.1101/2020.08.05.238956 ◽

2020 ◽

Author(s):

Madeline Mei ◽

Jacob Thomas ◽

Stephen P. Diggle

Keyword(s):

Cystic Fibrosis ◽

Pseudomonas Aeruginosa ◽

Genotypic Diversity ◽

Opportunistic Pathogen ◽

Chronic Infections ◽

Bacterial Populations ◽

Heterogeneous Populations ◽

Lung Infections ◽

The Impact ◽

Lps Binding

AbstractBacteriocins are proteinaceous antimicrobials produced by bacteria which are active against other strains of the same species. R-type pyocins are phage tail-like bacteriocins produced by Pseudomonas aeruginosa. Due to their anti-pseudomonal activity, R-pyocins have potential as therapeutics in infection. P. aeruginosa is a Gram-negative opportunistic pathogen and is particularly problematic for individuals with cystic fibrosis (CF). P. aeruginosa from CF lung infections develop increasing resistance to antibiotics, making new treatment approaches essential. P. aeruginosa populations become phenotypically and genotypically diverse during infection, however little is known of the efficacy of R-pyocins against heterogeneous populations. R-pyocins vary by subtype (R1-R5), distinguished by binding to different residues on the lipopolysaccharide (LPS). Each type varies in killing spectrum, and each strain produces only one R-type. To evaluate the prevalence of different R-types, we screened P. aeruginosa strains from the International Pseudomonas Consortium Database (IPCD) and from our biobank of CF strains. We found that (i) R1-types were the most prevalent R-type among strains from respiratory sources and (ii) isolates collected from the same patient have the same R-type. We then assessed the impact of diversity on R-pyocin susceptibility and found a heterogenous response to R-pyocins within populations, likely due to differences in the LPS core. Our work reveals that heterogeneous populations of microbes exhibit variable susceptibility to R-pyocins and highlights that there is likely heterogeneity in response to other types of LPS-binding antimicrobials, including phage.ImportanceR-pyocins have potential as alternative therapeutics against Pseudomonas aeruginosa in chronic infection, however little is known about the efficacy of R-pyocins in heterogeneous bacterial populations. P. aeruginosa is known to become resistant to multiple antibiotics, as well as evolve phenotypic and genotypic diversity over time; thus it is particularly difficult to eradicate in chronic cystic fibrosis (CF) lung infections. In this study, we found that P. aeruginosa populations from CF lungs maintain the same R-pyocin genotype but exhibit heterogeneity in susceptibility to R-pyocins from other strains. Our findings suggest there is likely heterogeneity in response to other types of LPS-binding antimicrobials, such as phage, highlighting the necessity of further studying the potential of LPS-binding antimicrobial particles as alternative therapies in chronic infections.

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Distinct Contributions of Interleukin-1α (IL-1α) and IL-1β to Innate Immune Recognition of Pseudomonas aeruginosa in the Lung

Infection and Immunity ◽

10.1128/iai.02218-14 ◽

2014 ◽

Vol 82 (10) ◽

pp. 4204-4211 ◽

Cited By ~ 20

Author(s):

Khatoun Al Moussawi ◽

Barbara I. Kazmierczak

Keyword(s):

Pseudomonas Aeruginosa ◽

Immune Responses ◽

Bacterial Pathogen ◽

Innate Immune ◽

Immune Recognition ◽

Content Type ◽

Caspase 1 ◽

Rapid Responses ◽

Subsequent Activation ◽

Deficient Mice

ABSTRACTThe bacterial pathogenPseudomonas aeruginosacauses acute infections associated with significant morbidity and mortality.P. aeruginosaelicits strong innate immune responses in immunocompetent hosts, and the resulting recruitment of neutrophils to the site of infection is necessary for bacterial clearance.P. aeruginosalipopolysaccharide and flagellin are recognized by extracellular Toll-like receptors, but the most rapid responses to infection occur when cytosolic receptors sense flagellin or type 3 secretion system (T3SS) structural proteins. The subsequent activation of the NLRC4 inflammasome and caspase-1 generates an interleukin-1β (IL-1β) signal that is required for the rapid neutrophilic response. A T3SS effector, exotoxin U (ExoU), can inhibit activation of the NLRC4 inflammasome and caspase-1. Thus, our observation that IL-1 receptor (IL-1R)-mediated signals were still required to initiate a response to ExoU-producing bacteria was unexpected. As both IL-1α and IL-1β signal via the IL-1R, we examined immune responses in mice lacking either of these cytokines. IL-1β-deficient mice responded to ExoU-producingP. aeruginosabacteria similarly to wild-type animals; however, IL-1α-deficient mice had an attenuated immune response. The situation was reversed following infections by ExoU-negative bacteria: here, IL-1α was dispensable for neutrophil recruitment, while IL-1β was required. IL-1α secretion by macrophages infected with ExoU-producingP. aeruginosaisolates was independent of both caspase-1 and caspase-11. This study documents distinct roles for IL-1α and IL-1β in the response toP. aeruginosainfection as a function of the T3SS effectors produced by the infecting strain. The redundancy of these two cytokines nonetheless allows the infected host to mount a response to ExoU-positive and -negative bacterial isolates.

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Rapid diversification of Pseudomonas aeruginosa in cystic fibrosis lung-like conditions

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1721270115 ◽

2018 ◽

Vol 115 (42) ◽

pp. 10714-10719 ◽

Cited By ~ 20

Author(s):

Alana Schick ◽

Rees Kassen

Keyword(s):

Cystic Fibrosis ◽

Pseudomonas Aeruginosa ◽

Chronic Infection ◽

Opportunistic Pathogen ◽

Chronic Infections ◽

Evolutionary Diversification ◽

Nutritional Conditions ◽

Patient Health ◽

Rapid Diversification

Chronic infection of the cystic fibrosis (CF) airway by the opportunistic pathogen Pseudomonas aeruginosa is the leading cause of morbidity and mortality for adult CF patients. Prolonged infections are accompanied by adaptation of P. aeruginosa to the unique conditions of the CF lung environment, as well as marked diversification of the pathogen into phenotypically and genetically distinct strains that can coexist for years within a patient. Little is known, however, about the causes of this diversification and its impact on patient health. Here, we show experimentally that, consistent with ecological theory of diversification, the nutritional conditions of the CF airway can cause rapid and extensive diversification of P. aeruginosa. Mucin, the substance responsible for the increased viscosity associated with the thick mucus layer in the CF airway, had little impact on within-population diversification but did promote divergence among populations. Furthermore, in vitro evolution recapitulated traits thought to be hallmarks of chronic infection, including reduced motility and increased biofilm formation, and the range of phenotypes observed in a collection of clinical isolates. Our results suggest that nutritional complexity and reduced dispersal can drive evolutionary diversification of P. aeruginosa independent of other features of the CF lung such as an active immune system or the presence of competing microbial species. We suggest that diversification, by generating extensive phenotypic and genetic variation on which selection can act, may be a key first step in the development of chronic infections.

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PrtR Homeostasis Contributes to Pseudomonas aeruginosa Pathogenesis and Resistance against Ciprofloxacin

Infection and Immunity ◽

10.1128/iai.01388-13 ◽

2014 ◽

Vol 82 (4) ◽

pp. 1638-1647 ◽

Cited By ~ 28

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.

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Recent advances in understanding Pseudomonas aeruginosa as a pathogen

F1000Research ◽

10.12688/f1000research.10506.1 ◽

2017 ◽

Vol 6 ◽

pp. 1261 ◽

Cited By ~ 63

Author(s):

Jens Klockgether ◽

Burkhard Tümmler

Keyword(s):

Pseudomonas Aeruginosa ◽

Population Biology ◽

Recent Progress ◽

Human Subjects ◽

Opportunistic Pathogen ◽

Mammalian Host ◽

Secretion Systems ◽

Chronic Infections ◽

Type Vi Secretion

The versatile and ubiquitousPseudomonas aeruginosais an opportunistic pathogen causing acute and chronic infections in predisposed human subjects. Here we review recent progress in understandingP. aeruginosapopulation biology and virulence, its cyclic di-GMP-mediated switches of lifestyle, and its interaction with the mammalian host as well as the role of the type III and type VI secretion systems inP. aeruginosainfection.

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Mutational Analysis of RetS, an Unusual Sensor Kinase-Response Regulator Hybrid Required for Pseudomonas aeruginosa Virulence

Infection and Immunity ◽

10.1128/iai.00575-06 ◽

2006 ◽

Vol 74 (8) ◽

pp. 4462-4473 ◽

Cited By ~ 53

Author(s):

Michelle A. Laskowski ◽

Barbara I. Kazmierczak

Keyword(s):

Pseudomonas Aeruginosa ◽

Mutational Analysis ◽

Response Regulator ◽

Acute Infection ◽

Opportunistic Pathogen ◽

Sensor Kinase ◽

Chronic Infections ◽

Reciprocal Regulation ◽

Wide Range

ABSTRACT Pseudomonas aeruginosa is an opportunistic pathogen capable of causing both acute and chronic infections in a wide range of hosts. Expression of the type III secretion system (T3SS) proteins is correlated with virulence in models of acute infection, while downregulation of the T3SS and upregulation of genes important for biofilm formation are observed during chronic infections. RetS, a hybrid sensor kinase-response regulator protein of P. aeruginosa, plays a key role in the reciprocal regulation of virulence factors required for acute versus chronic infection and is postulated to act in concert with two other sensor kinase-response regulator hybrids, GacS and LadS. This work examines the roles of the putative sensing and signal transduction domains of RetS in induction of the T3SS in vitro and in a murine model of acute pneumonia. We identify distinct signaling roles for the tandem receiver domains of RetS and present evidence suggesting that RetS may serve as a substrate for another sensor kinase. Phenotypes associated with RetS alleles lacking periplasmic and/or transmembrane domains further indicate that the periplasmic domain of RetS may transmit a signal that inhibits RetS activity during acute infections.

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Immune recognition of Pseudomonas aeruginosa mediated by the IPAF/NLRC4 inflammasome

Journal of Experimental Medicine ◽

10.1084/jem.20071239 ◽

2007 ◽

Vol 204 (13) ◽

pp. 3235-3245 ◽

Cited By ~ 339

Author(s):

Fayyaz S. Sutterwala ◽

Lilia A. Mijares ◽

Li Li ◽

Yasunori Ogura ◽

Barbara I. Kazmierczak ◽

...

Keyword(s):

Pseudomonas Aeruginosa ◽

Cell Death ◽

Host Cell ◽

Proinflammatory Cytokine ◽

Opportunistic Infections ◽

Inflammatory Responses ◽

Innate Immune ◽

Immune Recognition ◽

Independent Manner ◽

Caspase 1

Pseudomonas aeruginosa is a Gram-negative bacterium that causes opportunistic infections in immunocompromised individuals. P. aeruginosa employs a type III secretion system to inject effector molecules into the cytoplasm of the host cell. This interaction with the host cell leads to inflammatory responses that eventually result in cell death. We show that infection of macrophages with P. aeruginosa results in activation of caspase-1 in an IPAF-dependent, but flagellin-independent, manner. Macrophages deficient in IPAF or caspase-1 were markedly resistant to P. aeruginosa–induced cell death and release of the proinflammatory cytokine interleukin (IL)-1β. A subset of P. aeruginosa isolates express the effector molecule exoenzyme U (ExoU), which we demonstrate is capable of inhibiting caspase-1–driven proinflammatory cytokine production. This study shows a key role for IPAF and capase-1 in innate immune responses to the pathogen P. aeruginosa, and also demonstrates that virulent ExoU-expressing strains of P. aeruginosa can circumvent this innate immune response.

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The LasB Elastase of Pseudomonas aeruginosa Acts in Concert with Alkaline Protease AprA To Prevent Flagellin-Mediated Immune Recognition

Infection and Immunity ◽

10.1128/iai.00939-15 ◽

2015 ◽

Vol 84 (1) ◽

pp. 162-171 ◽

Cited By ~ 35

Author(s):

Fiordiligie Casilag ◽

Anne Lorenz ◽

Jonas Krueger ◽

Frank Klawonn ◽

Siegfried Weiss ◽

...

Keyword(s):

Pseudomonas Aeruginosa ◽

Alkaline Protease ◽

Opportunistic Pathogen ◽

Airway Epithelial Cells ◽

Immune Recognition ◽

Airway Epithelial ◽

Content Type ◽

Persistent Infections ◽

Modulating Functions ◽

Immune Detection

The opportunistic pathogenPseudomonas aeruginosais capable of establishing severe and persistent infections in various eukaryotic hosts. It encodes a wide array of virulence factors and employs several strategies to evade immune detection. In the present study, we screened the Harvard Medical School transposon mutant library ofP. aeruginosaPA14 for bacterial factors that modulate interleukin-8 responses in A549 human airway epithelial cells. We found that in addition to the previously identified alkaline protease AprA, the elastase LasB is capable of degrading exogenous flagellin under calcium-replete conditions and prevents flagellin-mediated immune recognition. Our results indicate that the production of two proteases with anti-flagellin activity provides a failsafe mechanism forP. aeruginosato ensure the maintenance of protease-dependent immune-modulating functions.

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