scholarly journals Immunometabolic hijacking of immune cells by a Pseudomonas aeruginosa quorum-sensing signal

2021 ◽  
Author(s):  
Arunava Bandyopadhaya ◽  
Vijay K Singh ◽  
Arijit Chakraborty ◽  
A. Aria Tzika ◽  
Laurence G Rahme
Keyword(s):  
Pseudomonas Aeruginosa ◽  
Quorum Sensing ◽  
Immune Cells ◽  
Metabolic Pathways ◽  
Metabolic Reprogramming ◽  
Signal Molecule ◽  
Host Immune Responses ◽  
Pathogen Persistence ◽  
Mitochondrial Pyruvate Carrier ◽  
Inflammatory Milieu

AbstractMacrophages utilize metabolic pathways to generate energy and metabolites that may be vulnerable to pathogen hijacking to favor pathogen survival and persistence. It is unclear how bacterial pathogens alter metabolic pathways in immune cells for their benefit and persistence in the infected host. We have shown that the Pseudomonas aeruginosa quorum sensing (QS) signal molecule 2-aminoacetophenone (2-AA) allows pathogen persistence in host tissues by triggering host tolerization via histone deacetylase (HDAC)1-mediated epigenetic reprogramming. Here, we provide strong evidence that 2-AA-meditated persistence is linked to specific metabolic pathway alterations that reduce energy availability and biosynthetic macromolecules involved in host immune responses. 2-AA promotes a Warburg-like metabolic reprogramming effect, thereby increasing levels of lactate, which repressed inflammatory signaling in macrophages. Moreover, it interferes with pyruvate translocation to mitochondria, reducing mitochondrial (mt)-oxidative phosphorylation (OXPHOS) due to down-regulation of estrogen-regulated receptor (ERR)α and mitochondrial pyruvate carrier (MPC)-1. This metabolic reprogramming dampened energy production, reduced the acetyl-CoA pool, and generated an anti-inflammatory milieu that favors P. aeruginosa persistence. These findings provide evidence of first-in-class metabolic reprogramming in immune cells mediated by a QS signaling molecule. The specific metabolic programs affected provide insights that may guide the design and development of therapeutics and protective interventions against pathogen-induced immunometabolic alterations and persistence factors.

scholarly journals Azithromycin Inhibits MUC5AC Production Induced by the Pseudomonas aeruginosa Autoinducer N-(3-Oxododecanoyl) Homoserine Lactone in NCI-H292 Cells

2004 ◽  
Vol 48 (9) ◽  
pp. 3457-3461 ◽  
Author(s):  
Yoshifumi Imamura ◽  
Katsunori Yanagihara ◽  
Yohei Mizuta ◽  
Masafumi Seki ◽  
Hideaki Ohno ◽  
...  
Keyword(s):  
Pseudomonas Aeruginosa ◽  
Quorum Sensing ◽  
Bacterial Infection ◽  
Core Protein ◽  
Homoserine Lactone ◽  
Signal Molecule ◽  
Diffuse Panbronchiolitis ◽  
Mucin Production ◽  
Protein Levels ◽  
Extracellular Signal

ABSTRACT The features of chronic airway diseases, including chronic bronchitis, cystic fibrosis, bronchiectasis, and diffuse panbronchiolitis, include chronic bacterial infection and airway obstruction by mucus. Pseudomonas aeruginosa is one of the most common pathogens in chronic lung infection, and quorum-sensing systems contribute to the pathogenesis of this disease. The quorum-sensing signal molecule [N-(3-oxododecanoyl) homoserine lactone (3O-C12-HSL)] not only regulates bacterial virulence but also is associated with the immune response. In this study, we investigated whether 3O-C12-HSL could stimulate the production of a major mucin core protein, MUC5AC. The effect of a macrolide on MUC5AC production was also studied. 3O-C12-HSL induced NCI-H292 cells to express MUC5AC at both the mRNA and the protein levels in time- and dose-dependent manners. A 15-membered macrolide, azithromycin, inhibited MUC5AC production that was activated by 3O-C12-HSL. 3O-C12-HSL induced extracellular signal-regulated kinase (ERK) 1/2 and I-κB phosphorylation in cells, and this induction was suppressed by azithromycin. 3O-C12-HSL-induced MUC5AC production was blocked by the ERK pathway inhibitor PD98059. Our findings suggest that the P. aeruginosa autoinducer 3O-C12-HSL contributes to excessive mucin production in chronic bacterial infection. Azithromycin seems to reduce this mucin production by interfering with intracellular signal transduction.

scholarly journals Signal Synthase-Type versus Catabolic Monooxygenases: Retracing 3-Hydroxylation of 2-Alkylquinolones and Their N-Oxides by Pseudomonas aeruginosa and Other Pulmonary Pathogens

2021 ◽  
Vol 87 (6) ◽  
Author(s):  
Niklas H. Ritzmann ◽  
Steffen L. Drees ◽  
Susanne Fetzner
Keyword(s):  
Staphylococcus Aureus ◽  
Pseudomonas Aeruginosa ◽  
Quorum Sensing ◽  
Efflux Pump ◽  
Biological Activities ◽  
Multidrug Efflux Pump ◽  
Therapeutic Success ◽  
Signal Molecule ◽  
Physiological Level ◽  
Content Type

ABSTRACT The multiple biological activities of 2-alkylquinolones (AQs) are crucial for virulence of Pseudomonas aeruginosa, conferring advantages during infection and in polymicrobial communities. Whereas 2-heptyl-3-hydroxyquinolin-4(1H)-one (the “Pseudomonas quinolone signal” [PQS]) is an important quorum sensing signal molecule, 2-alkyl-1-hydroxyquinolin-4(1H)-ones (also known as 2-alkyl-4-hydroxyquinoline N-oxides [AQNOs]) are antibiotics inhibiting respiration. Hydroxylation of the PQS precursor 2-heptylquinolin-4(1H)-one (HHQ) by the signal synthase PqsH boosts AQ quorum sensing. Remarkably, the same reaction, catalyzed by the ortholog AqdB, is used by Mycobacteroides abscessus to initiate degradation of AQs. The antibiotic 2-heptyl-1-hydroxyquinolin-4(1H)-one (HQNO) is hydroxylated by Staphylococcus aureus to the less toxic derivative PQS-N-oxide (PQS-NO), a reaction probably also catalyzed by a PqsH/AqdB ortholog. In this study, we provide a comparative analysis of four AQ 3-monooxygenases of different organisms. Due to the major impact of AQ/AQNO 3-hydroxylation on the biological activities of the compounds, we surmised adaptations on the enzymatic and/or physiological level to serve either the producer or target organisms. Our results indicate that all enzymes share similar features and are incapable of discriminating between AQs and AQNOs. PQS-NO, hence, occurs as a native metabolite of P. aeruginosa although the unfavorable AQNO 3-hydroxylation is minimized by export as shown for HQNO, involving at least one multidrug efflux pump. Moreover, M. abscessus is capable of degrading the AQNO heterocycle by concerted action of AqdB and dioxygenase AqdC. However, S. aureus and M. abscessus orthologs disfavor AQNOs despite their higher toxicity, suggesting that catalytic constraints restrict evolutionary adaptation and lead to the preference of non-N-oxide substrates by AQ 3-monooxygenases. IMPORTANCE Pseudomonas aeruginosa, Staphylococcus aureus, and Mycobacteroides abscessus are major players in bacterial chronic infections and particularly common colonizers of cystic fibrosis (CF) lung tissue. Whereas S. aureus is an early onset pathogen in CF, P. aeruginosa establishes at later stages. M. abscessus occurs at all stages but has a lower epidemiological incidence. The dynamics of how these pathogens interact can affect survival and therapeutic success. 2-Alkylquinolone (AQ) and 2-alkylhydroxyquinoline N-oxide (AQNO) production is a major factor of P. aeruginosa virulence. The 3-position of the AQ scaffold is critical, both for attenuation of AQ toxicity or degradation by competitors, as well as for full unfolding of quorum sensing. Despite lacking signaling functionality, AQNOs have the strongest impact on suppression of Gram-positives. Because evidence for 3-hydroxylation of AQNOs has been reported, it is desirable to understand the extent by which AQ 3-monooxygenases contribute to manipulation of AQ/AQNO equilibrium, resistance, and degradation.

scholarly journals Conversion of the Pseudomonas aeruginosa Quinolone Signal and Related Alkylhydroxyquinolines by Rhodococcus sp. Strain BG43

2014 ◽  
Vol 80 (23) ◽  
pp. 7266-7274 ◽  
Author(s):  
Christine Müller ◽  
Franziska S. Birmes ◽  
Heiko Niewerth ◽  
Susanne Fetzner
Keyword(s):  
Pseudomonas Aeruginosa ◽  
Quorum Sensing ◽  
Rhodococcus Erythropolis ◽  
Opportunistic Pathogen ◽  
Biosynthetic Enzyme ◽  
Signal Molecule ◽  
Content Type ◽  
Cell Extracts ◽  
Specific Pathway ◽  
Rhodococcus Sp

ABSTRACTA bacterial strain, which based on the sequences of its 16S rRNA,gyrB,catA, andqsdAgenes, was identified as aRhodococcussp. closely related toRhodococcus erythropolis, was isolated from soil by enrichment on thePseudomonasquinolone signal [PQS; 2-heptyl-3-hydroxy-4(1H)-quinolone], a quorum sensing signal employed by the opportunistic pathogenPseudomonas aeruginosa. The isolate, termedRhodococcussp. strain BG43, cometabolically degraded PQS and its biosynthetic precursor 2-heptyl-4(1H)-quinolone (HHQ) to anthranilic acid. HHQ degradation was accompanied by transient formation of PQS, and HHQ hydroxylation by cell extracts required NADH, indicating that strain BG43 has a HHQ monooxygenase isofunctional to the biosynthetic enzyme PqsH ofP. aeruginosa. The enzymes catalyzing HHQ hydroxylation and PQS degradation were inducible by PQS, suggesting a specific pathway. Remarkably,Rhodococcussp. BG43 is also capable of transforming 2-heptyl-4-hydroxyquinoline-N-oxide to PQS. It thus converts an antibacterial secondary metabolite ofP. aeruginosato a quorum sensing signal molecule.

scholarly journals In vitro biosynthesis of the Pseudomonas aeruginosa quorum-sensing signal molecule N-butanoyl-L-homoserine lactone

2002 ◽  
Vol 28 (1) ◽  
pp. 193-203 ◽  
Author(s):  
Yan Jiang ◽  
Miguel Camara ◽  
Siri Ram Chhabra ◽  
Kim R. Hardie ◽  
Barrie W. Bycroft ◽  
...  
Keyword(s):  
Pseudomonas Aeruginosa ◽  
Quorum Sensing ◽  
Homoserine Lactone ◽  
Signal Molecule ◽  
In Vitro Biosynthesis

scholarly journals Cancer cell metabolic reprogramming: a keystone for the response to immunotherapy

2020 ◽  
Vol 11 (11) ◽  
Author(s):  
Michaël Cerezo ◽  
Stéphane Rocchi
Keyword(s):  
Tumor Microenvironment ◽  
Immune Cells ◽  
Metabolic Pathways ◽  
Immune Checkpoint Inhibitors ◽  
Antitumor Immunity ◽  
Checkpoint Inhibitors ◽  
Metabolic Reprogramming ◽  
Limited Resources ◽  
Antitumor Response ◽  
Secondary Resistance

Abstract By targeting the tumor microenvironment to stimulate antitumor immunity, immunotherapies have revolutionized cancer treatment. However, many patients do not respond initially or develop secondary resistance. Based on the limited resources in the tumor microenvironment and competition between tumor and immune cells, the field of immune metabolism has produced extensive knowledge showing that targeting metabolism could help to modulate antitumor immunity. However, among all the different potentially targetable metabolic pathways, it remains unclear which have more potential to overcome resistance to immune checkpoint inhibitors. Here, we explore metabolic reprogramming in cancer cells, which might inhibit antitumor immunity, and strategies that can be used to favor the antitumor response.

scholarly journals Bacterial mobbing behavior: coordinated communal attack of Pseudomonas aeruginosa on a protozoan predator

2020 ◽  
Author(s):  
N. Shteindel ◽  
Y. Gerchman
Keyword(s):  
Pseudomonas Aeruginosa ◽  
Quorum Sensing ◽  
Animal Species ◽  
Acanthamoeba Castellanii ◽  
Group Behavior ◽  
Predator Population ◽  
Signal Molecule ◽  
Predation Avoidance ◽  
Group Coordination

Mobbing, a group attack of prey on predator, is a strategy enacted by many animal species. Here we report bacterial mobbing carried out by the bacterium Pseudomonas aeruginosa towards Acanthamoeba castellanii, a common bacterivore. This behavior consists of bacterial taxis towards the amoebae, adhesion en masse to amoebae cells, and eventual killing of the amoebae. Mobbing behavior transpires in second’s timescale and responds to predator population density. A mutant defective in the production of a specific quorum sensing signal displays reduced adhesion to amoeba cells. This deficiency ameliorated by external addition of the missing signal molecule. The same quorum sensing mutant also expresses long term deficiency in its ability to cause amoeba death and shows higher susceptibility to predation, highlighting the importance of group coordination to mobbing and predation avoidance. These findings portray bacterial mobbing as a regulated and dynamic group behavior.

scholarly journals A Distinct QscR Regulon in the Pseudomonas aeruginosa Quorum-Sensing Circuit

2006 ◽  
Vol 188 (9) ◽  
pp. 3365-3370 ◽  
Author(s):  
Yannick Lequette ◽  
Joon-Hee Lee ◽  
Fouzia Ledgham ◽  
Andrée Lazdunski ◽  
E. Peter Greenberg
Keyword(s):  
Pseudomonas Aeruginosa ◽  
Quorum Sensing ◽  
Opportunistic Pathogen ◽  
Homoserine Lactone ◽  
Acyl Homoserine Lactone ◽  
Signal Molecule ◽  
Control Of Gene Expression ◽  
Signaling Systems ◽  
Sensing Systems

ABSTRACT The opportunistic pathogen Pseudomonas aeruginosa possesses two complete acyl-homoserine lactone (acyl-HSL) signaling systems. One system consists of LasI and LasR, which generate a 3-oxododecanoyl-homoserine lactone signal and respond to that signal, respectively. The other system is RhlI and RhlR, which generate butanoyl-homoserine lactone and respond to butanoyl-homoserine lactone, respectively. These quorum-sensing systems control hundreds of genes. There is also an orphan LasR-RhlR homolog, QscR, for which there is no cognate acyl-HSL synthetic enzyme. We previously reported that a qscR mutant is hypervirulent and showed that QscR transiently represses a few quorum-sensing-controlled genes. To better understand the role of QscR in P. aeruginosa gene regulation and to better understand the relationship between QscR, LasR, and RhlR control of gene expression, we used transcription profiling to identify a QscR-dependent regulon. Our analysis revealed that QscR activates some genes and represses others. Some of the repressed genes are not regulated by the LasR-I or RhlR-I systems, while others are. The LasI-generated 3-oxododecanoyl-homoserine lactone serves as a signal molecule for QscR. Thus, QscR appears to be an integral component of the P. aeruginosa quorum-sensing circuitry. QscR uses the LasI-generated acyl-homoserine lactone signal and controls a specific regulon that overlaps with the already overlapping LasR- and RhlR-dependent regulons.

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