Development of a model for the investigation of the impact of deficiency of endogenous hydrogen sulphide on resistance of multi-drug resistant bacteria (Pseudomonas aeruginosa & Klebsiella pneumonia) against antimicrobial treatment

Doctoral Dissertation uoadl:2945029 8 Read counter

Unit:
Faculty of Medicine
Library of the School of Health Sciences
Deposit date:
2021-05-12
Year:
2021
Author:
Renieris Georgios
Dissertation committee:
Ευάγγελος Ι. Γιαμαρέλλος- Μπουρμπούλης, Καθηγητής, Ιατρική Σχολή, ΕΚΠΑ
Γεώργιος Δημόπουλος, Καθηγητής, Ιατρική Σχολή, ΕΚΠΑ
Ηρακλής Τσαγκάρης, Καθηγητής, Ιατρική Σχολή, ΕΚΠΑ
Ερυφίλη Χατζηαγγελάκη, Καθηγήτρια, Ιατρική Σχολή, ΕΚΠΑ
Μιχαήλ Σαμάρκος, Αναπλ. Καθηγητής, Ιατρική Σχολή, ΕΚΠΑ
Ελένη Σαμπατάκου, Αναπλ. Καθηγήτρια, Ιατρική Σχολή, ΕΚΠΑ
Αντώνιος Παπαδόπουλος, Αναπλ. Καθηγητής, Ιατρική Σχολή, ΕΚΠΑ
Original Title:
Ανάπτυξη ενός μοντέλου για την μελέτη της επίδρασης της έλλειψης της ενδογενούς παραγωγής υδρόθειου στην ανθεκτικότητα πολυανθεκτικών μικροοργανισμών (Pseudomonas aeruginosa & Klebsiella pneumoniae) ενάντια στην αντιμικροβιακή αγωγή.
Languages:
Greek
Translated title:
Development of a model for the investigation of the impact of deficiency of endogenous hydrogen sulphide on resistance of multi-drug resistant bacteria (Pseudomonas aeruginosa & Klebsiella pneumonia) against antimicrobial treatment
Summary:
Hydrogen sulfide (H2S) has recently been recognized as a novel gaseous transmitterwith several anti-inflammatory properties. The role of host- derived H2S in infectionsby Pseudomonas aeruginosa was investigated in clinical and mouse models. H2Sconcentrations and survival was assessed in septic patients with lung infection. Animalexperiments using a model of severe systemic multidrug-resistant P. aeruginosainfection were performed using mice with a constitutive knock-out of cystathionine-γlyase (Cse) gene (Cse-/-) and wild-type mice with a physiological expression (Cse+/+).Experiments were repeated in mice after a) treatment with cyclophosphamide; b) bonemarrow transplantation (BMT) from a Cse+/+ donor; c) treatment with H2S synthesisinhibitor aminooxyacetic acid (ΑΟΑΑ) or propargylglycine (PAG) and d) H2S donorsodium thiosulfate (STS) or GYY3147. Bacterial loads and myeloperoxidase activitywere measured in tissue samples. The expression of quorum sensing genes (QS) wasdetermined in vivo and in vitro. Cytokine concentration was measured in serum andincubated splenocytes. Patients survivors at day 28 had significantly higher serum H2Scompared to non-survivors. A cut- off point of 5.3 μΜ discriminated survivors withsensitivity 92.3%. Mortality after 28 days was 30.9% and 93.7% in patients with H2Shigher and less than 5.3 μΜ (p= 7 x 10-6). In mice expression of Cse and applicationof STS afforded protection against infection with multidrug-resistant P. aeruginosa.Cyclophosphamide pretreatment eliminated the survival benefit of Cse+/+ mice,whereas BMT increased the survival of Cse-/- mice. Cse-/- mice had increasedpathogen loads compared to Cse+/+ mice. Phagocytic activity of leukocytes from Cse-/- mice was reduced but was restored after H2S supplementation. An H2S dependentdown- regulation of quorum sensing genes of P.aeruginosa could be demonstrated invivo and in vitro. Endogenous H2S is a potential independent parameter correlatingwith the outcome of P. aeruginosa. H2S provides resistance to infection by MDRbacterial pathogens.
Main subject category:
Health Sciences
Keywords:
Hydrogen sulfide, Pseudomonas aeruginosa, Ventilator associated pneumonia, Antimicrobial resistance
Index:
No
Number of index pages:
0
Contains images:
Yes
Number of references:
89
Number of pages:
107
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