In:
PLOS Pathogens, Public Library of Science (PLoS), Vol. 17, No. 3 ( 2021-3-26), p. e1009473-
Abstract:
Hydrogen sulfide (H 2 S) has recently been recognized as a novel gaseous transmitter with several anti-inflammatory properties. The role of host- derived H 2 S in infections by Pseudomonas aeruginosa was investigated in clinical and mouse models. H 2 S concentrations and survival was assessed in septic patients with lung infection. Animal experiments using a model of severe systemic multidrug-resistant P . aeruginosa infection were performed using mice with a constitutive knock-out of cystathionine-γ lyase ( Cse) gene ( Cse -/- ) and wild-type mice with a physiological expression ( Cse +/+ ). Experiments were repeated in mice after a) treatment with cyclophosphamide; b) bone marrow transplantation (BMT) from a Cse +/+ donor; c) treatment with H 2 S synthesis inhibitor aminooxyacetic acid (ΑΟΑΑ) or propargylglycine (PAG) and d) H 2 S donor sodium thiosulfate (STS) or GYY3147. Bacterial loads and myeloperoxidase activity were measured in tissue samples. The expression of quorum sensing genes (QS) was determined in vivo and in vitro. Cytokine concentration was measured in serum and incubated splenocytes. Patients survivors at day 28 had significantly higher serum H 2 S compared to non-survivors. A cut- off point of 5.3 μΜ discriminated survivors with sensitivity 92.3%. Mortality after 28 days was 30.9% and 93.7% in patients with H 2 S higher and less than 5.3 μΜ (p = 7 x 10 −6 ). In mice expression of Cse and application of 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 increased pathogen loads compared to Cse +/+ mice. Phagocytic activity of leukocytes from Cse -/- mice was reduced but was restored after H 2 S supplementation. An H 2 S dependent down- regulation of quorum sensing genes of P . aeruginosa could be demonstrated in vivo and in vitro . Endogenous H 2 S is a potential independent parameter correlating with the outcome of P . aeruginosa . H 2 S provides resistance to infection by MDR bacterial pathogens.
Type of Medium:
Online Resource
ISSN:
1553-7374
DOI:
10.1371/journal.ppat.1009473
DOI:
10.1371/journal.ppat.1009473.g001
DOI:
10.1371/journal.ppat.1009473.g002
DOI:
10.1371/journal.ppat.1009473.g003
DOI:
10.1371/journal.ppat.1009473.g004
DOI:
10.1371/journal.ppat.1009473.g005
DOI:
10.1371/journal.ppat.1009473.g006
DOI:
10.1371/journal.ppat.1009473.t001
DOI:
10.1371/journal.ppat.1009473.s001
DOI:
10.1371/journal.ppat.1009473.s002
DOI:
10.1371/journal.ppat.1009473.s003
DOI:
10.1371/journal.ppat.1009473.s004
DOI:
10.1371/journal.ppat.1009473.s005
DOI:
10.1371/journal.ppat.1009473.s006
DOI:
10.1371/journal.ppat.1009473.s007
DOI:
10.1371/journal.ppat.1009473.s008
DOI:
10.1371/journal.ppat.1009473.s009
DOI:
10.1371/journal.ppat.1009473.s010
DOI:
10.1371/journal.ppat.1009473.s011
DOI:
10.1371/journal.ppat.1009473.s012
DOI:
10.1371/journal.ppat.1009473.r001
DOI:
10.1371/journal.ppat.1009473.r002
DOI:
10.1371/journal.ppat.1009473.r003
DOI:
10.1371/journal.ppat.1009473.r004
Language:
English
Publisher:
Public Library of Science (PLoS)
Publication Date:
2021
detail.hit.zdb_id:
2205412-1