Host cystathionine-γ lyase derived hydrogen sulfide protects against Pseudomonas aeruginosa sepsis

PLoS Pathog. 2021 Mar 26;17(3):e1009473. doi: 10.1371/journal.ppat.1009473. eCollection 2021 Mar.

Abstract

Hydrogen sulfide (H2S) has recently been recognized as a novel gaseous transmitter with several anti-inflammatory properties. The role of host- derived H2S in infections by Pseudomonas aeruginosa was investigated in clinical and mouse models. H2S 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 H2S synthesis inhibitor aminooxyacetic acid (ΑΟΑΑ) or propargylglycine (PAG) and d) H2S 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 H2S 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 H2S 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 H2S supplementation. An H2S dependent down- regulation of quorum sensing genes of P.aeruginosa could be demonstrated in vivo and in vitro. Endogenous H2S is a potential independent parameter correlating with the outcome of P. aeruginosa. H2S provides resistance to infection by MDR bacterial pathogens.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cystathionine gamma-Lyase / metabolism*
  • Humans
  • Hydrogen Sulfide / metabolism*
  • Mice
  • Mice, Knockout
  • Pseudomonas Infections / complications
  • Pseudomonas Infections / metabolism*
  • Pseudomonas aeruginosa
  • Sepsis / metabolism*
  • Sepsis / microbiology

Substances

  • Cystathionine gamma-Lyase
  • Hydrogen Sulfide

Grants and funding

EJG-B has received honoraria (paid to the University of Athens) from AbbVie USA, Abbott CH, Angelini Italy, Biotest Germany, InflaRx GmbH, MSD Greece and XBiotech Inc. He has received independent educational grants from AbbVie, Abbott, Astellas Pharma, AxisShield, bioMérieux Inc, InflaRx GmbH and XBiotech Inc. He has received funding from the FrameWork 7 program HemoSpec and from the Horizon2020 Marie-Curie project European Sepsis Academy (granted to the National and Kapodistrian University of Athens). GR and EK are funded by the European Union's Horizon 2020 Marie Skłodowska-Curie grant European Sepsis Academy No 676129. CSz is supported by SNSF (Swiss National Research Foundation). MB is funded by the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation) under Germany’s Excellence Strategy – EXC 2051 – Project-ID 390713860. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.