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

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.