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The role of host- derived H<jats:sub>2<\/jats:sub>S in infections by <jats:italic>Pseudomonas aeruginosa<\/jats:italic> was investigated in clinical and mouse models. H<jats:sub>2<\/jats:sub>S concentrations and survival was assessed in septic patients with lung infection. Animal experiments using a model of severe systemic multidrug-resistant <jats:italic>P<\/jats:italic>. <jats:italic>aeruginosa<\/jats:italic> infection were performed using mice with a constitutive knock-out of cystathionine-\u03b3 lyase (<jats:italic>Cse)<\/jats:italic> gene (<jats:italic>Cse<\/jats:italic><jats:sup><jats:italic>-\/-<\/jats:italic><\/jats:sup>) and wild-type mice with a physiological expression (<jats:italic>Cse<\/jats:italic><jats:sup><jats:italic>+\/+<\/jats:italic><\/jats:sup>). Experiments were repeated in mice after a) treatment with cyclophosphamide; b) bone marrow transplantation (BMT) from a <jats:italic>Cse<\/jats:italic><jats:sup><jats:italic>+\/+<\/jats:italic><\/jats:sup> donor; c) treatment with H<jats:sub>2<\/jats:sub>S synthesis inhibitor aminooxyacetic acid (\u0391\u039f\u0391\u0391) or propargylglycine (PAG) and d) H<jats:sub>2<\/jats:sub>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<jats:sub>2<\/jats:sub>S compared to non-survivors. A cut- off point of 5.3 \u03bc\u039c discriminated survivors with sensitivity 92.3%. Mortality after 28 days was 30.9% and 93.7% in patients with H<jats:sub>2<\/jats:sub>S higher and less than 5.3 \u03bc\u039c (p = 7 x 10<jats:sup>\u22126<\/jats:sup>). In mice expression of <jats:italic>Cse<\/jats:italic> and application of STS afforded protection against infection with multidrug-resistant <jats:italic>P<\/jats:italic>. <jats:italic>aeruginosa<\/jats:italic>. Cyclophosphamide pretreatment eliminated the survival benefit of <jats:italic>Cse<\/jats:italic><jats:sup><jats:italic>+\/+<\/jats:italic><\/jats:sup> mice, whereas BMT increased the survival of <jats:italic>Cse<\/jats:italic><jats:sup><jats:italic>-\/-<\/jats:italic><\/jats:sup> mice. <jats:italic>Cse<\/jats:italic><jats:sup><jats:italic>-\/-<\/jats:italic><\/jats:sup> mice had increased pathogen loads compared to <jats:italic>Cse<\/jats:italic><jats:sup><jats:italic>+\/+<\/jats:italic><\/jats:sup> mice. Phagocytic activity of leukocytes from <jats:italic>Cse<\/jats:italic><jats:sup><jats:italic>-\/-<\/jats:italic><\/jats:sup> mice was reduced but was restored after H<jats:sub>2<\/jats:sub>S supplementation. An H<jats:sub>2<\/jats:sub>S dependent down- regulation of quorum sensing genes of <jats:italic>P<\/jats:italic>.<jats:italic>aeruginosa<\/jats:italic> could be demonstrated <jats:italic>in vivo<\/jats:italic> and <jats:italic>in vitro<\/jats:italic>. Endogenous H<jats:sub>2<\/jats:sub>S is a potential independent parameter correlating with the outcome of <jats:italic>P<\/jats:italic>. <jats:italic>aeruginosa<\/jats:italic>. H<jats:sub>2<\/jats:sub>S provides resistance to infection by MDR bacterial pathogens.<\/jats:p>","DOI":"10.1371\/journal.ppat.1009473","type":"journal-article","created":{"date-parts":[[2021,3,26]],"date-time":"2021-03-26T17:45:09Z","timestamp":1616780709000},"page":"e1009473","update-policy":"https:\/\/doi.org\/10.1371\/journal.ppat.corrections_policy","source":"Crossref","is-referenced-by-count":23,"title":["Host cystathionine-\u03b3 lyase derived hydrogen sulfide protects against Pseudomonas aeruginosa sepsis"],"prefix":"10.1371","volume":"17","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-2985-0901","authenticated-orcid":true,"given":"Georgios","family":"Renieris","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dionysia-Eirini","family":"Droggiti","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Konstantina","family":"Katrini","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7800-3306","authenticated-orcid":true,"given":"Panagiotis","family":"Koufargyris","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Theologia","family":"Gkavogianni","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eleni","family":"Karakike","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7552-5878","authenticated-orcid":true,"given":"Nikolaos","family":"Antonakos","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Georgia","family":"Damoraki","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Athanasios","family":"Karageorgos","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Labros","family":"Sabracos","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Antonia","family":"Katsouda","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4790-7860","authenticated-orcid":true,"given":"Elisa","family":"Jentho","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sebastian","family":"Weis","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rui","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1521-3514","authenticated-orcid":true,"given":"Michael","family":"Bauer","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3110-4235","authenticated-orcid":true,"given":"Csaba","family":"Szabo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2977-7895","authenticated-orcid":true,"given":"Kalliopi","family":"Platoni","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vasilios","family":"Kouloulias","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4253-5930","authenticated-orcid":true,"given":"Andreas","family":"Papapetropoulos","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4713-3911","authenticated-orcid":true,"given":"Evangelos J.","family":"Giamarellos-Bourboulis","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"340","published-online":{"date-parts":[[2021,3,26]]},"reference":[{"key":"ppat.1009473.ref001","doi-asserted-by":"crossref","first-page":"272","DOI":"10.1186\/1471-2334-14-272","article-title":"Bloodstream infections and sepsis in Greece: over-time change of epidemiology and impact of de-escalation on final outcome","volume":"14","author":"M Koupetori","year":"2014","journal-title":"BMC Infect Dis"},{"key":"ppat.1009473.ref002","doi-asserted-by":"crossref","first-page":"497","DOI":"10.1124\/pr.117.014050","article-title":"International union of basic and clinical pharmacology. 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