{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,6,24]],"date-time":"2026-06-24T05:59:23Z","timestamp":1782280763015,"version":"3.54.5"},"posted":{"date-parts":[[2025,9,28]]},"group-title":"Immunology","reference-count":49,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2025,9,28]],"date-time":"2025-09-28T00:00:00Z","timestamp":1759017600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/www.biorxiv.org\/about\/FAQ#license"}],"funder":[{"name":"R01","award":["AI160167"],"award-info":[{"award-number":["AI160167"]}]},{"name":"UCSF Physician Scientist Scholars Program"},{"name":"UCSF Parnassus Flow CoLab"},{"name":"DRC Center Grant NIH","award":["P30 DK063720"],"award-info":[{"award-number":["P30 DK063720"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2025,9,28]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                <jats:p>\n                  <jats:italic>Pseudomonas aeruginosa<\/jats:italic>\n                  (PA) is responsible for significant morbidity and mortality particularly in patients with chronic lung diseases such as chronic obstructive pulmonary disease (COPD), bronchiectasis, cystic fibrosis (CF) as well as hospital-acquired pneumonia (HAP) and ventilator-associated pneumonia (VAP). The rise of antibiotic-resistant PA strains necessitates alternative treatment strategies. Among the different toxins secreted by PA, Exotoxin-A (Exo-A) becomes cytotoxic when cleaved by furin. This study investigates the therapeutic potential of furin inhibitor BOS-318 in mitigating acute lung injury induced by Exo-A and PA infection. Furin inhibition significantly improved survival rates and reduced lung injury in mouse pneumonia models using Exo-A and PA103. Additionally, BOS-318 accelerated bacterial clearance in vivo, and increased phagocytosis by alveolar macrophages. Bulk RNA-seq immune profiling revealed modulation of the natural killer (NK) cell signaling pathway possibly due to a decrease in NK recruitment, suggesting a role of furin in shaping the immune response. Overall, our findings demonstrate that furin inhibition protects against PA-induced acute lung injury and hastens bacterial clearance. These results are the first to characterize furin inhibition in animal models and supports its potential use as an adjunctive therapeutic strategy for treating PA infections.\n                <\/jats:p>","DOI":"10.1101\/2025.09.25.678606","type":"posted-content","created":{"date-parts":[[2025,9,29]],"date-time":"2025-09-29T04:50:22Z","timestamp":1759121422000},"source":"Crossref","is-referenced-by-count":0,"title":["Furin Inhibition Protects Against Acute Lung Injury in a Mouse Model of Pseudomonas Aeruginosa Infection"],"prefix":"10.64898","author":[{"given":"Olivier","family":"Bernard","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael","family":"Kwon","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mark R","family":"Looney","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"M\u00e9lia","family":"Magnen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michelle A","family":"Yu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"54368","reference":[{"key":"2025100222002409000_2025.09.25.678606v1.1","doi-asserted-by":"publisher","DOI":"10.1097\/MCC.0000000000000526"},{"key":"2025100222002409000_2025.09.25.678606v1.2","doi-asserted-by":"publisher","DOI":"10.1007\/s40265-021-01635-6"},{"key":"2025100222002409000_2025.09.25.678606v1.3","unstructured":"https:\/\/www.ecfs.eu\/sites\/default\/files\/Annual%20Report_2021_09Jun2023.pdf."},{"key":"2025100222002409000_2025.09.25.678606v1.4","doi-asserted-by":"publisher","DOI":"10.1002\/ppul.23036"},{"key":"2025100222002409000_2025.09.25.678606v1.5","doi-asserted-by":"publisher","DOI":"10.1086\/533452"},{"key":"2025100222002409000_2025.09.25.678606v1.6","doi-asserted-by":"publisher","DOI":"10.1093\/clinids\/6.Supplement_3.S617"},{"key":"2025100222002409000_2025.09.25.678606v1.7","doi-asserted-by":"crossref","first-page":"104037","DOI":"10.1016\/j.meegid.2019.104037","article-title":"A systematic review and meta-analysis on Exo-toxins prevalence in hospital acquired Pseudomonas aeruginosa isolates","volume":"75","year":"2019","journal-title":"Infect Genet Evol"},{"issue":"4","key":"2025100222002409000_2025.09.25.678606v1.8","first-page":"648","article-title":"Association of systemic immune complexes, complement activation, and antibodies to Pseudomonas aeruginosa lipopolysaccharide and exotoxin A with mortality in cystic fibrosis","volume":"133","year":"1986","journal-title":"Am Rev Respir Dis"},{"issue":"1","key":"2025100222002409000_2025.09.25.678606v1.9","doi-asserted-by":"crossref","first-page":"138","DOI":"10.1128\/iai.15.1.138-144.1977","article-title":"Mechanism of action of Pseudomonas aeruginosa exotoxin Aiadenosine diphosphate-ribosylation of mammalian elongation factor 2 in vitro and in vivo","volume":"15","year":"1977","journal-title":"Infect Immun"},{"issue":"50","key":"2025100222002409000_2025.09.25.678606v1.10","doi-asserted-by":"crossref","first-page":"31831","DOI":"10.1016\/S0021-9258(18)31770-8","article-title":"Furin activates Pseudomonas exotoxin A by specific cleavage in vivo and in vitro","volume":"269","year":"1994","journal-title":"J Biol Chem"},{"key":"2025100222002409000_2025.09.25.678606v1.11","doi-asserted-by":"publisher","DOI":"10.1128\/IAI.63.1.82-87.1995"},{"issue":"5","key":"2025100222002409000_2025.09.25.678606v1.12","first-page":"353","article-title":"Association of the Exotoxin A and Exoenzyme S with Antimicrobial Resistance in Pseudomonas Aeruginosa Strains","volume":"19","year":"2016","journal-title":"Arch Iran Med"},{"key":"2025100222002409000_2025.09.25.678606v1.13","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2017.01283"},{"issue":"6","key":"2025100222002409000_2025.09.25.678606v1.14","doi-asserted-by":"crossref","first-page":"947","DOI":"10.1016\/j.chembiol.2022.02.001","article-title":"A highly selective, cell-permeable furin inhibitor BOS-318 rescues key features of cystic fibrosis airway disease","volume":"29","year":"2022","journal-title":"Cell Chem Biol"},{"issue":"3","key":"2025100222002409000_2025.09.25.678606v1.15","doi-asserted-by":"crossref","first-page":"eade8039","DOI":"10.1126\/sciadv.ade8039","article-title":"Codelivery of synergistic antimicrobials with polyelectrolyte nanocomplexes to treat bacterial biofilms and lung infections","volume":"9","year":"2023","journal-title":"Sci Adv"},{"key":"2025100222002409000_2025.09.25.678606v1.16","doi-asserted-by":"crossref","unstructured":"Lefrancais E , Mallavia B , Zhuo H , Calfee CS , and Looney MR . 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