{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,10]],"date-time":"2026-06-10T07:04:57Z","timestamp":1781075097362,"version":"3.54.1"},"reference-count":36,"publisher":"MDPI AG","issue":"1","license":[{"start":{"date-parts":[[2023,12,31]],"date-time":"2023-12-31T00:00:00Z","timestamp":1703980800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"the European Union\u2019s Horizon 2020 research and innovation program","award":["No. 954360"],"award-info":[{"award-number":["No. 954360"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Pathogens"],"abstract":"<jats:p>Innate immunity is essential for the anti-microbial defense, but excessive immune activation may cause severe disease. In this study, immunotherapy was shown to prevent excessive innate immune activation and restore the anti-bacterial defense. E. coli-infected Asc\u2212\/\u2212 mice develop severe acute cystitis, defined by IL-1 hyper-activation, high bacterial counts, and extensive tissue pathology. Here, the interleukin-1 receptor antagonist (IL-1RA), which inhibits IL-1 hyper-activation in acute cystitis, was identified as a more potent inhibitor of inflammation and NK1R- and substance P-dependent pain than cefotaxime. Furthermore, IL-1RA treatment inhibited the excessive innate immune activation in the kidneys of infected Irf3\u2212\/\u2212 mice and restored tissue integrity. Unexpectedly, IL-1RA also accelerated bacterial clearance from infected bladders and kidneys, including antibiotic-resistant E. coli, where cefotaxime treatment was inefficient. The results suggest that by targeting the IL-1 response, control of the innate immune response to infection may be regained, with highly favorable treatment outcomes, including infections caused by antibiotic-resistant strains.<\/jats:p>","DOI":"10.3390\/pathogens13010042","type":"journal-article","created":{"date-parts":[[2023,12,31]],"date-time":"2023-12-31T06:00:21Z","timestamp":1704002421000},"page":"42","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["Therapeutic Effects of IL-1RA against Acute Bacterial Infections, including Antibiotic-Resistant Strains"],"prefix":"10.3390","volume":"13","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-1470-671X","authenticated-orcid":false,"given":"Ines","family":"Ambite","sequence":"first","affiliation":[{"name":"Division of Microbiology, Immunology and Glycobiology, Department of Laboratory Medicine, Faculty of Medicine, Lund University, 221 84 Lund, Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thi Hien","family":"Tran","sequence":"additional","affiliation":[{"name":"Division of Microbiology, Immunology and Glycobiology, Department of Laboratory Medicine, Faculty of Medicine, Lund University, 221 84 Lund, Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6717-545X","authenticated-orcid":false,"given":"Daniel S. 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Antibiotic Resistance. Available online: www.who.int\/news-room\/fact-sheets\/detail\/antimicrobial-resistance."},{"key":"ref_2","doi-asserted-by":"crossref","unstructured":"Ambite, I., Puthia, M., Nagy, K., Cafaro, C., Nadeem, A., Butler, D.S., Rydstrom, G., Filenko, N.A., Wullt, B., and Miethke, T. (2016). Molecular Basis of Acute Cystitis Reveals Susceptibility Genes and Immunotherapeutic Targets. PLoS Pathog., 12.","DOI":"10.1371\/journal.ppat.1005848"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"336ra59","DOI":"10.1126\/scitranslmed.aaf1156","article-title":"IRF7 inhibition prevents destructive innate immunity\u2014A target for nonantibiotic therapy of bacterial infections","volume":"8","author":"Puthia","year":"2016","journal-title":"Sci. Transl. Med."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"11015","DOI":"10.1038\/s41598-018-28634-0","article-title":"Neuroepithelial control of mucosal inflammation in acute cystitis","volume":"8","author":"Butler","year":"2018","journal-title":"Sci. Rep."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"419","DOI":"10.1038\/s41585-022-00602-4","article-title":"Immunomodulation therapy offers new molecular strategies to treat UTI","volume":"19","author":"Butler","year":"2022","journal-title":"Nat. Rev. Urol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"468","DOI":"10.1038\/s41585-021-00477-x","article-title":"Molecular determinants of disease severity in urinary tract infection","volume":"18","author":"Ambite","year":"2021","journal-title":"Nat. Rev. Urol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"324","DOI":"10.1038\/nature01182","article-title":"Essential role for TIRAP in activation of the signalling cascade shared by TLR2 and TLR4","volume":"420","author":"Yamamoto","year":"2002","journal-title":"Nature"},{"key":"ref_8","doi-asserted-by":"crossref","unstructured":"Fischer, H., Lutay, N., Ragnarsdottir, B., Yadav, M., Jonsson, K., Urbano, A., Al Hadad, A., Ramisch, S., Storm, P., and Dobrindt, U. (2010). Pathogen specific, IRF3-dependent signaling and innate resistance to human kidney infection. PLoS Pathog., 6.","DOI":"10.1371\/journal.ppat.1001109"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"760","DOI":"10.1016\/j.chom.2016.05.016","article-title":"The Roles of Type I Interferon in Bacterial Infection","volume":"19","author":"Boxx","year":"2016","journal-title":"Cell Host Microbe"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"519","DOI":"10.1146\/annurev.immunol.021908.132612","article-title":"Immunological and inflammatory functions of the interleukin-1 family","volume":"27","author":"Dinarello","year":"2009","journal-title":"Annu. Rev. Immunol."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"e140333","DOI":"10.1172\/JCI140333","article-title":"Active bacterial modification of the host environment through RNA polymerase II inhibition","volume":"131","author":"Ambite","year":"2021","journal-title":"J. Clin. Investig."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"564","DOI":"10.1128\/iai.31.2.564-570.1981","article-title":"Adhesion, hemagglutination, and virulence of Escherichia coli causing urinary tract infections","volume":"31","author":"Hagberg","year":"1981","journal-title":"Infect. Immun."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"1281","DOI":"10.1128\/iai.58.5.1281-1289.1990","article-title":"Pyelonephritogenic Escherichia coli and killing of cultured human renal proximal tubular epithelial cells: Role of hemolysin in some strains","volume":"58","author":"Mobley","year":"1990","journal-title":"Infect. Immun."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"539","DOI":"10.1016\/S1074-7613(00)00053-4","article-title":"Distinct and essential roles of transcription factors IRF-3 and IRF-7 in response to viruses for IFN-alpha\/beta gene induction","volume":"13","author":"Sato","year":"2000","journal-title":"Immunity"},{"key":"ref_15","doi-asserted-by":"crossref","unstructured":"Rudick, C.N., Bryce, P.J., Guichelaar, L.A., Berry, R.E., and Klumpp, D.J. (2008). Mast cell-derived histamine mediates cystitis pain. PLoS ONE, 3.","DOI":"10.1371\/journal.pone.0002096"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"223","DOI":"10.2165\/00003495-198325030-00001","article-title":"Cefotaxime. A review of its antibacterial activity, pharmacological properties and therapeutic use","volume":"25","author":"Carmine","year":"1983","journal-title":"Drugs"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"10791","DOI":"10.1038\/ncomms10791","article-title":"IL-1 receptor antagonist ameliorates inflammasome-dependent inflammation in murine and human cystic fibrosis","volume":"7","author":"Iannitti","year":"2016","journal-title":"Nat. Commun."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"e393","DOI":"10.1016\/S2665-9913(20)30164-8","article-title":"Anakinra for severe forms of COVID-19: A cohort study","volume":"2","author":"Huet","year":"2020","journal-title":"Lancet Rheumatol."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"172","DOI":"10.1038\/sc.2015.206","article-title":"Role of neurokinin type 1 receptor in nociception at the periphery and the spinal level in the rat","volume":"54","author":"Gautam","year":"2016","journal-title":"Spinal Cord"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"49","DOI":"10.1016\/j.euros.2021.07.003","article-title":"Immunomodulation-A Molecular Solution to Treating Patients with Severe Bladder Pain Syndrome?","volume":"31","author":"Wullt","year":"2021","journal-title":"Eur. Urol. Open Sci."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"151","DOI":"10.1016\/j.peptides.2014.04.003","article-title":"Changes in urine levels of substance P, vasoactive intestinal peptide and calcitonin-gene-related peptide in patients with urinary tract infections","volume":"56","author":"Altuntas","year":"2014","journal-title":"Peptides"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"129","DOI":"10.1016\/S0090-4295(01)01100-1","article-title":"Urinary substance P concentration correlates with urinary frequency and urgency in interstitial cystitis patients treated with intravesical dimethyl sulfoxide and not intravesical anesthetic cocktail","volume":"57","author":"Kushner","year":"2001","journal-title":"Urology"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"436","DOI":"10.1016\/S0090-4295(99)80469-5","article-title":"Mast cell and substance P-positive nerve involvement in a patient with both irritable bowel syndrome and interstitial cystitis","volume":"47","author":"Pang","year":"1996","journal-title":"Urology"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"653","DOI":"10.1038\/nrurol.2010.190","article-title":"The epidemiology of urinary tract infection","volume":"7","author":"Foxman","year":"2010","journal-title":"Nat. Rev. Urol."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"269","DOI":"10.1038\/nrmicro3432","article-title":"Urinary tract infections: Epidemiology, mechanisms of infection and treatment options","volume":"13","author":"Walker","year":"2015","journal-title":"Nat. Rev. Microbiol."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"788","DOI":"10.1099\/jmm.0.000498","article-title":"Spectrum and antibiotic resistance of uropathogens between 2004 and 2015 in a tertiary care hospital in Hungary","volume":"66","author":"Magyar","year":"2017","journal-title":"J. Med. Microbiol."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"S32","DOI":"10.1086\/514920","article-title":"Antibiotic resistance caused by gram-negative multidrug efflux pumps","volume":"27","author":"Nikaido","year":"1998","journal-title":"Clin. Infect. Dis."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"500","DOI":"10.1016\/S1369-5274(00)00242-3","article-title":"Multidrug resistance in Gram-negative bacteria","volume":"4","author":"Poole","year":"2001","journal-title":"Curr. Opin. Microbiol."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"2255","DOI":"10.1128\/AAC.37.11.2255","article-title":"Antibiotic-supersusceptible mutants of Escherichia coli and Salmonella typhimurium","volume":"37","author":"Vaara","year":"1993","journal-title":"Antimicrob. Agents Chemother."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"107","DOI":"10.4103\/0974-777X.56255","article-title":"Antibiotic Sensitivity and Plasmid Profiles of Escherichia coli Isolated from Pediatric Diarrhea","volume":"1","author":"Uma","year":"2009","journal-title":"J. Glob. Infect. Dis."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"302","DOI":"10.4315\/0362-028X.JFP-17-191","article-title":"Antibiotic Resistance Profile of Commensal Escherichia coli Isolated from Broiler Chickens in Qatar","volume":"81","author":"Eltai","year":"2018","journal-title":"J. Food Prot."},{"key":"ref_32","doi-asserted-by":"crossref","unstructured":"Terlizzi, M.E., Gribaudo, G., and Maffei, M.E. (2017). UroPathogenic Escherichia coli (UPEC) Infections: Virulence Factors, Bladder Responses, Antibiotic, and Non-antibiotic Antimicrobial Strategies. Front. Microbiol., 8.","DOI":"10.3389\/fmicb.2017.01566"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"1846","DOI":"10.1016\/S0022-5347(01)64882-1","article-title":"Pediatric Vesicoureteral Reflux Guidelines Panel summary report on the management of primary vesicoureteral reflux in children","volume":"157","author":"Elder","year":"1997","journal-title":"J. Urol."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"239","DOI":"10.1056\/NEJMra1007755","article-title":"Febrile urinary tract infections in children","volume":"365","author":"Montini","year":"2011","journal-title":"N. Engl. J. Med."},{"key":"ref_35","first-page":"CD001534","article-title":"Long-term antibiotics for preventing recurrent urinary tract infection in children","volume":"4","author":"Williams","year":"2019","journal-title":"Cochrane Database Syst. Rev."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"255","DOI":"10.1016\/j.diagmicrobio.2013.11.011","article-title":"Prevalence of antibiotic resistance in US hospitals","volume":"78","author":"Edelsberg","year":"2014","journal-title":"Diagn. Microbiol. Infect. Dis."}],"container-title":["Pathogens"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2076-0817\/13\/1\/42\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T21:45:13Z","timestamp":1760132713000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2076-0817\/13\/1\/42"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,12,31]]},"references-count":36,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2024,1]]}},"alternative-id":["pathogens13010042"],"URL":"https:\/\/doi.org\/10.3390\/pathogens13010042","relation":{},"ISSN":["2076-0817"],"issn-type":[{"value":"2076-0817","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,12,31]]}}}