{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,7]],"date-time":"2026-08-07T23:53:44Z","timestamp":1786146824657,"version":"build-2736575974"},"reference-count":54,"publisher":"MDPI AG","issue":"11","license":[{"start":{"date-parts":[[2022,11,21]],"date-time":"2022-11-21T00:00:00Z","timestamp":1668988800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Viruses"],"abstract":"<jats:p>Bacterial sepsis characterised by an immunosuppressive and cytokine storm state is a challenge to treat clinically. While conventional antibiotics have been associated with exacerbating the cytokine storm, the role that bacteriophages may play in immune modulation of sepsis remains unclear. Bacteriophages are bacterial viruses that have the capacity to lyse specific bacteria and hence provide a natural alternative to antibiotics. K. pneumoniae is known to cause sepsis in humans, and in this study we isolated two lytic bacteriophages against this pathogen, one of which was a novel jumbo bacteriophage. We employed THP-1 monocyte cell lines, with different functional phenotypes for the interleukin-1 receptor associated kinase 3 (IRAK3- a cytoplasmic homeostatic mediator and prognostic marker of inflammation), to evaluate the role of the K. pneumoniae bacteriophages in modulating the immune response in-vitro. We showed for the first time that bacteriophages did not stimulate excessive production of tumour necrosis factor alpha, or interleukin-6, in THP-1 monocyte cell lines which displayed varying levels of IRAK3 expression.<\/jats:p>","DOI":"10.3390\/v14112582","type":"journal-article","created":{"date-parts":[[2022,11,22]],"date-time":"2022-11-22T03:04:20Z","timestamp":1669086260000},"page":"2582","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["Effects of Klebsiella pneumoniae Bacteriophages on IRAK3 Knockdown\/Knockout THP-1 Monocyte Cell Lines"],"prefix":"10.3390","volume":"14","author":[{"given":"Bryce Dylan","family":"Schubert","sequence":"first","affiliation":[{"name":"Department of Rural Clinical Sciences, La Trobe Rural Health School, La Trobe University, P.O. Box 199, Bendigo, VIC 3550, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Heng","family":"Ku","sequence":"additional","affiliation":[{"name":"Commonwealth Scientific and Industrial Research Organisation, Oceans & Atmosphere, Ecosciences Precinct, Dutton Park, QLD 4102, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6321-9080","authenticated-orcid":false,"given":"Mwila","family":"Kabwe","sequence":"additional","affiliation":[{"name":"Department of Rural Clinical Sciences, La Trobe Rural Health School, La Trobe University, P.O. Box 199, Bendigo, VIC 3550, Australia"},{"name":"La Trobe Institute for Molecular Science, La Trobe University, P.O. Box 199, Bendigo, VIC 3550, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Trang Hong","family":"Nguyen","sequence":"additional","affiliation":[{"name":"Department of Rural Clinical Sciences, La Trobe Rural Health School, La Trobe University, P.O. Box 199, Bendigo, VIC 3550, Australia"},{"name":"La Trobe Institute for Molecular Science, La Trobe University, P.O. Box 199, Bendigo, VIC 3550, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1514-0909","authenticated-orcid":false,"given":"Helen","family":"Irving","sequence":"additional","affiliation":[{"name":"Department of Rural Clinical Sciences, La Trobe Rural Health School, La Trobe University, P.O. Box 199, Bendigo, VIC 3550, Australia"},{"name":"La Trobe Institute for Molecular Science, La Trobe University, P.O. Box 199, Bendigo, VIC 3550, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4495-6931","authenticated-orcid":false,"given":"Joseph","family":"Tucci","sequence":"additional","affiliation":[{"name":"Department of Rural Clinical Sciences, La Trobe Rural Health School, La Trobe University, P.O. Box 199, Bendigo, VIC 3550, Australia"},{"name":"La Trobe Institute for Molecular Science, La Trobe University, P.O. Box 199, Bendigo, VIC 3550, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2022,11,21]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"589","DOI":"10.1128\/CMR.11.4.589","article-title":"Klebsiella spp. as nosocomial pathogens: Epidemiology, taxonomy, typing methods, and pathogenicity factors","volume":"11","author":"Podschun","year":"1998","journal-title":"Clin. Microbiol. Rev."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"e191","DOI":"10.1097\/INF.0000000000001154","article-title":"Etiology, Antibiotic Resistance and Risk Factors for Neonatal Sepsis in a Large Referral Center in Zambia","volume":"35","author":"Kabwe","year":"2016","journal-title":"Pediatr. Infect. Dis. J."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"785","DOI":"10.1016\/S1473-3099(13)70190-7","article-title":"Clinical epidemiology of the global expansion of Klebsiella pneumoniae carbapenemases","volume":"13","author":"Poirel","year":"2013","journal-title":"Lancet Infect. Dis."},{"key":"ref_4","unstructured":"Antimicrobial Resistance Collaborators (2022). Global burden of bacterial antimicrobial resistance in 2019: A systematic analysis. Lancet, 399, 629\u2013655."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"16045","DOI":"10.1038\/nrdp.2016.45","article-title":"Sepsis and septic shock","volume":"2","author":"Hotchkiss","year":"2016","journal-title":"Nat. Rev. Dis. Primers"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"146","DOI":"10.1017\/S0265021507003389","article-title":"Advances in understanding sepsis","volume":"42","author":"Shimaoka","year":"2008","journal-title":"Eur. J. Anaesthesiol."},{"key":"ref_7","first-page":"3042","article-title":"Identification of key pathogenic genes of sepsis based on the Gene Expression Omnibus database","volume":"17","author":"Lu","year":"2018","journal-title":"Mol. Med. Rep."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"a011247","DOI":"10.1101\/cshperspect.a011247","article-title":"Toll-like receptor signaling","volume":"5","author":"Lim","year":"2013","journal-title":"Cold Spring Harb. Perspect. Biol."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"553","DOI":"10.3389\/fimmu.2014.00553","article-title":"IL-1 Receptor-Associated Kinase Signaling and Its Role in Inflammation, Cancer Progression, and Therapy Resistance","volume":"5","author":"Jain","year":"2014","journal-title":"Front. Immunol."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"191","DOI":"10.1016\/S0092-8674(02)00827-9","article-title":"IRAK-M is a negative regulator of Toll-like receptor signaling","volume":"110","author":"Kobayashi","year":"2002","journal-title":"Cell"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"19403","DOI":"10.1074\/jbc.274.27.19403","article-title":"IRAK-M is a novel member of the Pelle\/interleukin-1 receptor-associated kinase (IRAK) family","volume":"274","author":"Wesche","year":"1999","journal-title":"J. Biol. Chem."},{"key":"ref_12","doi-asserted-by":"crossref","unstructured":"Nguyen, T.H., Turek, I., Meehan-Andrews, T., Zacharias, A., and Irving, H.R. (2022). A systematic review and meta-analyses of interleukin-1 receptor associated kinase 3 (IRAK3) action on inflammation in in vivo models for the study of sepsis. PLoS ONE, 17.","DOI":"10.1371\/journal.pone.0263968"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"195","DOI":"10.1016\/j.molmed.2014.01.007","article-title":"Why have clinical trials in sepsis failed?","volume":"20","author":"Marshall","year":"2014","journal-title":"Trends Mol. Med."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"109750","DOI":"10.1016\/j.celrep.2021.109750","article-title":"Inappropriate use of antibiotics exacerbates inflammation through OMV-induced pyroptosis in MDR Klebsiella pneumoniae infection","volume":"36","author":"Ye","year":"2021","journal-title":"Cell Rep."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"739","DOI":"10.1128\/AAC.42.4.739","article-title":"Antibiotic-induced lipopolysaccharide (LPS) release from Salmonella typhi: Delay between killing by ceftazidime and imipenem and release of LPS","volume":"42","author":"Kwappenberg","year":"1998","journal-title":"Antimicrob. Agents Chemother."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"191","DOI":"10.1002\/alr.21646","article-title":"Bactericidal antibiotics promote reactive oxygen species formation and inflammation in human sinonasal epithelial cells","volume":"6","author":"Kohanski","year":"2016","journal-title":"Int. Forum Allergy Rhinol."},{"key":"ref_17","first-page":"1193","article-title":"Frapper fort ou frapper doucement: A Gram-negative dilemma","volume":"2","author":"Hopkin","year":"1978","journal-title":"Lancet"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"1075","DOI":"10.1038\/s41564-022-01157-1","article-title":"Phage\u2013host coevolution in natural populations","volume":"7","author":"Piel","year":"2022","journal-title":"Nat. Microbiol."},{"key":"ref_19","doi-asserted-by":"crossref","unstructured":"Van Belleghem, J.D., Dabrowska, K., Vaneechoutte, M., Barr, J.J., and Bollyky, P.L. (2018). Interactions between Bacteriophage, Bacteria, and the Mammalian Immune System. Viruses, 11.","DOI":"10.3390\/v11010010"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"1163","DOI":"10.1182\/blood.V80.5.1163.1163","article-title":"Antibody responses to bacteriophage phi X174 in patients with adenosine deaminase deficiency","volume":"80","author":"Ochs","year":"1992","journal-title":"Blood"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"279","DOI":"10.5694\/mja2.50355","article-title":"Phage therapy for severe bacterial infections: A narrative review","volume":"212","author":"Khalid","year":"2020","journal-title":"Med. J. Aust."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"465","DOI":"10.1038\/s41564-019-0634-z","article-title":"Safety of bacteriophage therapy in severe Staphylococcus aureus infection","volume":"5","author":"Lin","year":"2020","journal-title":"Nat. Microbiol."},{"key":"ref_23","first-page":"267720","article-title":"Proinflammatory Cytokine Levels in Sepsis and in Health and TNF\u03b1 Association with Sepsis Mortality and patient characteristics: A Systematic Review and Meta-analysis","volume":"12","author":"Gharamti","year":"2021","journal-title":"medRxiv"},{"key":"ref_24","doi-asserted-by":"crossref","unstructured":"Song, J., Park, D.W., Moon, S., Cho, H.-J., Park, J.H., Seok, H., and Choi, W.S. (2019). Diagnostic and prognostic value of interleukin-6, pentraxin 3, and procalcitonin levels among sepsis and septic shock patients: A prospective controlled study according to the Sepsis-3 definitions. BMC Infect. Dis., 19.","DOI":"10.1186\/s12879-019-4618-7"},{"key":"ref_25","first-page":"31","article-title":"Effective phage therapy is associated with normalization of cytokine production by blood cell cultures","volume":"48","author":"Zimecki","year":"2000","journal-title":"Arch. Immunol. Ther. Exp. Warsz."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"569","DOI":"10.1097\/CCM.0b013e318194b1bf","article-title":"Immunosuppression associated with interleukin-1R-associated-kinase-M upregulation predicts mortality in Gram-negative sepsis (melioidosis)","volume":"37","author":"Wiersinga","year":"2009","journal-title":"Crit. Care Med."},{"key":"ref_27","doi-asserted-by":"crossref","unstructured":"Nguyen, T.H., Axell, A., Turek, I., Wright, B., Meehan-Andrews, T., and Irving, H.R. (2022). Modulation of Inflammatory Cytokine Production in Human Monocytes by cGMP and IRAK3. Int. J. Mol. Sci., 23.","DOI":"10.3390\/ijms23052552"},{"key":"ref_28","doi-asserted-by":"crossref","unstructured":"Brown, T.L., Petrovski, S., Hoyle, D., Chan, H.T., Lock, P., and Tucci, J. (2017). Characterization and formulation into solid dosage forms of a novel bacteriophage lytic against Klebsiella oxytoca. PLoS ONE, 12.","DOI":"10.1371\/journal.pone.0183510"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"51","DOI":"10.1007\/978-1-0716-1518-8_4","article-title":"Isolation and Functional Characterization of Fusobacterium nucleatum Bacteriophage","volume":"2327","author":"Kabwe","year":"2021","journal-title":"Methods Mol. Biol."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"1714","DOI":"10.1002\/bit.25571","article-title":"A non-chromatographic method for the removal of endotoxins from bacteriophages","volume":"112","author":"Branston","year":"2015","journal-title":"Biotechnol. Bioeng."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"671","DOI":"10.1038\/nmeth.2089","article-title":"NIH Image to ImageJ: 25 years of image analysis","volume":"9","author":"Schneider","year":"2012","journal-title":"Nat. Methods"},{"key":"ref_32","doi-asserted-by":"crossref","unstructured":"Wick, R.R., Judd, L.M., Gorrie, C.L., and Holt, K.E. (2017). Unicycler: Resolving bacterial genome assemblies from short and long sequencing reads. PLoS Comput. Biol., 13.","DOI":"10.1371\/journal.pcbi.1005595"},{"key":"ref_33","doi-asserted-by":"crossref","unstructured":"Aziz, R.K., Bartels, D., Best, A.A., DeJongh, M., Disz, T., Edwards, R.A., Formsma, K., Gerdes, S., Glass, E.M., and Kubal, M. (2008). The RAST Server: Rapid Annotations using Subsystems Technology. BMC Genom., 9.","DOI":"10.1186\/1471-2164-9-75"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"2379","DOI":"10.1093\/bioinformatics\/btx157","article-title":"ViPTree: The viral proteomic tree server","volume":"33","author":"Nishimura","year":"2017","journal-title":"Bioinformatics"},{"key":"ref_35","first-page":"pdb-top17","article-title":"Using the Basic Local Alignment Search Tool (BLAST)","volume":"2007","author":"Mount","year":"2007","journal-title":"CSH Protoc."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"289","DOI":"10.1093\/bioinformatics\/btg412","article-title":"APE: Analyses of Phylogenetics and Evolution in R language","volume":"20","author":"Paradis","year":"2004","journal-title":"Bioinformatics"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"28","DOI":"10.1111\/2041-210X.12628","article-title":"ggtree: An R package for visualization and annotation of phylogenetic trees with their covariates and other associated data","volume":"8","author":"Yu","year":"2017","journal-title":"Methods Ecol. Evol."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"W54","DOI":"10.1093\/nar\/gkw413","article-title":"tRNAscan-SE On-line: Integrating search and context for analysis of transfer RNA genes","volume":"44","author":"Lowe","year":"2016","journal-title":"Nucleic Acids Res."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"W52","DOI":"10.1093\/nar\/gkm360","article-title":"CRISPRFinder: A web tool to identify clustered regularly interspaced short palindromic repeats","volume":"35","author":"Grissa","year":"2007","journal-title":"Nucleic Acids Res."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"D566","DOI":"10.1093\/nar\/gkw1004","article-title":"CARD 2017: Expansion and model-centric curation of the comprehensive antibiotic resistance database","volume":"45","author":"Jia","year":"2017","journal-title":"Nucleic Acids Res."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"e01404","DOI":"10.1128\/MRA.01404-20","article-title":"Complete Genome Sequence of Klebsiella pneumoniae Jumbo Phage Miami","volume":"10","author":"Mora","year":"2021","journal-title":"Microbiol. Resour. Announc."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"194","DOI":"10.3389\/fmicb.2020.00194","article-title":"Novel Bacteriophages Capable of Disrupting Biofilms From Clinical Strains of Aeromonas hydrophila","volume":"11","author":"Kabwe","year":"2020","journal-title":"Front. Microbiol."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"1486","DOI":"10.1101\/gr.6649807","article-title":"Causes for the intriguing presence of tRNAs in phages","volume":"17","author":"Vergassola","year":"2007","journal-title":"Genome Res."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"1263","DOI":"10.1177\/1535370221995154","article-title":"Bacteriophages immunomodulate the response of monocytes","volume":"246","author":"Perea","year":"2021","journal-title":"Exp. Biol. Med."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"1767","DOI":"10.1161\/01.CIR.101.15.1767","article-title":"Plasma concentration of interleukin-6 and the risk of future myocardial infarction among apparently healthy men","volume":"101","author":"Ridker","year":"2000","journal-title":"Circulation"},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"681","DOI":"10.1016\/j.chom.2021.02.007","article-title":"Rethinking phage-bacteria-eukaryotic relationships and their influence on human health","volume":"29","author":"Wahida","year":"2021","journal-title":"Cell Host Microbe"},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"2559","DOI":"10.1172\/JCI106756","article-title":"Immunologic responses to bacteriophage \u03d5X 174 in immunodeficiency diseases","volume":"50","author":"Ochs","year":"1971","journal-title":"J. Clin. Investig."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"e2055","DOI":"10.1002\/rmv.2055","article-title":"Interaction of phages, bacteria, and the human immune system: Evolutionary changes in phage therapy","volume":"29","author":"Jariah","year":"2019","journal-title":"Rev. Med. Virol."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"3730519","DOI":"10.1155\/2019\/3730519","article-title":"Bacteriophages: Uncharacterized and Dynamic Regulators of the Immune System","volume":"2019","author":"Sinha","year":"2019","journal-title":"Mediat. Inflamm."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"8004","DOI":"10.1038\/s41598-017-08336-9","article-title":"Pro- and anti-inflammatory responses of peripheral blood mononuclear cells induced by Staphylococcus aureus and Pseudomonas aeruginosa phages","volume":"7","author":"Clement","year":"2017","journal-title":"Sci. Rep."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"1614","DOI":"10.3389\/fmicb.2018.01614","article-title":"Staphylococcus aureus Bacteriophage Suppresses LPS-Induced Inflammation in MAC-T Bovine Mammary Epithelial Cells","volume":"9","author":"Zhang","year":"2018","journal-title":"Front. Microbiol."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"285","DOI":"10.1016\/j.chom.2019.01.008","article-title":"Expansion of Bacteriophages Is Linked to Aggravated Intestinal Inflammation and Colitis","volume":"25","author":"Gogokhia","year":"2019","journal-title":"Cell Host Microbe"},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"730","DOI":"10.1038\/s41591-019-0437-z","article-title":"Engineered bacteriophages for treatment of a patient with a disseminated drug-resistant Mycobacterium abscessus","volume":"25","author":"Dedrick","year":"2019","journal-title":"Nat. Med."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"1179","DOI":"10.1164\/rccm.201904-0839LE","article-title":"Bacteriophage Therapy of Ventilator-associated Pneumonia and Empyema Caused by Pseudomonas aeruginosa","volume":"200","author":"Maddocks","year":"2019","journal-title":"Am. J. Respir. Crit. Care Med."}],"container-title":["Viruses"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1999-4915\/14\/11\/2582\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T01:22:55Z","timestamp":1760145775000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1999-4915\/14\/11\/2582"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,11,21]]},"references-count":54,"journal-issue":{"issue":"11","published-online":{"date-parts":[[2022,11]]}},"alternative-id":["v14112582"],"URL":"https:\/\/doi.org\/10.3390\/v14112582","relation":{},"ISSN":["1999-4915"],"issn-type":[{"value":"1999-4915","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,11,21]]}}}