{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,2]],"date-time":"2026-09-02T17:12:50Z","timestamp":1788369170668,"version":"build-2803163510"},"reference-count":45,"publisher":"Oxford University Press (OUP)","issue":"2","license":[{"start":{"date-parts":[[2026,5,6]],"date-time":"2026-05-06T00:00:00Z","timestamp":1778025600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2026,9,2]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Finding new ways of treating bacterial infections is essential. The NlpD protein, which inhibits RNA polymerase II (Pol II), has shown therapeutic efficacy against urinary tract infection. This study investigated the mechanism of Pol II inhibition and protection by NlpD and its LytM peptide.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>Recombinant NlpD and LytM were screened for interactions with constituents of the Pol II complex, using AlphaFold predictions and protein interaction technology. Treatment effects were quantified in infected tissues and regulated host response pathways identified by genome-wide transcriptomics analysis in models of acute pyelonephritis and acute cystitis in Irf3\u2212\/\u2212 and Asc\u2212\/\u2212 mice, respectively.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>LytM was shown to interact with constituents of the Pol II multiprotein complex, inhibiting the CDK12 kinase from phosphorylating the Pol II subunit RPB1 and disrupting Pol II complex formation by interfering with the interaction between PAF1C and RPB1. The protection by LytM against acute pyelonephritis was accompanied by a reduction in gene expression in infected kidneys from &amp;gt;1900 significantly regulated genes (fold change &amp;gt;6) in the placebo group to about 150 in LytM-treated mice. The inhibition of gene expression in infected kidneys particularly targeted the excessive innate immune response. A similar effect was observed in acute cystitis. Bacterial clearance was accelerated in both model by LytM treatment, with effects against antibiotic-sensitive and resistant Escherichia coli strains.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>The results suggest that inhibiting the disease response of the host, using NlpD or LytM, may offer an efficient alternative to antibiotics in these models.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1093\/infdis\/jiag243","type":"journal-article","created":{"date-parts":[[2026,5,4]],"date-time":"2026-05-04T11:20:03Z","timestamp":1777893603000},"page":"e316-e329","source":"Crossref","is-referenced-by-count":0,"title":["Targeting the Disease Response With NlpD and LytM for Effective Nonantibiotic Treatment of Urinary Tract Infections"],"prefix":"10.1093","volume":"234","author":[{"given":"Hien Thi","family":"Tran","sequence":"first","affiliation":[{"name":"Department of Laboratory Medicine, Division of Microbiology, Immunology and Glycobiology, Lund University , Lund ,","place":["Sweden"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"In\u00eas","family":"Gomes","sequence":"additional","affiliation":[{"name":"Department of Laboratory Medicine, Division of Microbiology, Immunology and Glycobiology, Lund University , Lund ,","place":["Sweden"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Arunima","family":"Chaudhuri","sequence":"additional","affiliation":[{"name":"Department of Laboratory Medicine, Division of Microbiology, Immunology and Glycobiology, Lund University , Lund ,","place":["Sweden"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Atefeh","family":"Nazari","sequence":"additional","affiliation":[{"name":"Department of Laboratory Medicine, Division of Microbiology, Immunology and Glycobiology, Lund University , Lund ,","place":["Sweden"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shahram","family":"Ahmadi","sequence":"additional","affiliation":[{"name":"Department of Laboratory Medicine, Division of Microbiology, Immunology and Glycobiology, Lund University , Lund ,","place":["Sweden"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0007-3516-3140","authenticated-orcid":false,"given":"Hanna","family":"V\u00e9gh","sequence":"additional","affiliation":[{"name":"Department of Laboratory Medicine, Division of Microbiology, Immunology and Glycobiology, Lund University , Lund ,","place":["Sweden"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ant\u00f3nio N B M","family":"Carneiro","sequence":"additional","affiliation":[{"name":"Department of Laboratory Medicine, Division of Microbiology, Immunology and Glycobiology, Lund University , Lund ,","place":["Sweden"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Urban","family":"H\u00f6glund","sequence":"additional","affiliation":[{"name":"Legado Bio , Stockholm ,","place":["Sweden"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christian","family":"Krintel","sequence":"additional","affiliation":[{"name":"Department of Laboratory Medicine, Division of Microbiology, Immunology and Glycobiology, Lund University , Lund ,","place":["Sweden"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Catharina","family":"Svanborg","sequence":"additional","affiliation":[{"name":"Department of Laboratory Medicine, Division of Microbiology, Immunology and Glycobiology, Lund University , Lund ,","place":["Sweden"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1470-671X","authenticated-orcid":false,"given":"Ines","family":"Ambite","sequence":"additional","affiliation":[{"name":"Department of Laboratory Medicine, Division of Microbiology, Immunology and Glycobiology, Lund University , Lund ,","place":["Sweden"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2026,5,6]]},"reference":[{"key":"2026090212174089300_jiag243-B1","doi-asserted-by":"crossref","first-page":"i939","DOI":"10.1136\/bmj.i939","article-title":"Global prevalence of antibiotic resistance in paediatric urinary tract infections caused by Escherichia coli and association with routine use of antibiotics in primary care: systematic review and meta-analysis","volume":"352","author":"Bryce","year":"2016","journal-title":"BMJ"},{"key":"2026090212174089300_jiag243-B2","doi-asserted-by":"crossref","first-page":"586","DOI":"10.1038\/s41585-020-0362-4","article-title":"Epidemiology, definition and treatment of complicated urinary tract infections","volume":"17","author":"Wagenlehner","year":"2020","journal-title":"Nat Rev Urol"},{"key":"2026090212174089300_jiag243-B3","doi-asserted-by":"crossref","first-page":"1199","DOI":"10.1016\/S0140-6736(24)01867-1","article-title":"Global burden of bacterial antimicrobial resistance 1990-2021: a systematic analysis with forecasts to 2050","volume":"404","author":"Naghavi","year":"2024","journal-title":"Lancet"},{"key":"2026090212174089300_jiag243-B4","doi-asserted-by":"crossref","first-page":"e897","DOI":"10.1016\/S2468-2667(22)00225-0","article-title":"The burden of bacterial antimicrobial resistance in the WHO European region in 2019: a cross-country systematic analysis","volume":"7","author":"Mestrovic","year":"2022","journal-title":"Lancet Public Health"},{"key":"2026090212174089300_jiag243-B5","first-page":"1","volume-title":"Pathogen-derived immunomodulatory molecules","author":"Donaldson","year":"2009"},{"key":"2026090212174089300_jiag243-B6","doi-asserted-by":"crossref","first-page":"3787","DOI":"10.2147\/DDDT.S261283","article-title":"Bacterial natural compounds with anti-inflammatory and immunomodulatory properties (mini review)","volume":"14","author":"Jenab","year":"2020","journal-title":"Drug Des Devel Ther"},{"key":"2026090212174089300_jiag243-B7","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":"2026090212174089300_jiag243-B8","doi-asserted-by":"crossref","first-page":"2366","DOI":"10.1172\/JCI66451","article-title":"Bacterial control of host gene expression through RNA polymerase II","volume":"123","author":"Lutay","year":"2013","journal-title":"J Clin Invest"},{"key":"2026090212174089300_jiag243-B9","doi-asserted-by":"crossref","DOI":"10.1172\/JCI153234","article-title":"Collateral effects of deletion of nlpD on rpoS and rpoS-dependent genes. Reply","volume":"131","author":"Ambite","year":"2021","journal-title":"J Clin Invest"},{"key":"2026090212174089300_jiag243-B10","doi-asserted-by":"crossref","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 Invest"},{"key":"2026090212174089300_jiag243-B11","doi-asserted-by":"crossref","DOI":"10.1101\/cshperspect.a000414","article-title":"The bacterial cell envelope","volume":"2","author":"Silhavy","year":"2010","journal-title":"Cold Spring Harb Perspect Biol"},{"key":"2026090212174089300_jiag243-B12","doi-asserted-by":"crossref","first-page":"679","DOI":"10.1038\/s41592-022-01488-1","article-title":"ColabFold: making protein folding accessible to all","volume":"19","author":"Mirdita","year":"2022","journal-title":"Nat Methods"},{"key":"2026090212174089300_jiag243-B13","doi-asserted-by":"crossref","first-page":"6778","DOI":"10.1038\/s41598-025-88093-2","article-title":"Multitarget mechanism of MYC inhibition by the bacterial lon protease in disease","volume":"15","author":"Ambite","year":"2025","journal-title":"Sci Rep"},{"key":"2026090212174089300_jiag243-B14","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":"2026090212174089300_jiag243-B15","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":"2026090212174089300_jiag243-B16","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":"2026090212174089300_jiag243-B17","doi-asserted-by":"crossref","first-page":"42","DOI":"10.3390\/pathogens13010042","article-title":"Therapeutic effects of IL-1RA against acute bacterial infections, including antibiotic-resistant strains","volume":"13","author":"Ambite","year":"2024","journal-title":"Pathogens"},{"key":"2026090212174089300_jiag243-B18","doi-asserted-by":"crossref","first-page":"1113","DOI":"10.1006\/jmbi.2000.3778","article-title":"The structure of a LysM domain from E. coli membrane-bound lytic murein transglycosylase D (MltD)","volume":"299","author":"Bateman","year":"2000","journal-title":"J Mol Biol"},{"key":"2026090212174089300_jiag243-B19","doi-asserted-by":"crossref","first-page":"690","DOI":"10.1111\/mmi.12304","article-title":"Structure\u2013function analysis of the LytM domain of EnvC, an activator of cell wall remodelling at the Escherichia coli division site","volume":"89","author":"Peters","year":"2013","journal-title":"Mol Microbiol"},{"key":"2026090212174089300_jiag243-B20","doi-asserted-by":"crossref","first-page":"47","DOI":"10.1186\/1742-4690-4-47","article-title":"Inhibition of HIV-1 replication by P-TEFb inhibitors DRB, seliciclib and flavopiridol correlates with release of free P-TEFb from the large, inactive form of the complex","volume":"4","author":"Biglione","year":"2007","journal-title":"Retrovirology"},{"key":"2026090212174089300_jiag243-B21","doi-asserted-by":"crossref","first-page":"27176","DOI":"10.1074\/jbc.271.43.27176","article-title":"Control of RNA polymerase II elongation potential by a novel carboxyl-terminal domain kinase","volume":"271","author":"Marshall","year":"1996","journal-title":"J Biol Chem"},{"key":"2026090212174089300_jiag243-B22","doi-asserted-by":"crossref","first-page":"2303","DOI":"10.1101\/gad.1968210","article-title":"CDK12 is a transcription elongation-associated CTD kinase, the metazoan ortholog of yeast Ctk1","volume":"24","author":"Bartkowiak","year":"2010","journal-title":"Genes Dev"},{"key":"2026090212174089300_jiag243-B23","doi-asserted-by":"crossref","first-page":"7712","DOI":"10.1093\/nar\/gkaa514","article-title":"CDK12 globally stimulates RNA polymerase II transcription elongation and carboxyl-terminal domain phosphorylation","volume":"48","author":"Tellier","year":"2020","journal-title":"Nucleic Acids Res"},{"key":"2026090212174089300_jiag243-B24","doi-asserted-by":"crossref","first-page":"4691","DOI":"10.1128\/MCB.06267-11","article-title":"Interaction of cyclin-dependent kinase 12\/CrkRS with cyclin K1 is required for the phosphorylation of the C-terminal domain of RNA polymerase II","volume":"32","author":"Cheng","year":"2012","journal-title":"Mol Cell Biol"},{"key":"2026090212174089300_jiag243-B25","doi-asserted-by":"crossref","first-page":"1383","DOI":"10.1126\/science.aad2338","article-title":"RNA polymerase II\u2013associated factor 1 regulates the release and phosphorylation of paused RNA polymerase II","volume":"350","author":"Yu","year":"2015","journal-title":"Science"},{"key":"2026090212174089300_jiag243-B26","doi-asserted-by":"crossref","first-page":"612","DOI":"10.1128\/MCB.25.2.612-620.2005","article-title":"The parafibromin tumor suppressor protein is part of a human Paf1 complex","volume":"25","author":"Rozenblatt-Rosen","year":"2005","journal-title":"Mol Cell Biol"},{"key":"2026090212174089300_jiag243-B27","doi-asserted-by":"crossref","first-page":"3505","DOI":"10.1038\/ncomms4505","article-title":"The structure and substrate specificity of human Cdk12\/cyclin K","volume":"5","author":"B\u00f6sken","year":"2014","journal-title":"Nat Commun"},{"key":"2026090212174089300_jiag243-B28","doi-asserted-by":"crossref","first-page":"359","DOI":"10.1038\/nature17970","article-title":"Near-atomic resolution visualization of human transcription promoter opening","volume":"533","author":"He","year":"2016","journal-title":"Nature"},{"key":"2026090212174089300_jiag243-B29","doi-asserted-by":"crossref","first-page":"859","DOI":"10.1038\/s41594-018-0118-5","article-title":"Architecture of Pol II(G) and molecular mechanism of transcription regulation by Gdown1","volume":"25","author":"Jishage","year":"2018","journal-title":"Nat Struct Mol Biol"},{"key":"2026090212174089300_jiag243-B30","doi-asserted-by":"crossref","first-page":"397","DOI":"10.1038\/s41594-019-0220-3","article-title":"Transcription preinitiation complex structure and dynamics provide insight into genetic diseases","volume":"26","author":"Yan","year":"2019","journal-title":"Nat Struc Mol Biol"},{"key":"2026090212174089300_jiag243-B31","doi-asserted-by":"crossref","DOI":"10.1126\/science.aba8490","article-title":"Structural insights into preinitiation complex assembly on core promoters","volume":"372","author":"Chen","year":"2021","journal-title":"Science"},{"key":"2026090212174089300_jiag243-B32","doi-asserted-by":"crossref","first-page":"52","DOI":"10.1126\/science.abg3074","article-title":"Structure of the human mediator-bound transcription preinitiation complex","volume":"372","author":"Abdella","year":"2021","journal-title":"Science"},{"key":"2026090212174089300_jiag243-B33","doi-asserted-by":"crossref","first-page":"698","DOI":"10.1093\/procel\/pwad010","article-title":"Structural basis of INTAC-regulated transcription","volume":"14","author":"Zheng","year":"2023","journal-title":"Protein Cell"},{"key":"2026090212174089300_jiag243-B34","doi-asserted-by":"crossref","DOI":"10.1371\/journal.ppat.1005848","article-title":"Molecular basis of acute cystitis reveals susceptibility genes and immunotherapeutic targets","volume":"12","author":"Ambite","year":"2016","journal-title":"PLoS Pathog"},{"key":"2026090212174089300_jiag243-B35","doi-asserted-by":"crossref","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":"2026090212174089300_jiag243-B36","doi-asserted-by":"crossref","first-page":"281","DOI":"10.1186\/1471-2407-9-281","article-title":"The cyclin-dependent kinase inhibitor 5, 6-dichloro-1-beta-D-ribofuranosylbenzimidazole induces nongenotoxic, DNA replication-independent apoptosis of normal and leukemic cells, regardless of their p53 status","volume":"9","author":"Turinetto","year":"2009","journal-title":"BMC Cancer"},{"key":"2026090212174089300_jiag243-B37","doi-asserted-by":"crossref","first-page":"3354","DOI":"10.3390\/ijms21093354","article-title":"Therapeutic targeting of the general RNA polymerase II transcription machinery","volume":"21","author":"Martin","year":"2020","journal-title":"Int J Mol Sci"},{"key":"2026090212174089300_jiag243-B38","doi-asserted-by":"crossref","first-page":"640","DOI":"10.1021\/jm301475f","article-title":"Substituted 4-(thiazol-5-yl)-2-(phenylamino)pyrimidines are highly active CDK9 inhibitors: synthesis, X-ray crystal structures, structure\u2013activity relationship, and anticancer activities","volume":"56","author":"Shao","year":"2013","journal-title":"J Med Chem"},{"key":"2026090212174089300_jiag243-B39","doi-asserted-by":"crossref","first-page":"39","DOI":"10.1007\/s12032-021-01636-1","article-title":"CDK9 inhibitors in multiple myeloma: a review of progress and perspectives","volume":"39","author":"Borowczak","year":"2022","journal-title":"Med Oncol"},{"key":"2026090212174089300_jiag243-B40","doi-asserted-by":"crossref","first-page":"186","DOI":"10.1038\/nature08449","article-title":"Defining mechanisms that regulate RNA polymerase II transcription in vivo","volume":"461","author":"Fuda","year":"2009","journal-title":"Nature"},{"key":"2026090212174089300_jiag243-B41","doi-asserted-by":"crossref","first-page":"881","DOI":"10.1084\/jem.192.6.881","article-title":"Interleukin 8 receptor deficiency confers susceptibility to acute experimental pyelonephritis and may have a human counterpart","volume":"192","author":"Frendeus","year":"2000","journal-title":"J Exp Med"},{"key":"2026090212174089300_jiag243-B42","doi-asserted-by":"crossref","first-page":"1227","DOI":"10.1086\/512620","article-title":"Inherited susceptibility to acute pyelonephritis: a family study of urinary tract infection","volume":"195","author":"Lundstedt","year":"2007","journal-title":"J Infect Dis"},{"key":"2026090212174089300_jiag243-B43","doi-asserted-by":"crossref","DOI":"10.1371\/journal.ppat.1001109","article-title":"Pathogen specific, IRF3-dependent signaling and innate resistance to human kidney infection","volume":"6","author":"Fischer","year":"2010","journal-title":"PLoS Pathog"},{"key":"2026090212174089300_jiag243-B44","doi-asserted-by":"crossref","first-page":"1064","DOI":"10.1038\/ki.2011.257","article-title":"Acute pyelonephritis and renal scarring are caused by dysfunctional innate immunity in mCxcr2 heterozygous mice","volume":"80","author":"Svensson","year":"2011","journal-title":"Kidney Int"},{"key":"2026090212174089300_jiag243-B45","doi-asserted-by":"crossref","DOI":"10.1128\/mBio.00262-10","article-title":"Dissemination and systemic colonization of uropathogenic Escherichia coli in a murine model of bacteremia","volume":"1","author":"Smith","year":"2010","journal-title":"mBio"}],"container-title":["The Journal of Infectious Diseases"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/academic.oup.com\/jid\/advance-article-pdf\/doi\/10.1093\/infdis\/jiag243\/68235239\/jiag243.pdf","content-type":"application\/pdf","content-version":"am","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/jid\/article-pdf\/234\/2\/e316\/68235239\/jiag243.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/jid\/article-pdf\/234\/2\/e316\/68235239\/jiag243.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,9,2]],"date-time":"2026-09-02T16:18:39Z","timestamp":1788365919000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/jid\/article\/234\/2\/e316\/8671387"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,5,6]]},"references-count":45,"journal-issue":{"issue":"2","published-online":{"date-parts":[[2026,5,6]]},"published-print":{"date-parts":[[2026,9,2]]}},"URL":"https:\/\/doi.org\/10.1093\/infdis\/jiag243","relation":{},"ISSN":["0022-1899","1537-6613"],"issn-type":[{"value":"0022-1899","type":"print"},{"value":"1537-6613","type":"electronic"}],"subject":[],"published-other":{"date-parts":[[2026,8,15]]},"published":{"date-parts":[[2026,5,6]]}}}