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Expression data from mice kidneys with urinary tract infection treated with NlpD or LytM

ABSTRACT: 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. Recombinant NlpD and LytM were screened for interactions with constituents of the RNA Polymerase 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-/- and Asc-/- mice, respectively. 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 >1,900 significantly regulated genes (FC>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. 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.

ORGANISM(S): Mus musculus

PROVIDER: GSE330388 | GEO | 2026/05/15

REPOSITORIES: GEO

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Project description:Acute cystitis is rapidly becoming a therapeutic enigma, as antibiotic resistance is reducing the options to a minimum. Fortunately, new insights are now making it possible to explore immune response modifiers as alternatives to antibiotics. In patients with acute cystitis, infection triggers a rapid and potent inflammatory response in the bladder mucosa and clinical symptoms include pain, urgency and frequency of urination. The molecular basis of these symptoms is not well understood, but bacterial interactions with the bladder epithelium have been shown to create inflammatory cascades. This study examined how innate immune response genes influence the outcome of bladder infection and the pathogenesis of acute cystitis with a particular focus on IL-1β. C57BL/6 mice were intravesically infected with relevant uropathogenic Escherichia coli strain, CFT073. Acute cystitis in infected bladders was defined by macroscopic inspection of edema, hyperemia and purulent discharge followed by histology and immunohistochemistry, after 24 hours and seven days. Genetic determinants of transient bladder inflammation versus severe disease were subsequently identified using C57BL/6 mice with specific inflammasome gene deletions (Il1b-/-, Casp1-/-, Asc-/- and Nlrp3-/-). Using genome-wide transcriptomic analysis to characterize genes regulated by infection in the bladders of these mice, we identified acute cystitis as an IL-1β-driven, hyper-inflammatory disease. Consistent with such a role, Il1b-/- mice were protected from infection and pathology. In contrast Asc-/- and Nlrp3-/- mice developed progressive IL-1β-driven bladder inflammation and severe pathology, caused by a new, non-canonical IL-1β processing mechanism, involving the metalloproteinase MMP-7. Using IL-1β and MMP-7 as targets for immunotherapy, we succeeded in protecting susceptible Asc-/- mice against acute cystitis, confirming the potential of immunotherapy for this indication. The results reproduce important aspects of human cystitis in the murine urinary tract infection (UTI) model and provide a comprehensive molecular framework for the pathogenesis and immunotherapy of acute cystitis, one of the most common bacterial infections in man.

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Expression data from mice kidneys with urinary tract infection treated with NlpD or LytM

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