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Single nucleus transcriptomics to study sex differences during murine E. coli pyelonephritis

ABSTRACT: This project employs models of urinary tract infection (UTI) in female, androgen-exposed female, and male mice to determine molecular mechanisms by which host androgen exposure promotes Escherichia coli pyelonephritis as well as renal scarring, a common sequela of upper-tract UTI. Our prior findings indicated that the influence of sex, including androgen exposure, on these common bacterial infections is more complex than previously appreciated. Specifically, male sex was associated with increased risk for chronic cystitis and high-titer pyelonephritis, as well as formation of renal abscesses. These snRNA-seq experiments were designed to interrogate the fundamental sex differences impacting the host-pathogen interaction and cellular responses in E. coli pyelonephritis, thereby influencing pathogenicity and outcome of infection.

ORGANISM(S): Mus musculus

PROVIDER: GSE296327 | GEO | 2026/02/18

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.

Project description:Renal scarring is a serious complication of chronic pyelonephritis due to vesicoureteral reflux, and requires specific biomarker for indication of early intervention. We investigated global expression profile of kidney during renal scarring formation using rat pyelonephritis model. An inoculum of the DS-17 strain Escherchia coli was injected directly into renal cortex of Wister rat. Histologically, renal scarring developed during 3 and 4 weeks after injection. The time course expression profile of approximately 20,500 genes was analyzed using high density oligonucleotide microarray followed by validation using real time RT-PCR. Most of up-regulated genes during this experimental renal scarring were associated with immune and defense response, including cytokines, chemokines, their receptors, complements, and adhesion molecules as well as proteins related to extra cellular matrix. These genes were up-regulated as early as 1 week after injection when histological examination did not show fibrotic change yet, peaked at 2 weeks and gradually decreased thereafter. However, a subset of cytokine genes is persistently activated even in 6 weeks after the injection, which are involved in TGF-Î² related tissue regeneration pathway or IL-1Î² related pathway. The products of these genes may potentially be the source of novel non-invasive diagnostic or prognostic biomarkers for renal scarring. Experiment Overall Design: Experimental pyelonephritis was produced by standard method of direct infection of rat kidney. In brief, animals were anesthetized with pentobarbital intraperitoneally. The kidneys were exposed through a midline abdominal incision. An inoculum of 1x109 colony-forming units / 0.1 ml of Escherchia coli was injected directly into bilateral renal cortex of Wister rat using 26-gauge needle. We used DS-17 or NU-14 strains, both of which has type 1 and P pili, and SEC strain, which has only type 1 pili. Control rats received isotonic saline instead of bacterial solution. Both test and control kidneys were harvested at 1, 2, 4 and 6 weeks after injection. The kidney samples (1x1x2 mm each) were obtained including the injection site, which was easily identified by surface color change. Then we cut the kidney into half; one was used for microscopic examination and the other half was immediately frozen in liquid nitrogen for later RNA extraction.

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Single nucleus transcriptomics to study sex differences during murine E. coli pyelonephritis

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