Single-nucleus transcriptomics illuminates sex differences during murine Escherichia coli pyelonephritis.

Area of Science:

• Immunology
• Genomics
• Urology

Background:

• Urinary tract infections (UTI) display significant sex disparities in prevalence and outcomes.
• Males experience higher morbidity and mortality from upper-tract UTI compared to females.
• Preclinical models show males and androgen-exposed females are susceptible to severe pyelonephritis.

Purpose of the Study:

• To investigate sex-discrepant cellular and molecular responses in the kidney during high-titer pyelonephritis.
• To generate the first whole-kidney single-nucleus transcriptomic dataset of renal infection.

Main Methods:

• Single-nucleus RNA sequencing (snRNA-seq) was performed on kidneys from female, male, and androgen-exposed female mice with pyelonephritis.
• Control groups received phosphate-buffered saline (PBS) inoculation.
• Bioinformatic analysis identified cell populations and transcriptional changes.

Main Results:

• Sex-discrepant transcriptional responses were observed across multiple kidney cell types.
• Female UTI response involved fewer cell types with upregulated pro-inflammatory genes.
• Male mice showed a predisposition to injury pathways and responded across more cell types, even with saline control.

Conclusions:

• Kidney infections elicit distinct sex-specific transcriptional responses.
• Understanding these sex differences is crucial for addressing disparities in UTI outcomes.
• The generated dataset provides a foundation for further cellular and molecular dissection of renal infection responses.