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

Area of Science:

• Nephrology
• Immunology
• Genomics

Background:

• Urinary tract infections (UTI) exhibit significant sex-based disparities in prevalence and severity.
• Males experience higher morbidity and mortality from upper-tract UTI, with preclinical models showing heightened susceptibility in males and androgen-exposed females to severe pyelonephritis.

Purpose of the Study:

• To investigate sex-discrepant transcriptional responses in the kidney during pyelonephritis using single-nucleus RNA sequencing.
• To create the first whole-kidney single-nucleus transcriptomic dataset of an infected state.

Main Methods:

• Single-nucleus RNA sequencing was performed on kidneys from female, male, and androgen-exposed female mice with pyelonephritis, alongside PBS-exposed controls.
• Analysis differentiated healthy kidney cell populations from those affected by UTI, identifying sex-specific transcriptional changes.

Main Results:

• Sex-discrepant responses to UTI were observed across multiple kidney cell types, extending beyond direct bacterial interaction sites.
• Female responses involved a narrower range of cell types with upregulated inflammatory genes and transcription factor regulons.
• Male mice showed a predisposition to injury pathways even with saline inoculation and responded to UTI across more cell types but with less intensity than females.

Conclusions:

• The study reveals distinct sex-based transcriptional patterns in renal infection, highlighting differential cellular and molecular mechanisms.
• These findings provide a detailed cellular and molecular basis for understanding sex differences in kidney infection outcomes.