Abstract
Urinary tract infections are one of the most common infections in humans. Here we tested the utility of urinary cell-free DNA (cfDNA) to comprehensively monitor host and pathogen dynamics in bacterial and viral urinary tract infections. We isolated cfDNA from 141 urine samples from a cohort of 82 kidney transplant recipients and performed next-generation sequencing. We found that urinary cfDNA is highly informative about bacterial and viral composition of the microbiome, antimicrobial susceptibility, bacterial growth dynamics, kidney allograft injury, and host response to infection. These different layers of information are accessible from a single assay and individually agree with corresponding clinical tests based on quantitative PCR, conventional bacterial culture, and urinalysis. In addition, cfDNA reveals the frequent occurrence of pathologies that remain undiagnosed with conventional diagnostic protocols. Our work identifies urinary cfDNA as a highly versatile analyte to monitor infections of the urinary tract.
Highlights
Urinary tract infections are one of the most common infections in humans
Urinary cell-free DNA (cfDNA) is composed of human chromosomal, mitochondrial, and microbial cfDNA released from host cells and microbes in the urinary tract and of plasma-derived cfDNA that passes from blood into urine[21]
We find that single-stranded library preparation enables sequence analyses of urinary cfDNA from just 1 mL of urine supernatant
Summary
In 40 of these 41 samples, sequencing of urinary cfDNA detected the clinically reported organisms to the species level (Fig. 2b). Whereas bacterial culture is skewed toward species that are readily isolated on routine bacteriological media employed for urine culture, cfDNA sequence analyses permit the identification of a broader spectrum of bacterial species To evaluate this concept further, we assayed two samples collected from one of the subjects included in the analysis above diagnosed with Haemophilus influenzae bacteruria. Korem and colleagues reported that the pattern of metagenomic sequencing read coverage across a microbial genome can be used to quantify microbial genome replication rates for microbes in complex communities[33] We tested whether this concept can be used to estimate bacterial population growth from measurements of cfDNA. Molecular techniques to track DAMPs in urine released in the setting of kidney graft injury may provide a non-invasive window into the potential role of these molecules in immune-related complications
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