Human Genetic Approach for UTI Points to Novel Immune Defense Cells of the Kidney Epithelia

Project Summary / Abstract Urinary tract infections (UTI) affect 13.3% of women and 2.3% of men annually with a high rate of recurrence. Infection can be localized to the bladder (cystitis) or track to the kidneys (pyelonephritis), causing life-threatening bacteremia. Increasing antibiotic resistance and indeterminate diagnostics underscore the need for more precise and discriminant UTI diagnostic tools and individualized therapeutics. This proposal aims to perform human genome-wide association studies (GWAS) to identify risk variants associated with UTI. Preliminary data demonstrated candidate genes within novel loci, such as PSCA, that localize their expression to the bladder and kidney papilla, constituting new forms of immune defense. This candidate will be tested in bacterial binding assays and in functional assays using UTI mouse models. Cell type-specific RNA labeling of the bladder urothelium and single nucleus RNA-sequencing (snRNA-seq) of the kidney papilla will be performed to understand the transcriptomic responses of specific cell types to UTIs in a Psca knockout mouse model. The discoveries from this work will reveal novel roles for this candidate gene, as well as clarify mechanisms of the bladder and kidney’s response to UTI. Furthermore, the insights from this research will help accurately identify patients at risk for recurrent UTI or pyelonephritis, informing them to use prevention strategies when exposed to a high burden of bacteria i.e, childbirth, sexual activity, invasive procedures. Along with an exceptional team of leading experts in human genetics of kidney diseases, single cell transcriptomics, bladder malformations, and urinary tract infections, this K01 award will support Dr. Katherine Xu in accomplishing the aims in her proposal, as well as foster her professional development at Columbia University. She will complete additional training in performing and interpreting large-scale human genomic datasets and snRNA-seq datasets, while also expanding her knowledge in host-microbial interactions and in the molecular physiology of diverse cell types in the kidney and bladder. Throughout the award, Dr. Xu will acquire essential skills in leadership, mentorship, scientific writing, and grantsmanship necessary to support a career as an independent scientist. She hopes to eventually lead a multidisciplinary team focused on redefining the genetic basis of human UTI susceptibility and mapping risk variants onto specific cell types, which will help her develop an antimicrobial cell atlas of the kidney and bladder.