Genetic variation influences the severity of urinary tract infections and subsequent immune responses in the bladder and remote tissues in the collaborative cross mouse model

Summary: Immunogenetics is the study of the genetic basis of the immune response and has significant potential to provide insight into health and disease. Initial insights have come from studying circulating peripheral immune cell populations and correlating these cells with clinical outcomes, however immune cells vary across tissues and some cell types including macrophages can only be found in tissues and not in the circulation. Regulation of the tissue specific immune response is complex and involves multiple molecular mechanisms. Tissue specific immunity is significantly influenced by the secretion of cytokines and growth factors by tissue specific cells. Utilizing the inbred mouse model has allowed scientists to evaluate these regulators of tissue specific immunity, as mice and humans share 99% of genes. One significant advantage of the inbred mouse model is availability of numerous immunological tools including gene knock-out and gene knock-in that can be employed to identify the role of a specific protein in immune pathways. However, the genetic variation found in humans results in a variety of individualized immune responses to infectious and autoimmune diseases, and this cannot not be captured in the traditional inbred laboratory mouse model. In contrast, the genetically diverse collaborative cross mice have permitted the application of genetic approaches to study the diversity of tissue specific immunity in the lung and have identified genes associated with infection resistance, susceptibility, and severity. However, this approach as not been applied in the field of urology, bladder immunity and to urinary tract infections (UTI), one of the most common bacterial infections. UTI are predominantly caused by uropathogenic Escherichia coli which infect a healthy population with incidence in women much higher than in men and nearly half of all women have reoccurring UTIs. Currently, mechanisms for the high rates of reoccurrence and severity are unknown, albeit genetics and immunity must play an important role in controlling UTI. There have been some focused studies that have identified a few genes that lead to either increased resistance or susceptibility to UTI. However, the immunogenetics of the bladder and kidney in the steady state and during a UTI is less well studied at the genome wide scale. This project will use the collaborative cross mice in order to evaluate the heterogenicity of UTI and the subsequent immune responses, more accurately mimicking observations made in the human population. We will evaluate the immune response in the bladder and remote tissues (including the kidney, spleen, and brain) that may give insight into UTI complications and comorbidities. Using the publicly available whole genome sequencing data we will identify quantitative trait loci and genes associated with the severity, susceptibility, or resistance to UTIs and bladder macrophage immunoregulation. Our work will define novel subsets of macrophages, differentially activated in the diverse collaborative cross mice. Furthermore, these results will inform the selection of additional strains of mice to be used in further investigation of UTI pathogenesis.