Doctor of Philosophy, The Ohio State University, 2023, Comparative Biomedical Sciences
Urinary tract infections (UTIs), including cystitis and pyelonephritis, are one of the most common infections across species. Approximately 80% of these infections are caused by uropathogenic Escherichia coli (UPEC). The host's innate immune response is paramount in the defense against UPEC and is initiated by urinary tract epithelial cells with subsequent recruitment of leukocytes. Despite a robust immune response, UPEC can persist in the urinary tract, can cause recurrent infections, and can be resistant to antibiotic therapy. There is a growing and imminent risk for antibiotic resistant UTIs, thus necessitating investigations into alternative therapeutic options. One possibility is utilizing mechanisms to enhance existing host innate immune defenses; however, our understanding of innate immunity against UPEC, especially in the kidney, is limited. In this work, we aimed to characterize the host immune response to UPEC in cell culture and in various important mouse models of UTI to identify potential targets for augmenting host defense against UPEC.
The first portion of this thesis investigates the in vitro pathogenesis of UPEC in one of the host's most important UTI renal defenders, the kidney collecting duct intercalated cell. Previous work from our lab and others have shown that intercalated cells are required for protection against UPEC due to direct binding to these cells, their role in immune cell recruitment, and secretion of bactericidal antimicrobial peptides. We found that upon UPEC infection, intercalated cells activate multiple innate immune pathways including those associated with pattern recognition receptor (PRR) signaling. We identified that nucleotide oligomerization domain (NOD) 2 and Toll-like receptor (TLR) 4 are two intercalated cell PRRs that, upon initial activation, can protect against subsequent UPEC infection. Additionally, NOD2 activation induces upregulation of multiple innate immune pathway genes along with genes associated with vari (open full item for complete abstract)
Committee: John David Spencer (Advisor); Kara Corps (Committee Member); Rachel Cianciolo (Committee Member); Brian Becknell (Committee Member); Sheryl Justice (Advisor)
Subjects: Biology; Immunology; Microbiology; Molecular Biology; Pathology