ORCID

http://orcid.org/0000-0001-6632-1163

Date of Award

Spring 5-15-2022

Author's School

Graduate School of Arts and Sciences

Author's Department

Biology & Biomedical Sciences (Molecular Microbiology & Microbial Pathogenesis)

Degree Name

Doctor of Philosophy (PhD)

Degree Type

Dissertation

Abstract

Urinary tract infections (UTIs) are the most common infection of women, affecting roughly half of all women during their lifetime. UTIs frequently recur within 6 months to 1 year of the initial infection to cause recurrent UTIs (rUTIs). Repeated treatment of rUTIs with antibiotics may lead to antibiotic resistance, disruption of the microbiota, and adverse effects of the drugs. To avoid excess antibiotic use, there is an urgent need to understand the mechanisms of host defense against infection to identify new targets for UTI treatment and prophylaxis in women with rUTIs. Postmenopausal and older women have the highest risk of rUTIs; however, why rUTIs become more frequent after menopause and during old age is incompletely understood. Aging has substantial effects on the immune system that lead to impaired protection against pathogens yet heightened and prolonged inflammation. How the immune system and its responses to infection changes within the bladder mucosae during aging remains unknown. In this thesis, I investigated how the cellular and molecular immune landscape within the bladder was altered during aging and clinical implications of these changes. I first found that aged mice developed bladder tertiary lymphoid tissues (bTLTs), which are absent in young mice. TLTs resemble the composition and organization of secondary lymphoid organs, such as lymph nodes and Peyer's patches, but arise ectopically in chronically inflamed tissues rather than during development. bTLTs contained large numbers of T cells and B cells and were capable of germinal center formation, class-switch recombination, and plasma cell differentiation to secrete IgA into the urine. The formation of bTLTs in mice occured as a function of age and was independent of microbes but dependent on TNFa, as aged germ-free mice also harbored bTLTs while aged TNFa-deficient mice did not. Furthermore, bTLTs were predominantly found in female bladders and rarely in male bladders. Together, my results have identified a profound age-associated change to the immune landscape of aging female bladders that might drive the significant increase in UTI susceptibility. To determine the relevance of age-associated bTLTs in humans, I examined biopsies of nodular lesions, known as cystitis cystica, that are frequently found by cystoscopy (bladder endoscopy) in women with rUTIs. These biopsies resembled the structure and composition of bTLTs found in aged mice. To further define the role of bTLT in rUTIs, I performed a clinical retrospective analysis of women that have had a cystoscopy. From a cohort of 138 women with culture-proven rUTIs, 38.4% of women had cystitis cystica (CC). Women with CC were significantly older than those without, had a greater number of culture-proven UTIs in the past year, and were more likely to have pelvic floor myofascial pain upon examination. Furthermore, after controlling for the number of prior UTIs, those with CC had a significantly shorter time to next UTI after cystoscopy than those without CC and a greater number of UTIs in the year following cystoscopy. These clinical data suggest that if postmenopausal bladders contain TLTs, they are more likely to be pathogenic than protective. In concordance with these clinical findings, I showed that aged mice were also more susceptible to UTI recurrences than young mice. Together these findings demonstrate that age-associated immune dysfunction at the bladder mucosae contributes to altered immune responses and adverse UTI outcomes. My work establishes a new avenue of investigation of the bladder immune system in homeostasis, aging, and disease.

Language

English (en)

Chair and Committee

Indira U. Mysorekar

Committee Members

Rajendra S. Apte

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