Abstract

Indwelling medical devices are essential components of patient care. However, they can also be a source of opportunistic infections that lead to significant patient morbidity and mortality. Within the human urogenital tract, the two most common medical devices are urinary catheters, which are used in both inpatient and outpatient settings, and intrauterine devices (IUDs), which are the most popular long-acting reversible contraceptive method worldwide. Urinary catheters are extremely prone to infection: the risk of catheter-associated urinary tract infection (CAUTI) is estimated to rise by 8% per 24-hour period and reaches 100% with prolonged catheter use. Conversely, IUDs are rarely associated with symptomatic infection despite close contact with many of the same urogenital flora that cause CAUTI. Investigations into the mechanisms of CAUTI pathogenesis over the past decade have revealed how CAUTI pathogens take advantage of host inflammatory responses to colonize the surface of urinary catheters. These data have both uncovered promising targets for antibiotic-sparing therapies for CAUTI, and raised the question of whether similar mechanisms may be at play within the reproductive tract. In this thesis, I have developed two therapeutic strategies for the treatment of CAUTI and investigated the composition of microbial biofilms on the surface of intrauterine devices. The pathogenesis of CAUTI begins with insertion of a urinary catheter into the urethra and bladder, which initiates a pro-inflammatory foreign-body reaction leading to the deposition of serum proteins, including the serum clotting factor fibrinogen (Fg), onto the catheter surface. Multiple uropathogens express adhesive pili that bind to deposited Fg to colonize the catheter and cause disease. The Gram-negative bacterium Acinetobacter baumannii, which is considered a “pathogen of urgent concern” by the World Health Organization and the US Centers for Disease Control and Prevention due to high levels of carbapenem resistance, expresses two pili, Abp1 and Abp2, that facilitate binding to Fg to cause CAUTI. I investigated both a vaccine, which targets the Acinetobacter adhesins, and monoclonal antibody (mAb) approach to target A. baumannii CAUTI. I first determined that immunization with Abp2D, and not Abp1D, conferred protection from CAUTI. The vaccine elicits strong antigen-specific memory B cell and bone marrow plasma cell responses in immunized mice which result in high levels of circulating antigen-specific IgG. The immune serum was used to passively immunize naïve mice to show that protection is antibody-mediated, providing proof-of-concept that an adhesin-based vaccine is an effective prevention strategy for A. baumannii CAUTI. I also cloned more than 60 mAbs against Abp2D and screened them for inhibition of the Abp2D-Fg interaction as well as binding to whole A. baumannii bacterial cells in vitro. The top mAb candidates from each screen were tested for in vivo protection. None of the mAbs tested provided any degree of protection from CAUTI, suggesting that the polyclonal antibody response generated by the vaccine may be required for protection. Similar to the role of host Fg deposition on urinary catheters, host protein deposition and biofilm formation has been described on every type of medical device investigated to date, such as artificial heart valves, stents and shunts, and breast implants, which range in the severity of clinical implications. As intrauterine devices 1) may be in place for up to 12 years, 2) feature a string which extends through the cervix to make contact with the vaginal microbiome, and 3) exist in an organ which receives extensive immune surveillance (the uterus), we wondered whether IUDs are subject to the same processes of host protein, and in particular Fg, deposition and whether vaginal flora and/or opportunistic bacteria may take advantage of these host proteins to colonize the surface of the IUD. To investigate this question, we collected 45 IUDs and paired vaginal swabs from healthy women without symptoms of a pelvic infection (including UTI, bacterial vaginosis, vulvovaginal candidiasis, or sexually transmitted infection). IUDs and swabs were aerobically cultured and subjected to 16S sequencing. Of the 45 collected IUDs, 30 were hormonal and 15 were copper to facilitate comparisons by IUD type. Patient metadata such as the duration of IUD use, infection history, and history of antibiotic use were also collected. Some degree of bacterial colonization was detectable on all tested devices by 16S sequencing. The most frequently identified culturable species included Enterococcus faecalis, Streptococcus agalactiae, and Staphylococcus spp. This work represents the first investigation of IUD flora in asymptomatic patients and lays the groundwork for future microbiological studies of this overlooked yet ubiquitous medical device.

Committee Chair

Scott Hultgren

Committee Members

Ali Ellebedy; Andrew Kau; Christina Stallings; Nicole Gilbert

Degree

Doctor of Philosophy (PhD)

Author's Department

Biology & Biomedical Sciences (Immunology)

Author's School

Graduate School of Arts and Sciences

Document Type

Dissertation

Date of Award

4-21-2026

Language

English (en)

Author's ORCID

https://orcid.org/0000-0002-2947-9508

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Available for download on Friday, April 16, 2027

Included in

Microbiology Commons

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