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Microbial Cooperation During Clostridioides difficile Infection / Alexander B Smith.
- Format:
- Book
- Thesis/Dissertation
- Author/Creator:
- Smith, Alexander B., author.
- Language:
- English
- Subjects (All):
- Microbiology.
- Ecology.
- Cellular biology.
- Pathology.
- Cell and Molecular Biology--Penn dissertations.
- Penn dissertations--Cell and Molecular Biology.
- Local Subjects:
- Microbiology.
- Ecology.
- Cellular biology.
- Pathology.
- Cell and Molecular Biology--Penn dissertations.
- Penn dissertations--Cell and Molecular Biology.
- Physical Description:
- 1 online resource (165 pages)
- Distribution:
- Ann Arbor : ProQuest Dissertations & Theses, 2023
- Contained In:
- Dissertations Abstracts International 85-08B.
- Place of Publication:
- [Philadelphia, Pennsylvania] : University of Pennsylvania, 2022.
- Language Note:
- English
- Summary:
- Clostridioides difficile is the most common nosocomial pathogen in the United States and an urgent public health threat. Despite the known link between the gut microbiota and susceptibility to C. difficile infection (CDI), the impact of synergistic interactions between the gut microbiota and pathogens on the outcome of infection is largely unknown. Enterococci are abundant members of the microbiota in the CDI gut. Using murine models of infection, human patient data, and in silico metabolic modeling, we have demonstrated robust direct and indirect interactions between these two pathogens. Through nutrient restriction and cross-feeding, we hypothesize that enterococci shape the metabolic environment in the gut and reprogram C. difficile metabolism. Metabolomic analysis of in vitro co-culture systems and in vivo coinfection models reveals that nutrient exchange provides a reversible cue for C. difficile that facilitates increased virulence. In return, C. difficile-induced damage of host tissues releases nutrients that provide a fitness advantage to enterococci, contributing to high abundance in the CDI gut and completing a positive feedback loop that exacerbates disease. Through competitive coinfections in a mouse model of CDI, we find that enterococci deficient in heme-dependent respiration suffer a fitness advantage within the CDI gut. These findings demonstrate that interactions between the host, resident microbiota, and pathogens in the gut have a profound impact on pathogen virulence and provide mechanistic insights into the cooperative roles of the microbiota on susceptibility to and severity of C. difficile infection.
- Notes:
- Source: Dissertations Abstracts International, Volume: 85-08, Section: B.
- Advisors: Zackular, Joseph; Committee members: Grice, Elizabeth; St. Geme, Joseph, III; Silverman, Michael; Beiting, Daniel.
- Department: Cell and Molecular Biology.
- Ph.D. University of Pennsylvania 2023.
- Local Notes:
- School code: 0175
- ISBN:
- 9798381510089
- Access Restriction:
- Restricted for use by site license.
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