Balancing protection and pathology regulation of intestinal innate immunity during <em>clostridioides difficile</em> infection Orlaith Keenan

Format:

Book

Thesis/Dissertation

Author/Creator:

Keenan, Orlaith, author.

Contributor:

University of Pennsylvania. Cell and Molecular Biology., degree granting institution.

Language:

English

Subjects (All):

Immunology.

Microbiology.

Public health.

0982.

0410.

0573.

Local Subjects:

Immunology.

Microbiology.

Public health.

0982.

0410.

0573.

Genre:

Academic theses

Physical Description:

1 online resource (125 pages)

Contained In:

Dissertations Abstracts International 87-12B

Place of Publication:

Ann Arbor : ProQuest Dissertations and Theses, 2026

Language Note:

English

Summary:

Clostridioides difficile is a leading cause of antibiotic-associated diarrhea and remains an urgent public health threat due to its high morbidity, mortality, and rates of recurrence. C. difficile infection (CDI) disease severity is driven not only by C. difficile toxin-induced epithelial damage but also by the host inflammatory response, particularly recruitment of neutrophils. While neutrophils are necessary for survival during infection, excessive accumulation contributes to tissue damage and worsened clinical outcomes. Despite this dual role, the mechanisms regulating neutrophil responses during CDI and how they can be therapeutically modulated remain poorly understood. Additionally, infants frequently harbor toxigenic C. difficile yet remain asymptomatic, highlighting an important gap in understanding how host immune responses determine disease versus tolerance. Here, we investigate how modulation of the host innate immunity shapes CDI outcomes, with a particular focus on neutrophil regulation. Using a murine model of acute infection, we demonstrate that the prostaglandin analog misoprostol reduces CDI severity by limiting intestinal inflammation and systemic neutrophil abundance without altering bacterial burden or toxin production. Mechanistically, misoprostol reduces circulating levels of granulocyte colony-stimulating factor (G-CSF), restricting neutrophil mobilization from the bone marrow. Beyond these findings, we show that misoprostol-mediated immunomodulation produces context-dependent effects across models of intestinal inflammation but does not reduce recurrent CDI, highlighting the different contributions of host inflammation and microbiota-driven disease processes. Finally, we examine neonatal responses to C. difficile colonization and demonstrate that neonates mount a markedly reduced systemic neutrophil response and fail to undergo infection-induced hematopoietic remodeling, suggesting that restrained innate immune responses may contribute to protection during early life. Together, these studies identify systemic regulation of neutrophil responses as a major determinant of CDI severity and reveal how modulation of this axis can alter disease outcomes. These findings provide new insight into the fundamental biology of CDI and highlight host-directed immunomodulation as a promising strategy to limit pathology and improve treatment of intestinal inflammatory diseases

Notes:

Source: Dissertations Abstracts International, Volume: 87-12, Section: B.

Advisors: Zackular, Joseph P. Committee members: St. Geme, Joseph, III; Cadwell, Ken; Goulian, Mark; Pohlschroder, Mechthild; Zhu, Jun Jay

Ph.D. University of Pennsylvania 2026

Vendor supplied data

Local Notes:

School code: 0175

ISBN:

9798247978848

Access Restriction:

Restricted for use by site license