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Investigating Cellular Innate Immune Responses to Intestinal Yersinia Infection / Jenna Zhang.
- Format:
- Book
- Thesis/Dissertation
- Author/Creator:
- Zhang, Jenna, author.
- Language:
- English
- Subjects (All):
- Microbiology.
- Immunology.
- Cellular biology.
- Pathology.
- Molecular biology.
- Cell and Molecular Biology--Penn dissertations.
- Penn dissertations--Cell and Molecular Biology.
- Local Subjects:
- Microbiology.
- Immunology.
- Cellular biology.
- Pathology.
- Molecular biology.
- Cell and Molecular Biology--Penn dissertations.
- Penn dissertations--Cell and Molecular Biology.
- Physical Description:
- 1 online resource (190 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:
- Enteric pathogens make up a large global burden of disease, causing gastrointestinal disease in human hosts. The Gram-negative bacterial pathogen Yersinia pseudotuberculosis is widely prevalent within global farmed livestock and causes gastroenteritis and mesenteric lymphadenitis in immunocompetent human hosts after ingestion of contaminated meat. As part of its virulence strategy, Yersinia uses its type three secretion system (T3SS) to inject virulence factors termed Yersinia outer proteins (Yops) into the host cytoplasm in order to subvert essential components of innate immune signaling. However T3SS activity elicits host immune activation aimed at containing infection and eliminating the bacterial niche.One such immune response involves the formation of immune complexes known as inflammasomes, which promote an inflammatory form of cell death and cytokine release, collectively termed pyroptosis, in order to restrict infection. The requirement of different inflammasomes, as well as the role of Yops in activating or evading inflammasome activation, have been studied extensively in murine macrophages. However, fundamental differences in inflammasome responses exist between mice and humans, making studying inflammasome responses in human cells models critical. We found that in contrast to murine cells, in human cells Yersina infection fails to induce YopJ-dependent cell death. Furthermore, Yersinia deploys three of its Yops, YopE, YopH and YopK to evade caspase-4 inflammasome and GSDMD-dependent pyroptosis. Mechanistically, the antiphagocytic Yops, YopE and YopH, evade inflammasome activation by blocking bacterial internalization downstream of Yersinia adhesin and host integrin signaling.Another immune response elicited by Yersinia virulence is formation of granulomas, immune structures that form to sequester hard-to-clear pathogens. Intestinal pyogranulomas rich in neutrophils and inflammatory monocytes form acutely during early Yersinia infection. Inflammatory monocytes are required for control and clearance of Yersinia within intestinal pyogranulomas, but their mechanism of restriction is still unknown. We found that TNF signaling in monocytes is required for bacterial restriction during Yersinia infection and critically promotes monocyte-intrinsic IL-1 cytokine production within intestinal pyogranulomas. Monocyte-derived IL-1 signals to IL-1 receptor on non-hematopoietic cells to enable control of Yersinia in pyogranulomas and systemic organs.Overall our findings further define mechanisms of intestinal Yersinia restriction in humans and mice and highlight strategies for the immune system to respond to Yersinia virulence at the cellular and multicellular network levels.
- Notes:
- Source: Dissertations Abstracts International, Volume: 85-08, Section: B.
- Advisors: Shin, Sunny; Brodsky, Igor E.; Committee members: Grice, Elizabeth; St. Geme, Joseph W., III; Zackular, Joseph P.; Abt, Michael C.
- Department: Cell and Molecular Biology.
- Ph.D. University of Pennsylvania 2023.
- Local Notes:
- School code: 0175
- ISBN:
- 9798381472103
- Access Restriction:
- Restricted for use by site license.
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