Dissertation
MEROCYTOPHAGY TRANSFER EVENTS INFLUENCE THE IMMUNE RESPONSE TO FRANCISELLA TULARENSIS INFECTION
Washington State University
Doctor of Philosophy (PhD), Washington State University
05/2025
DOI:
https://doi.org/10.7273/000007360
Abstract
Trogocytosis is a process by which cells partially phagocytose, or nibble, other cells and in some cases, cells decorate their own surface with protein acquired from the surface of others. This process is gaining attention in immunology research as it has been observed in the context of dendritic cell (DC) cross-dressing, in which DCs acquire antigen complexes to present for T cell activation, and it has implications in the immune response to cancer and in the efficacy of engineered T cell therapies. The trogocytosis-related behavior merocytophagy was first characterized as an alternative strategy for Francisella tularensis dissemination among macrophages. In contrast to trogocytosis, merocytophagy is characterized by transfer of both surface protein and cytosolic content, forming a double-membrane vacuole in recipient cells. Little is known about this process and the molecular factors which facilitate it, as well as whether it is driven by bacteria or by the host. Here, we demonstrate that several bacterial pathogens with diverse replication strategies enhance merocytophagy transfer and that pattern recognition receptor (PRR) agonists are sufficient to trigger enhanced transfer. We also identify the Spleen Tyrosine Kinase (Syk) signaling pathway as a major contributor to transfer and primarily in a MyD88-independent manner. Further we observed that several surface integrins are upregulated as a result of Syk signaling and form a synapse-like structure at the site of protein transfer. Additionally, we found that merocytophagy occurs in DCs through use of a BMDC model and observed that inflammatory cytokine expression is delayed or lengthened in response to merocytophagy downstream of F. tularensis infection in vitro. This delay coincides with significantly enhanced antigen cross-presentation for activation of CD8+ T cells as well as a slight increase in multifunctional CD8 + T cells in vitro. Finally, we implement merocytophagy and bacterial localization in the vaccination response to F. tularensis in vivo, observing that mice vaccinated with a strain engineered to confer limited replication and dissemination are protected from re-challenge as effectively as those vaccinated with wildtype bacteria.
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Details
- Title
- MEROCYTOPHAGY TRANSFER EVENTS INFLUENCE THE IMMUNE RESPONSE TO FRANCISELLA TULARENSIS INFECTION
- Creators
- Kelly Nicole Deobald
- Contributors
- Thomas Kawula (Chair)Santanu Bose (Committee Member)Bronwyn Gunn (Committee Member)Leigh Knodler (Committee Member)
- Awarding Institution
- Washington State University
- Academic Unit
- College of Veterinary Medicine
- Theses and Dissertations
- Doctor of Philosophy (PhD), Washington State University
- Publisher
- Washington State University
- Number of pages
- 111
- Identifiers
- 99901220475601842
- Language
- English
- Resource Type
- Dissertation