Date of Award

Fall 1-1-2025

Document Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Department

Immunobiology

First Advisor

MacMicking, John

Abstract

Traditional views of host defense often focus on antibody-mediated neutralization, cytotoxic T-cell plus NK-cell-mediated killing, and phagocytic activities by cell populations originating in the bone marrow as part of the classical immune system. Additional e?ector activities, however, also operate in non-immune cells which compose the stroma or parenchyma of host tissues. These latter cell populations often mobilize antimicrobial activities in response to cytokines such as type II IFN (IFN-gamma; IFN-?) against a wide variety of intracellular pathogens. Among the most prominent IFN-?-stimulated genes are a family of immune dynamin-like GTPases termed the Guanylate Binding Proteins (GBPs). GBPs are widely expressed in most nucleated cells, although their functions outside the immune system are poorly understood. Here, we generated six tissue-specific knockout mouse strains lacking all the murine Gbp genes either on chromosome 3H1 (Gbp1, Gbp2, Gbp3, Gbp5, Gbp7) or chromosome 5E5 (Gbp6, Gbp8, Gbp9, Gbp10, Gbp11) in certain immune and non-immune lineages. These mice were ?oxed for deletion in myeloid cells (LysM-Cre+), hepatocytes (Albumin-Cre+), and villus epithelial cells (Villin-Cre+), respectively (Chapter 2). We discovered that en bloc deletion of the chromosome 3H1 Gbp gene cluster in liver hepatocytes (Alb-Gbp?3H1) renders2 mice highly susceptible to Gram-negative bacterial (Salmonella enterica serovar Typhimurium) infection (Chapter 3). In particular, the lack of specific Gbps within this cluster, especially Gbp7, causes defects in hepatocytic control of bacterial replication and accelerated cell death (Chapter 4). Subsequent investigation found that hepatocyte protection by specific chr. 3H1 Gbps is independent of in?ammasome activation and associated with ROS production as part of a broader host defense network (Chapter 5). Importantly, it shows that non-immune cells are essential for direct elimination of Gram-negative bacteria, in this case Salmonella Typhimurium, as part of a natural mammalian host-pathogen infection model. It extends our understanding of antimicrobial defense beyond the confines of the classical immune system.

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