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Interferon-Inducible GTPases as Positive and Negative Regulators of Inflammasomes

dc.contributor.advisor Coers, Jorn Finethy, Ryan Harold 2019-04-02T16:27:38Z 2018
dc.description Dissertation
dc.description.abstract <p>Through the action of pattern recognition receptors (PRRs) the vertebrate immune system is able to detect and respond to invading pathogens. PRRs bind conserved microbial components and subsequently initiate pro-inflammatory defense programs. While effective at eliminating pathogens, these inflammatory responses can have deleterious effects; excessive inflammation can result in tissue damage. In order to minimize infection-induced pathology while still ensuring pathogen clearance the immune system has evolved mechanisms to precisely regulate PRR activity. This is accomplished in part through the activity of immunomodulatory cytokines. </p><p>Interferons are a group of cytokines notable for their ability to shape immune responses. To some extent, this is accomplished through their ability to induce expression of families of GTPases. Herein, I describe my work characterizing the immunomodulatory activity of two families of interferon-inducible GTPases: the guanylate-binding proteins (GBPs) and the immunity related GTPases (IRGs). Previous studies have associated these proteins with immune regulation, but many questions remain surrounding their functions. </p><p>In the first part of this dissertation, I detail my work exploring the pro-inflammatory functions of the GBPs in mice. Previous work from our lab and others identified a role for the GBPs in promoting activity of a set of PRRs known as inflammasomes, which not only sense pathogens but also directly produce pro-inflammatory cytokines. I first explore this observation in the context of chlamydial infection. Using a macrophage cell culture model, I demonstrate that GBPs are essential for a rapid inflammasome response to infection with Chlamydia species. I also show that this function is independent of GBP targeting to pathogen-containing vacuoles (PVs), revealing that GBPs can regulate inflammasome activity outside the host-pathogen interface. I go on to identify a role for GBPs in promoting inflammasome activity in response to bacteria-derived outer membrane vesicles both in cell culture and in vivo. Finally, I show that GBP-deficient mice are more susceptible to endotoxin challenge. Together, these results highlight the ability of GBPs to promote caspase-11 activity independent of pathogen- or PV- lysis. </p><p>In the second part of this dissertation, I describe my work surrounding the roles of a sub-family of IRGs, the IRGMs, in regulating inflammation. In order to better understand how the IRGMs regulate inflammation, I characterized cytokine production in IRGM deficient mice challenged with LPS. I found that loss of one IRGM, IRGM2, lead to excessive LPS-induced production of inflammasome-associated cytokines. I go on to show that IRGM2 specifically regulates the cytosolic LPS-sensing caspase-11 inflammasome. I also show that IRGM2 may do so by minimizing cytosolic availability of LPS. These results reveal a novel association between IRGMs and inflammasomes and potentially highlight a unique mechanism for regulating caspase-11 activity. </p><p>The work described throughout this thesis highlights the ability of the vertebrate immune system to precisely regulate inflammation. It demonstrates how interferons can both promote and suppress inflammasome activity, thereby fine-tuning an immune response.</p>
dc.subject Immunology
dc.subject Cellular biology
dc.title Interferon-Inducible GTPases as Positive and Negative Regulators of Inflammasomes
dc.type Dissertation
dc.department Molecular Genetics and Microbiology
duke.embargo.months 21
duke.embargo.release 2021-01-09T00:00:00Z

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