Browsing by Subject "Interferon Regulatory Factors"
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Item Dendritic Cells Suppress Pathogen-Induced Inflammasome Activation to Prime Naïve T Cells(2021-05-01T05:00:00.000Z) McDaniel, Margaret Mae; van Oers, Nicolai S. C.; Pasare, Chandrashekhar; Fu, Yang-Xin; Alto, Neal; Satterthwaite, Anne B.Activation of inflammasome leads to pyroptotic cell death thereby eliminating the replicative niche of virulent pathogens, a process integral to innate immunity. While inflammasome-associated cytokines such as IL-1β and IL-18 have an established role in T cell function, whether inflammasome activation in dendritic cells (DCs) is critical for T cell priming is not clear. Here, we find that lymphoid organ resident conventional DCs (cDCs) actively suppress inflammasome activation to prevent pyroptotic cell death. This protection from inflammasome-induced cell death preserves the ability of cDCs to prime both CD4 and CD8 T cells. Transcription factors IRF8 and IRF4, in cDC1s and cDC2s respectively, mediate this suppression of inflammasome activation by limiting the expression of inflammasome-associated genes. Additionally, overexpression of either of IRF4 or IRF8 is sufficient to inhibit inflammasome activation in macrophages, cells that are normally permissive to inflammasome activation. Furthermore, we find that reduced expression of IRF8 leads to aberrant inflammasome activation in cDC1s which hampers their ability to prime CD8 T cells. These results uncover the importance as well as the molecular mechanism of inflammasome suppression in cDCs and ascribe a novel post-developmental role for IRF4 and IRF8 in cDC function.Item Discovery of Unique Antiviral Pathways in a Bat Viral Reservoir, the Black Flying Fox(2018-04-03) De La Cruz Rivera, Pamela Cristina; Alto, Neal; Schoggins, John W.; Pfeiffer, Julie K.; Russell, David W.Bats are asymptomatic reservoirs for a number of viral pathogens. How they manage to host highly pathogenic viruses such a Nipah and Marburg without showing clinical symptoms remains unclear. One of the earliest defenses vertebrates use to control viral infections is the interferon response. Upon viral infection, cells produce interferon which inhibits viral infection through downstream effectors called interferon stimulated genes. I questioned whether bat interferon stimulated genes contained unique properties that would make bats less susceptible to damage from viral infection. To address this, I used genetic tools to identify which interferon stimulated genes were expressed in cells from the black flying fox (Pteropus alecto). I found that RNASEL is uniquely induced in cells from the black flying fox, and that its activation is important for preventing viral infection. To determine if any bat interferon stimulated genes had evolved especially potent antiviral properties, I compared a group of bat and human interferon stimulated genes in a high-throughput format and discovered that bat IRF7 is more antiviral than human IRF7. Further studies demonstrated that bat IRF7 is active even in uninfected cells, and can induce a subset of protective antiviral genes without signaling through interferon. This function was in part due to unique serine residues at the C-terminal regulatory region of the protein that confer constitutive activity to bat IRF7. This work has uncovered two different mechanisms by which antiviral responses between bat and human hosts differ, and provides insight regarding how bats manage to keep numerous viral infections under control.Item Regulatory Mechanisms in Innate Immunity(2018-07-16) Ren, Junyao; Olson, Eric N.; Chen, Zhijian J.; Hooper, Lora V.; Beutler, BruceInnate immunity is the frontline for the host to defend against infections. This process entails the cooperation among pathogen recognition receptors, adaptor proteins, kinases, and transcription factors that elicit the production of effector cytokines. As an important transcription factor, IRF5 was known to be essential for the host cytokine production in response to various ligands and SNPs in IRF5 have been closely related to autoimmune diseases. However, the mechanism by which IRF5 is activated is not well understood. In the first part of this dissertation, I presented evidence that the kinase IKK2 phosphorylates IRF5 on Serine 445, leading to its dimerization and nuclear translocation. cGAMP is the first cyclic di-nucleotide discovered in metazoan. It is produced by the cytosolic DNA sensor cGAS in response to pathogen or self DNA as a second messenger to activate STING. cGAMP has been proven to be very important in anti-viral response and anti-tumor process. In the second part of the dissertation, I used next-generation sequencing techniques and presented that STING is the predominant receptor for cGAMP and innate immune response. As the essential and general DNA sensor, cGAS was purified and identified from cellular cytosols. Upon DNA binding, cGAS utilize ATP and GTP to synthesize cGAMP. However, the regulation of cGAS activity in cells is still poorly understood. Here I presented that certain RNA species that is interferon inducible could inhibit cGAS catalytic activity in vitro and probably regulate cGAS mediated immune response in cells. Besides, I have discovered that during the cell cycle, cGAS is recruited and co-localize with chromosome and in actively dividing cells, cGAS remains in the nucleus. I further presented evidence that certain protein(s) in the nucleus can inhibit cGAS activity thus prevent cGAS from being activated by host DNA in the nucleus.