Interferons (IFNs), first identified for their potent antiviral activity, can be divided into two major classes. Of these, type II or immune IFN (a.k.a. IFN-gamma) has earned much notoriety, but the type I IFNs (IFN-Is; e.g., IFN-alpha, IFN-beta, etc.) represent a much larger and complex family. Consistent with this, viruses have evolved numerous strategies to thwart IFN-I activity. More recently, IFN-Is have also achieved some celebrity with the recognition that they are the major effector cytokine secreted by plasmacvtoid dendritic cells (pDCs, a.k.a. """"""""Natural IFN-I Producing Cells""""""""). These IFN-Is then regulate aspects of both innate and adaptive immunity. There is also intriguing new evidence that IFN-Is and pDCs play an important role in the pathogenesis of Systemic Lupus Erythematosis (SLE). Like other cytokines, IFN-Is induce their potent activity through the induction of new genes. Characterization of the ability of IFN-alpha to rapidly induce genes led to the identification of Stat1 and Stat2, the first two STAT transcription factors. These STATs are recruited to the type I IFN receptor (IFNAR) by unknown mechanisms, whereupon they become activated (by tyrosine phosphorylation), dimerize, translocate to the nucleus and activate genes. In contrast, IFN-gamma transduces its signals solely through Stat1, albeit with differing kinetics. To determine the unique role Stat2 plays in the biological response to IFN-Is, Stat2 knockout mice were generated. These mice were highly susceptible to viral infection and partially unresponsive to IFN-Is. Unexpectedly, they exhibited tissue-specific differences in IFN-I stimulated Statl activation and a loss in the normal regulation of the Major Histocompatibility Complex class II (MHC-II). These observations highlight the important role type I IFNs play in regulating innate and adaptive immunity. To understand how IFN-Is mediate their many potent effects we propose to: 1. Determine how STATs are activated at the type I IFN receptor, including tissue specific differences. 2. Determine the unique role Stat2 exhibits in regulating MHC-II expression in macrophages 3. Explore the role SUMOylation may play in regulating the kinetics of IFN stimulated STATs.
| Abdul-Sater, Ali A; Majoros, Andrea; Plumlee, Courtney R et al. (2015) Different STAT Transcription Complexes Drive Early and Delayed Responses to Type I IFNs. J Immunol 195:210-216 |
| Abdul-Sater, Ali A; Tattoli, Ivan; Jin, Lei et al. (2013) Cyclic-di-GMP and cyclic-di-AMP activate the NLRP3 inflammasome. EMBO Rep 14:900-6 |
| Abdul-Sater, Ali A; Grajkowski, Andrzej; Erdjument-Bromage, Hediye et al. (2012) The overlapping host responses to bacterial cyclic dinucleotides. Microbes Infect 14:188-97 |
| Song, Li; Lee, Carolyn; Schindler, Christian (2011) Deletion of the murine scavenger receptor CD68. J Lipid Res 52:1542-50 |
| Melillo, Jessica A; Song, Li; Bhagat, Govind et al. (2010) Dendritic cell (DC)-specific targeting reveals Stat3 as a negative regulator of DC function. J Immunol 184:2638-45 |
| Hanafy, Khalid A; Stuart, R Morgan; Khandji, Alexander G et al. (2010) Relationship between brain interstitial fluid tumor necrosis factor-? and cerebral vasospasm after aneurysmal subarachnoid hemorrhage. J Clin Neurosci 17:853-6 |
| Ashour, Joseph; Morrison, Juliet; Laurent-Rolle, Maudry et al. (2010) Mouse STAT2 restricts early dengue virus replication. Cell Host Microbe 8:410-21 |
| Grajkowski, Andrzej; Cieýýlak, Jacek; Gapeev, Alexei et al. (2010) Convenient synthesis of a propargylated cyclic (3'-5') diguanylic acid and its ""click"" conjugation to a biotinylated azide. Bioconjug Chem 21:2147-52 |
| Plumlee, Courtney R; Lee, Carolyn; Beg, Amer A et al. (2009) Interferons direct an effective innate response to Legionella pneumophila infection. J Biol Chem 284:30058-66 |
| Zhao, Wenli; Lee, Carolyn; Piganis, Rebecca et al. (2008) A conserved IFN-alpha receptor tyrosine motif directs the biological response to type I IFNs. J Immunol 180:5483-9 |
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