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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
3R01AI058211-05S2
Application #
8145027
Study Section
Allergy and Immunology Study Section (ALY)
Program Officer
Leitner, Wolfgang W
Project Start
2004-04-15
Project End
2011-03-31
Budget Start
2010-09-22
Budget End
2011-03-31
Support Year
5
Fiscal Year
2010
Total Cost
$144,869
Indirect Cost
Name
Columbia University (N.Y.)
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
621889815
City
New York
State
NY
Country
United States
Zip Code
10032
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
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
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
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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