RNA and DNA elicit inflammatory responses which are critical for anti-microbial immunity. DNA is a potent trigger of inflammatory cytokine and type I IFN gene transcription, as well as caspase-1-mediated processing of the pro-inflammatory cytokines IL-1? and IL-18. Growing evidence indicates that DNA recognition is central not only to anti-microbial host defenses but is also a major contributor to the adjuvant activity of DNA vaccines as well as the pathology associated with autoimmune diseases such as Systemic Lupus Erythematosis. It is therefore critical that we understand the molecular basis of DNA recognition. Recent work from our group has implicated the PYHIN family members Absent in melanoma-2 (AIM2) and the interferon-inducible protein (IFI16) as sensors of microbial DNA. Both proteins bind DNA via HIN domains.
AIM2 engages ASC via a pyrin domain to form a caspase-1 activating inflammasome while IFI16 activates a cytosolic signaling pathway involving Stimulator of IFN genes (STING), TANK binding kinase-1 (TBK-1) and interferon regulatory factor 3 (IRF3) to regulate transcription of type I IFN genes. Knockdown of IFI16, or its murine ortholog p204 prevents viral DNA from triggering IRF3 activation and IFN? gene induction, while not affecting responses to cytosolic RNA. Recent evidence also indicates that IFI16 can form an inflammasome in responses to nuclear sensing of Kaposi's Sarcoma Herpes Virus infection. Additional work from our laboratories has also implicated the DEAD box helicase DEAD box protein 3x (DDX3x) in the TBK1/IRF3 signaling pathway important for both RNA and cytoplasmic DNA pathways (including for IFI16), but its role in innate immunity remains to be fully characterized. The underlying hypothesis to be tested in this proposal is that IFI16 plays a central role in innate immunity and host-defense to microbial pathogens by regulating inflammatory responses and that DDX3x is an important downstream component of the IFI16 signaling pathway. We propose to explore the molecular mechanisms of IFI16 activation and define the role of IFI16 and DDX3x in anti-viral host-defenses. This project will increase our understanding of how the innate immune system senses pathogens, leading to novel therapeutic targets.

Public Health Relevance

Cells have immune sensors that detect DNA from invading viruses, giving rise to appropriate protective anti-viral cellular responses controlled by interferons. These responses are at times inappropriately activated by self-DNA, leading to pathological autoimmune responses. We have discovered that a cellular protein called IFI16 is such a sensor, and understanding how it works will lead to therapies to enhance or dampen immune responses to fight pathogens or suppressing autoimmune responses respectively.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI093752-03
Application #
8606390
Study Section
Innate Immunity and Inflammation (III)
Program Officer
Palker, Thomas J
Project Start
2012-02-15
Project End
2017-01-31
Budget Start
2014-02-01
Budget End
2015-01-31
Support Year
3
Fiscal Year
2014
Total Cost
Indirect Cost
Name
University of Massachusetts Medical School Worcester
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
City
Worcester
State
MA
Country
United States
Zip Code
01655
Schattgen, Stefan A; Gao, Guangping; Kurt-Jones, Evelyn A et al. (2016) Cutting Edge: DNA in the Lung Microenvironment during Influenza Virus Infection Tempers Inflammation by Engaging the DNA Sensor AIM2. J Immunol 196:29-33
Pawaria, Sudesh; Sharma, Shruti; Baum, Rebecca et al. (2016) Taking the STING out of TLR-driven autoimmune diseases: good, bad, or indifferent? J Leukoc Biol :
Baum, Rebecca; Nündel, Kerstin; Pawaria, Sudesh et al. (2016) Synergy between Hematopoietic and Radioresistant Stromal Cells Is Required for Autoimmune Manifestations of DNase II-/-IFNaR-/- Mice. J Immunol 196:1348-54
Baum, Rebecca; Sharma, Shruti; Carpenter, Susan et al. (2015) Cutting edge: AIM2 and endosomal TLRs differentially regulate arthritis and autoantibody production in DNase II-deficient mice. J Immunol 194:873-7
Dempsey, Alan; Bowie, Andrew G (2015) Innate immune recognition of DNA: A recent history. Virology 479-480:146-52
Sun, Chenglong; Schattgen, Stefan A; Pisitkun, Prapaporn et al. (2015) Evasion of innate cytosolic DNA sensing by a gammaherpesvirus facilitates establishment of latent infection. J Immunol 194:1819-31
Sharma, Shruti; Campbell, Allison M; Chan, Jennie et al. (2015) Suppression of systemic autoimmunity by the innate immune adaptor STING. Proc Natl Acad Sci U S A 112:E710-7
Pawaria, Sudesh; Moody, Krishna L; Busto, Patricia et al. (2015) An unexpected role for RNA-sensing toll-like receptors in a murine model of DNA accrual. Clin Exp Rheumatol 33:S70-3
Suschak, John J; Wang, Shixia; Fitzgerald, Katherine A et al. (2015) Identification of Aim2 as a sensor for DNA vaccines. J Immunol 194:630-6
Thompson, Mikayla R; Sharma, Shruti; Atianand, Maninjay et al. (2014) Interferon γ-inducible protein (IFI) 16 transcriptionally regulates type i interferons and other interferon-stimulated genes and controls the interferon response to both DNA and RNA viruses. J Biol Chem 289:23568-81

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