Viral Mediated Type I Interferon Induction View Homepage


Ontology type: schema:MonetaryGrant     


Grant Info

YEARS

2006-2022

FUNDING AMOUNT

4569064 USD

ABSTRACT

ABSTRACT The long term goal of this research proposal is to determine the mechanisms responsible for the important functions of TNF receptor associated factor 3 (TRAF3) and NF-?B inducing kinase (NIK) in regulating host defense against viral infections and autoimmune responses. We identified TRAF3 over 20 years ago as an adaptor molecule associated with a subset of TNF receptors including CD40, BAFFR and LT?R. We subsequently generated TRAF3 knockout mice and found that they die within two weeks after birth with over- reactive inflammatory responses. In the past several years, we have defined a TRAF/cIAP/NIK complex responsible for suppressing non-canonical NF-?B activity in unstimulated cells through constitutively degrading NIK. The significance of our findings is supported by the observation that mutations in the genes encoding components of the TRAF/cIAP/NIK complex are associated with inflammatory and autoimmune diseases, as well as several hematological cancers such as multiple myeloma and diffuse B-cell lymphoma. Our recent studies have also discovered a novel NIK/IKK/CRL protein complex, which acts as a negative feedback control in preventing over-reactive non-canonical NF-?B activity after receptor activation. In addition, our preliminary studies have identified a novel NIK/STING/TBK1 complex, which can enhance DNA-induced Type I interferon (IFN-I) production. Based on our genetic and biochemical studies, we found TRAF3 has opposing roles in regulating DNA vs. RNA-induced IFN-I induction. We have provided evidence that crosstalk between the non- canonical NF-?B and IFN-I indcution pathways may play important roles not only in regulating host defense against DNA virus infection but also in DNA and BAFF-mediated syngergistic pruduction of IFN-I and auto- antibodies, which are a hallmark of certain autoimmune diseases such as Lupus. Our overall hypothesis is that TRAF3 and NIK play important roles in regulating anti-viral immunity and auto-immune responses through controlling non-canonical NF-?B activation and its crosstalk with IFN-I production. Our goal is to gain a functional and mechanistic understanding on TRAF3 and NIK in regulating non-canonical NF-?B activation and IFN-I production. In Aim 1, we will define the major components of the NIK/IKK/CRL complex and determine their roles in the negative feedback control of the non-canonical NF-?B pathway. In Aim 2, we will define the major components of the NIK/STING/TBK1 complex and determine their roles in regulating the crosstalk between non-canonical NF-?B and IFN-I induction pathways. In Aim 3, we will determine the contributions of the crosstalk between non-canonical NF-?B activation and IFN-I responses in host defense against DNA virus infections and its association with autoimmune diseases. Finally, we will explore the possibility of using small molecular regulators of the non-canonical NF-?B pathway as novel agents to protect viral infections and treat autoimmune diseases. We believe our proposed studies will assist in future attempts to pharmacologically intervene against infectious and autoimmune diseases. More... »

URL

http://projectreporter.nih.gov/project_info_description.cfm?aid=9458084

Related SciGraph Publications

  • 2018-12. A TRAF3-NIK module differentially regulates DNA vs RNA pathways in innate immune signaling in NATURE COMMUNICATIONS
  • 2018-12. E90 subunit vaccine protects mice from Zika virus infection and microcephaly in ACTA NEUROPATHOLOGICA COMMUNICATIONS
  • 2018-12. Zika virus shedding in the stool and infection through the anorectal mucosa in mice in EMERGING MICROBES & INFECTIONS
  • 2015-05. Integrating computational modeling and functional assays to decipher the structure-function relationship of influenza virus PB1 protein in SCIENTIFIC REPORTS
  • 2015-05. Interferon-Inducible Cholesterol-25-Hydroxylase Inhibits Hepatitis C Virus Replication via Distinct Mechanisms in SCIENTIFIC REPORTS
  • 2014-12. Retinoid X receptor α attenuates host antiviral response by suppressing type I interferon in NATURE COMMUNICATIONS
  • 2014-03. Structural analysis of asparaginyl endopeptidase reveals the activation mechanism and a reversible intermediate maturation stage in CELL RESEARCH
  • 2013-08. Crystal structure and nucleotide selectivity of human IFIT5/ISG58 in CELL RESEARCH
  • 2013-06. Structural basis for termination of AIM2-mediated signaling by p202 in CELL RESEARCH
  • 2012-12. The helicase DDX41 recognizes the bacterial secondary messengers cyclic di-GMP and cyclic di-AMP to activate a type I interferon immune response in NATURE IMMUNOLOGY
  • 2012-05. Crystal structure of the ubiquitin-like domain of human TBK1 in PROTEIN & CELL
  • 2010-02. TRAF-mediated regulation of immune and inflammatory responses in SCIENCE CHINA LIFE SCIENCES
  • 2008-12. Antibody-fused interferons as an effective approach to enhance target specificity and antiviral efficacy of type I interferons in CELL RESEARCH
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