Regulation of Type I Interferon Gene Expression in the Innate Immune Response

Summary

Principal Investigator: Katherine A Fitzgerald
Abstract: Successful host defense against viral infection, relies on the early detection of the virus followed by the rapid production of type IIFN genes and the establishment of a cellular anti-viral state. Detection is mediated by germline-encoded innate immune receptors, often referred to as pattern recognition receptors (PRRs). These PRRs, which include both TLRs (TLR3, TLR7, TLR8 and TLR9) and cytoplasmic RNA helicases (RIG-I, Mda-5 and possibly others) are capable of detecting viral nucleic acids. Double stranded RNA, a key signature of viral replication is recognised by TLRS, in the endosomal compartment, or by the RNAhelicases, if in the cytoplasm. Type I IFNgene induction downstream of TLRS and RIG-I requires the signal-dependent phosphorylation of IRF3, enabling IRF3 to dimerize, translocate to the nucleas and activate IFN gene transcription. TBK-1 and IKKE phosphorylate and activate IRF3. TBK1 and IKKe are required for TLR and RNA helicase signaling. Little else is known however, about the molecular events that connect TLRs or RNA helicases with these kinases. Our goal is to understand in detail these molecular events. We will use a combination of biochemical, visual and molecular genetic approaches to understand how viral pathogens are recognized by the innate immune response during infection and how these PRR- pathways activate these kinases. Successful completion of these studies will help us understand the molecular mechanisms responsible for the innate immune sensing of viral pathogens. These studies are also vital for the rational design of therapeutic agents to enhance innate immunity in host defense against infectious pathogens. Since type I IFNs also occupy centre stage inthe pathogenesis of systemic and organ-specific autoimmune diseases including Systemic Lupus Erythematosus (SLE), a clearer understanding of the regulation of these important immune mediators will also be useful for the treatment of these and other related autoimmune diseases. In summary, defining these pathways in great detail will be important to allow us to design therapies which could be used to turn on these kinases, as a way to assist in clearance of a viral pathogen, which would be advantageous to the host, or alternatively, to turn them off in situations, such as autoimmune disease, where production of IFN is disadvantageous to the host.
Funding Period: ----------------2006 - ---------------2011-
more information: NIH RePORT

Top Publications

  1. pmc The chemotherapeutic agent DMXAA potently and specifically activates the TBK1-IRF-3 signaling axis
    Zachary J Roberts
    Department of Microbiology and Immunology, University of Maryland Baltimore, Baltimore, MD 21201, USA
    J Exp Med 204:1559-69. 2007
  2. pmc Functional characterization of murine interferon regulatory factor 5 (IRF-5) and its role in the innate antiviral response
    Andrea Paun
    Sidney Kimmel Comprehensive Cancer Center, The Johns Hopkins University, Baltimore, MD 21231, USA
    J Biol Chem 283:14295-308. 2008
  3. pmc Silica crystals and aluminum salts activate the NALP3 inflammasome through phagosomal destabilization
    Veit Hornung
    Department of Infectious Diseases and Immunology, University of Massachusetts Medical School, Worcester, Massachusetts 01605, USA
    Nat Immunol 9:847-56. 2008
  4. pmc The E3 ubiquitin ligase Ro52 negatively regulates IFN-beta production post-pathogen recognition by polyubiquitin-mediated degradation of IRF3
    Rowan Higgs
    Molecular and Cellular Therapeutics, Research Institute, Royal College of Surgeons in Ireland, Dublin, Ireland
    J Immunol 181:1780-6. 2008
  5. pmc Superior immunogenicity of inactivated whole virus H5N1 influenza vaccine is primarily controlled by Toll-like receptor signalling
    Felix Geeraedts
    Department of Medical Microbiology, Molecular Virology Section, University Medical Center Groningen and University of Groningen, Groningen, The Netherlands
    PLoS Pathog 4:e1000138. 2008
  6. pmc Functional regulation of MyD88-activated interferon regulatory factor 5 by K63-linked polyubiquitination
    Mumtaz Yaseen Balkhi
    Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, MD 21231, USA
    Mol Cell Biol 28:7296-308. 2008
  7. pmc Insights into interferon regulatory factor activation from the crystal structure of dimeric IRF5
    Weijun Chen
    Department of Biochemistry and Molecular Pharmacology, 364 Plantation Street, Worcester, Massachusetts 01605, USA
    Nat Struct Mol Biol 15:1213-20. 2008
  8. pmc A novel IFN regulatory factor 3-dependent pathway activated by trypanosomes triggers IFN-beta in macrophages and fibroblasts
    Anne Danielle C Chessler
    Department of Immunology and Infectious Diseases, Harvard School of Public Health, Boston, MA 02115, USA
    J Immunol 181:7917-24. 2008
  9. ncbi Toll-like receptor-dependent and -independent viperin gene expression and counter-regulation by PRDI-binding factor-1/BLIMP1
    Martina Severa
    Division of Infectious Disease and Immunology, Department of Medicine, The University of Massachusetts Medical School, Worcester, Massachusetts 01605, USA
    J Biol Chem 281:26188-95. 2006
  10. pmc The tyrosine kinase c-Src enhances RIG-I (retinoic acid-inducible gene I)-elicited antiviral signaling
    Ingvild B Johnsen
    Department of Laboratory Medicine, Children s and Women s Health, Faculty of Medicine, Norwegian University of Science and Technology, Trondheim N 7006, Norway
    J Biol Chem 284:19122-31. 2009

Scientific Experts

  • Søren R Paludan
  • AMY HISE
  • Katherine A Fitzgerald
  • Veit Hornung
  • Augustine Choi
  • Zhaozhao Jiang
  • Nadege Goutagny
  • Mumtaz Yaseen Balkhi
  • Eicke Latz
  • Shizuo Akira
  • Vijay A K Rathinam
  • Shruti Sharma
  • Douglas T Golenbock
  • Brian G Monks
  • Paula M Pitha
  • Martina Severa
  • Kiichi Nakahira
  • Lijian Wang
  • Peggy Parroche
  • Leonie Unterholzner
  • Shenghua Zhou
  • Leah E Cole
  • Amit K Pandey
  • Ingvild B Johnsen
  • Gunther Hartmann
  • Sybille Kenzel
  • Franz G Bauernfeind
  • Kamalpreet Nagpal
  • Martin Schlee
  • Wenji Piao
  • Andrea Ablasser
  • Stefanie N Vogel
  • Andrea Paun
  • Anne Danielle C Chessler
  • Hiroki Kato
  • Felix Geeraedts
  • Weijun Chen
  • Rowan Higgs
  • Taro Kawai
  • Zachary J Roberts
  • Hilaire C Lam
  • Ying Fu
  • Estela Trebicka
  • Joshua A Englert
  • Stefan W Ryter
  • Parisa Kalantari
  • Marlene Rabinovitch
  • Tamas Dolinay
  • Jonathan C Kagan
  • Jeffrey Adam Haspel
  • J Perry Hall
  • Manuela Cernadas
  • Fanny Lauw
  • Hong Pyo Kim
  • Glen N Barber
  • Ricardo T Gazzinelli
  • Lisa Waggoner
  • Seon Jin Lee
  • Jennie Chan
  • Rosane B Deoliveira
  • Bobby J Cherayil
  • Daniella C Bartholomeu
  • Marcin Baran
  • Michelle H W Laird
  • Kristy A Horan
  • Hong Ji
  • Araceli Santiago
  • An Zacharia
  • Nancy Ulbrandt
  • Jane Tian
  • Tengchuan Jin
  • Andrew G Bowie
  • Evelyn A Kurt-Jones
  • Kari Ann Shirey
  • Robert W Finberg
  • Eileen Barry
  • Anna M Cerny
  • Anna Seekatz
  • T Sam Xiao
  • Sinead E Keating
  • Peter A Kiener
  • Anthony J Coyle
  • Søren B Jensen
  • Cherilyn M Sirois
  • Jeanne Schickli
  • Bilge Ergin
  • Joyce Wong
  • Egil Lien
  • Gabor Horvath
  • Winfried Barchet

Detail Information

Publications32

  1. pmc The chemotherapeutic agent DMXAA potently and specifically activates the TBK1-IRF-3 signaling axis
    Zachary J Roberts
    Department of Microbiology and Immunology, University of Maryland Baltimore, Baltimore, MD 21201, USA
    J Exp Med 204:1559-69. 2007
    ..These findings detail a novel pathway for TBK1-mediated IRF-3 activation and provide new insights into the mechanism of this new class of chemotherapeutic drugs...
  2. pmc Functional characterization of murine interferon regulatory factor 5 (IRF-5) and its role in the innate antiviral response
    Andrea Paun
    Sidney Kimmel Comprehensive Cancer Center, The Johns Hopkins University, Baltimore, MD 21231, USA
    J Biol Chem 283:14295-308. 2008
    ..Altogether, these data reveal the cell type-specific importance of IRF-5 in MyD88-mediated antiviral pathways and the widespread role of IRF-5 in the regulation of inflammatory cytokines...
  3. pmc Silica crystals and aluminum salts activate the NALP3 inflammasome through phagosomal destabilization
    Veit Hornung
    Department of Infectious Diseases and Immunology, University of Massachusetts Medical School, Worcester, Massachusetts 01605, USA
    Nat Immunol 9:847-56. 2008
    ..Our results indicate that the NALP3 inflammasome senses lysosomal damage as an endogenous 'danger' signal...
  4. pmc The E3 ubiquitin ligase Ro52 negatively regulates IFN-beta production post-pathogen recognition by polyubiquitin-mediated degradation of IRF3
    Rowan Higgs
    Molecular and Cellular Therapeutics, Research Institute, Royal College of Surgeons in Ireland, Dublin, Ireland
    J Immunol 181:1780-6. 2008
    ..Collectively, this demonstrates a novel role for Ro52 in turning off and thus limiting IRF3-dependent type I IFN production by targeting the transcription factor for polyubiquitination and subsequent proteasomal degradation...
  5. pmc Superior immunogenicity of inactivated whole virus H5N1 influenza vaccine is primarily controlled by Toll-like receptor signalling
    Felix Geeraedts
    Department of Medical Microbiology, Molecular Virology Section, University Medical Center Groningen and University of Groningen, Groningen, The Netherlands
    PLoS Pathog 4:e1000138. 2008
    ....
  6. pmc Functional regulation of MyD88-activated interferon regulatory factor 5 by K63-linked polyubiquitination
    Mumtaz Yaseen Balkhi
    Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, MD 21231, USA
    Mol Cell Biol 28:7296-308. 2008
    ..Thus, our findings offer a new mechanistic insight into IRF-5 gene induction program through hitherto unknown processes of IRF-5 ubiquitination...
  7. pmc Insights into interferon regulatory factor activation from the crystal structure of dimeric IRF5
    Weijun Chen
    Department of Biochemistry and Molecular Pharmacology, 364 Plantation Street, Worcester, Massachusetts 01605, USA
    Nat Struct Mol Biol 15:1213-20. 2008
    ..Thus, phosphorylation is likely to activate IRF5 and other family members by triggering conformational rearrangements that switch the C-terminal segment from an autoinihibitory to a dimerization role...
  8. pmc A novel IFN regulatory factor 3-dependent pathway activated by trypanosomes triggers IFN-beta in macrophages and fibroblasts
    Anne Danielle C Chessler
    Department of Immunology and Infectious Diseases, Harvard School of Public Health, Boston, MA 02115, USA
    J Immunol 181:7917-24. 2008
    ..Together, these findings identify the existence of a novel TLR-independent pathogen-sensing mechanism in immune and nonimmune cells that converges on TBK1 and IFN regulatory factor 3 for activation of IFN-beta gene expression...
  9. ncbi Toll-like receptor-dependent and -independent viperin gene expression and counter-regulation by PRDI-binding factor-1/BLIMP1
    Martina Severa
    Division of Infectious Disease and Immunology, Department of Medicine, The University of Massachusetts Medical School, Worcester, Massachusetts 01605, USA
    J Biol Chem 281:26188-95. 2006
    ..Collectively, these studies identify Viperin as a tightly regulated ISGF3 target gene, which is counter-regulated by PRDI-BF1...
  10. pmc The tyrosine kinase c-Src enhances RIG-I (retinoic acid-inducible gene I)-elicited antiviral signaling
    Ingvild B Johnsen
    Department of Laboratory Medicine, Children s and Women s Health, Faculty of Medicine, Norwegian University of Science and Technology, Trondheim N 7006, Norway
    J Biol Chem 284:19122-31. 2009
    ..The interaction between c-Src and TRAF3 was found to occur within the RING domain of TRAF3. Taken together, our results suggest that c-Src enhances RIG-I-mediated signaling, acting at the level of TRAF3...
  11. pmc Cell type-specific recognition of human metapneumoviruses (HMPVs) by retinoic acid-inducible gene I (RIG-I) and TLR7 and viral interference of RIG-I ligand recognition by HMPV-B1 phosphoprotein
    Nadege Goutagny
    Division of Infectious Diseases and Immunology, Department of Medicine, University of Massachusetts Medical School, Worcester, MA 01605, USA
    J Immunol 184:1168-79. 2010
    ..Collectively, these data reveal differential mechanisms of sensing for two closely related viruses, which operate in cell type-specific manners...
  12. pmc Innate immune recognition of an AT-rich stem-loop DNA motif in the Plasmodium falciparum genome
    Shruti Sharma
    Division of Infectious Diseases and Immunology, Department of Medicine, University of Massachusetts Medical School, 364 Plantation Street, Worcester, MA 01605, USA
    Immunity 35:194-207. 2011
    ..Collectively, these observations implicate AT-rich DNA sensing via STING, TBK1 and IRF3-IRF7 in P. falciparum malaria...
  13. pmc Induction and inhibition of type I interferon responses by distinct components of lymphocytic choriomeningitis virus
    Shenghua Zhou
    Department of Medicine, University of Massachusetts Medical School, Worcester, Massachusetts, USA
    J Virol 84:9452-62. 2010
    ..These virus-host interactions may play important roles in the pathogeneses of LCMV and other human arenavirus diseases...
  14. pmc IFI16 is an innate immune sensor for intracellular DNA
    Leonie Unterholzner
    School of Biochemistry and Immunology, Trinity College Dublin, Dublin, Ireland
    Nat Immunol 11:997-1004. 2010
    ..IFI16 (p204) is the first PYHIN protein to our knowledge shown to be involved in IFN-β induction. Thus, the PYHIN proteins IFI16 and AIM2 form a new family of innate DNA sensors we call 'AIM2-like receptors' (ALRs)...
  15. pmc The interferon inducible gene: Viperin
    Katherine A Fitzgerald
    Division of Infectious Diseases and Immunology, Department of Medicine, University of Massachusetts Medical School, Worcester, Massachusetts 01605, USA
    J Interferon Cytokine Res 31:131-5. 2011
    ..Viperin is also induced by nonviral microbial products such as lipopolysaccharide (LPS) and by a wide range of bacteria, suggesting a broader role in innate antimicrobial defenses...
  16. pmc Autophagy proteins regulate innate immune responses by inhibiting the release of mitochondrial DNA mediated by the NALP3 inflammasome
    Kiichi Nakahira
    Division of Pulmonary and Critical Care Medicine, Brigham and Women s Hospital, Harvard Medical School, Boston, Massachusetts, USA
    Nat Immunol 12:222-30. 2011
    ..Our study suggests that autophagic proteins regulate NALP3-dependent inflammation by preserving mitochondrial integrity...
  17. pmc Recognition of herpesviruses by the innate immune system
    Søren R Paludan
    Department of Medical Microbiology and Immunology, The Bartholin Building, Aarhus University, DK 8000 Aarhus C, Denmark
    Nat Rev Immunol 11:143-54. 2011
    ....
  18. pmc Innate immune sensing of DNA viruses
    Vijay A K Rathinam
    Department of Medicine, University of Massachusetts Medical School, Worcester, MA 01605, USA
    Virology 411:153-62. 2011
    ..In this review, we discuss the recent advances in the innate immune sensing of DNA viruses and focus on the recognition mechanisms involved...
  19. pmc Regulation of lipopolysaccharide-induced translation of tumor necrosis factor-alpha by the toll-like receptor 4 adaptor protein TRAM
    Lijian Wang
    Mucosal Immunology Laboratory, Division of Pediatric Gastroenterology, Massachusetts General Hospital, Charlestown, Mass, USA
    J Innate Immun 3:437-46. 2011
    ..Our results indicate that TRAM- and TRIF-dependent signals have a previously unappreciated, cell type-specific role in regulating TNF-α translation...
  20. pmc Phagosomal retention of Francisella tularensis results in TIRAP/Mal-independent TLR2 signaling
    Leah E Cole
    Department of Microbiology and Immunology, University of Maryland, Baltimore, Baltimore, MD 21201, USA
    J Leukoc Biol 87:275-81. 2010
    ..Taken together, these data suggest that prolonging or enhancing the interaction between TLR2 and its agonist overcomes the "bridging" function ascribed previously to TIRAP...
  21. doi IKKalpha negatively regulates IRF-5 function in a MyD88-TRAF6 pathway
    Mumtaz Yaseen Balkhi
    Sidney Kimmel Cancer Center, Johns Hopkins University, Baltimore, MD 21218, USA
    Cell Signal 22:117-27. 2010
    ....
  22. pmc Endotoxin tolerance dysregulates MyD88- and Toll/IL-1R domain-containing adapter inducing IFN-beta-dependent pathways and increases expression of negative regulators of TLR signaling
    Wenji Piao
    Department of Microbiology and Immunology, University of Maryland School of Medicine, Baltimore, MD 21201, USA
    J Leukoc Biol 86:863-75. 2009
    ..These data demonstrate dysregulation of TLR4-triggered MyD88- and TRIF-dependent signaling pathways and increased expression of negative regulators of TLR signaling in endotoxin-tolerant human monocytes...
  23. pmc RIG-I-dependent sensing of poly(dA:dT) through the induction of an RNA polymerase III-transcribed RNA intermediate
    Andrea Ablasser
    Institute for Clinical Chemistry and Pharmacology, University of Bonn, Bonn, Germany
    Nat Immunol 10:1065-72. 2009
    ..This pathway was important in the sensing of Epstein-Barr virus-encoded small RNAs, which were transcribed by RNA polymerase III and then triggered RIG-I activation. Thus, RNA polymerase III and RIG-I are pivotal in sensing viral DNA...
  24. pmc NOD2, RIP2 and IRF5 play a critical role in the type I interferon response to Mycobacterium tuberculosis
    Amit K Pandey
    Department of Molecular Genetics and Microbiology, University of Massachusetts Medical School, Worcester, MA, USA
    PLoS Pathog 5:e1000500. 2009
    ....
  25. pmc Recognition of 5' triphosphate by RIG-I helicase requires short blunt double-stranded RNA as contained in panhandle of negative-strand virus
    Martin Schlee
    Institute of Clinical Chemistry and Pharmacology, University Hospital, University of Bonn, D 53127 Bonn, Germany
    Immunity 31:25-34. 2009
    ....
  26. pmc Cutting edge: NF-kappaB activating pattern recognition and cytokine receptors license NLRP3 inflammasome activation by regulating NLRP3 expression
    Franz G Bauernfeind
    Department of Infectious Diseases and Immunology, University of Massachusetts Medical School, Worcester, MA 01605, USA
    J Immunol 183:787-91. 2009
    ..Signals provided by NF-kappaB activators are necessary but not sufficient for NLRP3 activation, and a second stimulus such as ATP or crystal-induced damage is required for NLRP3 activation...
  27. pmc A TIR domain variant of MyD88 adapter-like (Mal)/TIRAP results in loss of MyD88 binding and reduced TLR2/TLR4 signaling
    Kamalpreet Nagpal
    Division of Infectious Diseases and Immunology, Department of Medicine, University of Massachusetts Medical School, Worcester, Massachusetts 01605, USA
    J Biol Chem 284:25742-8. 2009
    ..Genotyping of Mal D96N in three different cohorts suggested that it is a rare mutation. We, thus, describe a rare variant in Mal that exerts its effect via its inability to bind MyD88...
  28. pmc An essential role for the NLRP3 inflammasome in host defense against the human fungal pathogen Candida albicans
    Amy G Hise
    Center for Global Health and Diseases, Case Western Reserve University, Cleveland, OH 44106, USA
    Cell Host Microbe 5:487-97. 2009
    ..Therefore, in addition to sensing bacterial and viral pathogens, the NLRP3 inflammasome senses fungal pathogens and is critical in host defense against Candida...
  29. pmc Role of p38 and early growth response factor 1 in the macrophage response to group B streptococcus
    Sybille Kenzel
    Center for Pediatric and Adolescent Medicine, University Medical Center Freiburg, Freiburg, Germany
    Infect Immun 77:2474-81. 2009
    ..In conclusion, MyD88, p38, and Egr-1, but not Elk-1, essentially mediate the inflammatory cytokine response to GBS organisms...
  30. pmc AIM2 recognizes cytosolic dsDNA and forms a caspase-1-activating inflammasome with ASC
    Veit Hornung
    Division of Infectious Diseases and Immunology, Department of Medicine, University of Massachusetts Medical School, Worcester, Massachusetts 01605, USA
    Nature 458:514-8. 2009
    ..Collectively, these observations identify AIM2 as a new receptor for cytoplasmic DNA, which forms an inflammasome with the ligand and ASC to activate caspase-1...