Section: Research

Katherine Fitzgerald, Ph.D.

Academic Role: Assistant Professor

Faculty Appointment(s) In:
   Infectious Diseases and Immunology
   Medicine

Other Affiliation(s):
   Center for AIDS Research
   Interdisciplinary Graduate Program
   Program in Immunology and Virology

Academic Background

Kate Fitzgerald received her B.Sc. in 1995 from University College Cork, Ireland, and her Ph.D. in 1999 from Trinity College Dublin, Ireland. From 1999 to 2001, she was a post-doctoral fellow in the Department of Biochemistry at Trinity College Dublin, where her work was supported by a fellowship from the European Union. Dr. Fitzgerald joined the Division of Infectious Disease at the University of Massachusetts Medical School as a recipient of a Wellcome Trust International Award in 2001. In 2004 she joined the Faculty as an Assistant Professor of Medicine.

Research

Innate Anti-Viral Signaling; TLRs and beyond

My lab is interested in understanding how the immune system “senses” bacterial or viral infection and initiates the innate immune response. We are interested in the signaling mechanisms regulating the expression of these innate immune response genes. The induction of type I IFN (IFNa/b) is one of the earliest innate immune responses to viral as well as bacterial pathogens. Although best characterized for their ability to “interfere” with viral infection, type I IFNs have a range of additional effects on the immune response. They regulate the growth and enhance the immune activity of various cell types.

Transcriptional activation of the INFb gene is well characterized and requires assembly of an enhanceosome containing the transcription factors ATF-2/c-Jun, IRF-3/IRF-7, NF-kB and the architectural factor HMG-1Y. These factors cooperatively bind a composite DNA site and activate expression of the IFN-b gene. The molecular mechanisms regulating NFkB and ATF2-c-Jun are well-characterized while those regulating the IRFs, are much less clear. In order to be activated, IRF-3 must be phosphorylated on its C-terminus leading to its dimerization and translocation to the nucleus where together with NFkB and ATF2-C-Jun, it activates IFNb transcription.

We and others have recently identified two IkB kinase (IKK) related kinases, called TANK Binding Kinase-1 (TBK1) or IkB kinase-epsilon, as critical mediators of the IRF3 pathway. TBK1 and IKKe, are structurally related to IKKa and IKKb. In contrast to IKKa and IKKb which activate NFkB, IKKe and TBK1 directly phosphorylate and activate IRF3 and control type I IFN gene expression.

Other components of the signaling pathway involved in the phosphorylation of IRF-3 are still poorly characterized. Several studies have recently highlighted the TLR system as one way to activate IRF3. TLR3, TLR4, TLR7 and TLR9 which recognize double stranded (ds) RNA, LPS, single stranded (ss) RNA or double stranded DNA respectively, have all been shown to activate IRF3 and induce type I IFN. Transduction of intracellular signaling by TLRs depends upon the constitutive association and/or recruitment of specific adapter molecules to the intracytoplasmic COOH-terminus of TLRs through structurally conserved motifs called “Toll-Interleukin (IL)-1 Resistance” (TIR) domains present in both TLRs and adapter molecules. There are four TIR domain containing adapter molecules which participate in TLR signaling, namely MyD88, Mal, TRIF and TRAM. These adapters provide a structural platform to which various kinases and downstream effectors are recruited. The result of these events is the activation of pathway-specific transcription factors and the induction of immune response genes. TLRs which recruit TRIF or TRAM induce IFNb, while others which do not, such as TLR2 do not. TLR7 and TLR9 are also capable of inducing type I IFN, mainly IFNa. However in this case, the adapter molecule MyD88 is important.

TLR-independent mechanisms of anti-viral sensing and signaling have also been proposed. The DExD/H box-RNA helicases, RIG-I has emerged as a viral sensing mechanisms, which functions independently of the TLRs. RIG-I is an unusual helicase in that, in addition to a catalytic domain, it also has protein-interaction CARD modules. The CARD domain of RIG-I is required for activation of the transcription factor IRF3. CARDs, like other structurally related protein interaction modules found in innate immune adaptor molecules, such as death domains, Toll–interleukin 1 receptor (TIR) domains and death effector domains, promote the creation of platforms for nucleating signaling events. It is unclear at present how RIG-I induces IRF3 altough TBK1 is a component of the pathway.

The long-term objective of our research is to obtain a clear understanding of the signaling pathways regulating type I IFN in the innate immune response. We want to to determine the contribution of TLR-dependent and TLR-independent pathways to either viral or bacterial infections in vivo. Such studies are likely to reveal novel therapeutic and immune-modulation strategies to eliminate acute and chronic viral and bacterial infections.

IKKe and TBK1 are essential mediators of the type I IFN response.

Office: LRB 309
Phone: 508-856-6518
Fax: 508-856-5463
E-mail: Katherine.Fitzgerald@umassmed.edu
Keywords: Immunology, Virology, Signal Transduction

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