TLRMediated Activation of Type I Ifn During Antiviral Immune Responses Fighting the Battle to Win the

'Division of Infectious Disease and Immunology, Department of Medicine, The University of Massachusetts Medical School, Worcester, MA 01605, USA [email protected]

1 Introduction 168

2 ER-Localized TLRs: The Specialists in Virus Recognition 169

2.1 TLR3 169

2.2 TLR7 and TLR8 170

2.3 TLR9 172

3 IFN Gene Induction During Viral Infections:

Pathways Activated by TLRs 174

3.1 MyD88 or TRIF? This Is the Question! 174

3.2 MyD88-Dependent Pathways in pDCs 176

3.3 IRF5: The Outsider 179

3.4 Negative Regulators of MyD88 and TRIF Signaling 181

4 Concluding Remarks and Some Speculations 182

References 183

Abstract Toll-like receptors (TLRs) are crucially important in the sensing of viral infections and viral nucleic acids. TLR triggering leads to the induction of specific intracellular signaling cascades that result in the activation of two major families of transcription factors; the IFN-regulatory factors (IRFs) and nuclear factor-kappa B (NF-kB). IRFs and NF-kB work together to trigger the production of type I interferons (IFNa/P) or inflammatory cytokines leading to the maturation of dendritic cells and the establishment of antiviral immunity. This review will focus on the most recent findings relating to the regulation of IRF activity by TLRs, highlighting the increasing complexity of TLR-mediated signaling pathways.

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