Chapter 19 : Toll-Like Receptors: Novel Molecular Targets for Antiviral Immunotherapy

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This chapter reviews the role of toll-like receptors (TLRs) in innate antiviral responses and in coordinating the antiviral adaptive immune system, and discusses the potential for TLRs as novel molecular targets for antiviral immunomodulatory therapy. A mutation in the Toll gene in that results in defective protein was associated with reduced survival after fungal infection. The chapter discusses TLR recognition of pathogen-associated molecular patterns, TLR signaling pathway, biological outcomes of TLR activation, and TLRs and the pathogenesis of selected viral pathogens. The potential role for TLR-7 and TLR-8 in HSV pathogenesis is highlighted by ongoing research efforts to control herpes simplex virus (HSV) infections with the use of small-molecule TLR-7 and TLR-8 agonists. Many viruses, however, have evolved to develop strategies that block the effector mechanisms induced through TLR signaling pathways. Coronavirus, a contagious viral pathogen that causes the highly fatal severe acute respiratory syndrome (SARS), has an attenuated ability to induce type I interferons (IFNs), which are essential for the efficient control of the infection, because it has developed a TLR evasion mechanism characterized by failure of IRF-3 activation. The chapter describes TLRs as targets for immunomodulation and antiviral therapies. The successful clinical development of imiquimod, the prototype TLR immune response-modifying drug, provides a solid example of the promise and remarkable potential that TLR modulators have in bringing novel antiviral therapeutic strategies in the clinical setting.

Citation: Razonable R, Eid A, Henault M. 2009. Toll-Like Receptors: Novel Molecular Targets for Antiviral Immunotherapy, p 333-346. In LaFemina, Ph. D. R (ed), Antiviral Research. ASM Press, Washington, DC. doi: 10.1128/9781555815493.ch19
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Image of Figure 1.
Figure 1.

TLR signaling pathway. Cell surface-associated TLRs (TLR-1, TLR-2, TLR-4, TLR-5, and TLR-6) recognize lipids and proteins derived from viruses, while endosome-associated TLR-3, TLR-7, TLR-8, and TLR-9 recognize viral nucleic acid structures. Examples of viruses known to signal through these receptors are shown. Upon ligation of these microbial structures, an intracellular signaling cascade is activated that eventually leads to the nuclear translocation of transcription factors such as NF-KB and IRF-3. Abbreviations: TIRAP, TIR-domain-containing adapter protein; TRAF6, tumor necrosis factor-α receptor-associated factor 6; TRAM, TRIF-related adapter molecule; TRIF, TIR-domain-containing adapter protein inducing IFN-β.

Citation: Razonable R, Eid A, Henault M. 2009. Toll-Like Receptors: Novel Molecular Targets for Antiviral Immunotherapy, p 333-346. In LaFemina, Ph. D. R (ed), Antiviral Research. ASM Press, Washington, DC. doi: 10.1128/9781555815493.ch19
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Image of Figure 2.
Figure 2.

Chemical structures of selected TLR-7 and TLR-8 agonists.

Citation: Razonable R, Eid A, Henault M. 2009. Toll-Like Receptors: Novel Molecular Targets for Antiviral Immunotherapy, p 333-346. In LaFemina, Ph. D. R (ed), Antiviral Research. ASM Press, Washington, DC. doi: 10.1128/9781555815493.ch19
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Table 1.

TLRs and selected ligands TLR

Citation: Razonable R, Eid A, Henault M. 2009. Toll-Like Receptors: Novel Molecular Targets for Antiviral Immunotherapy, p 333-346. In LaFemina, Ph. D. R (ed), Antiviral Research. ASM Press, Washington, DC. doi: 10.1128/9781555815493.ch19
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Table 2.

Selected TLR agonists in preclinical and clinical stages of development for the treatment of virus infections

Citation: Razonable R, Eid A, Henault M. 2009. Toll-Like Receptors: Novel Molecular Targets for Antiviral Immunotherapy, p 333-346. In LaFemina, Ph. D. R (ed), Antiviral Research. ASM Press, Washington, DC. doi: 10.1128/9781555815493.ch19

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