title: Toll-like receptor (TLR)-3, but not TLR4, agonist protects against genital herpes infection in the absence of inflammation seen with CpG DNA.
abstract: We previously demonstrated that delivery of CpG oligodeoxynucleotide (ODN) to vaginal mucosa induced an innate mucosal antiviral state that protected against intravaginal challenge with herpes simplex virus (HSV)-2. We report that mucosal, but not systemic, delivery of ligands for Toll-like receptor (TLR)-3, but not TLR4, induced protection against genital HSV-2 challenge that was not accompanied by the local inflammation and splenomegaly seen after treatment with CpG ODN. Surprisingly, TLR4 messenger (m) RNA expression was shown to be higher than that of TLR3 or TLR9 in murine genital mucosa. Similarly, murine RAW264.7 cells were shown to express more mRNA for TLR4 than TLR3 or TLR9, yet treatment of these cells with double-stranded RNA provided greater protection than lipopolysaccharide or CpG ODN. These results indicate that TLR3 ligand induces a more potent antiviral response than TLR4 and TLR9 ligands and may be a safer means of protecting against sexually transmitted viral infections.
authors.affiliation: Centre for Gene Therapeutics, Department of Pathology and Molecular Medicine, McMaster University Health Sciences Centre, Hamilton, Ontario, Canada. ashkara@mcmaster.ca
authors.forename: Ali A
authors.initials: AA
authors.lastname: Ashkar
authors.forename: Xiao-Dan
authors.initials: XD
authors.lastname: Yao
authors.forename: Navkiran
authors.initials: N
authors.lastname: Gill
authors.forename: Dusan
authors.initials: D
authors.lastname: Sajic
authors.forename: Amy J
authors.initials: AJ
authors.lastname: Patrick
authors.forename: Kenneth L
authors.initials: KL
authors.lastname: Rosenthal
mesh_terms: D000818:Animals; D002460:Cell Line; D004195:Disease Models, Animal; D005260:Female; D006558:Herpes Genitalis / Q000517:prevention & control*; D018258:Herpesvirus 2, Human / Q000276:immunology; D007371:Interferon-gamma / Q000378:metabolism; D008024:Ligands; D008070:Lipopolysaccharides / Q000276:immunology; D008562:Membrane Glycoproteins / Q000819:agonists* / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D009092:Mucous Membrane / Q000276:immunology / Q000821:virology; D009838:Oligodeoxyribonucleotides / Q000008:administration & dosage; D011070:Poly I-C / Q000008:administration & dosage; D012330:RNA, Double-Stranded / Q000008:administration & dosage; D012333:RNA, Messenger / Q000032:analysis; D011956:Receptors, Cell Surface / Q000819:agonists* / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D015398:Signal Transduction; D016019:Survival Analysis; D051196:Toll-Like Receptor 3; D051197:Toll-Like Receptor 4; D051193:Toll-Like Receptors; D014158:Transcription, Genetic; D014621:Vagina / Q000276:immunology; D010948:Viral Plaque Assay
chemical_list: C408982:CPG-oligonucleotide; D008024:Ligands; D008070:Lipopolysaccharides; D008562:Membrane Glycoproteins; D009838:Oligodeoxyribonucleotides; D012330:RNA, Double-Stranded; D012333:RNA, Messenger; D011956:Receptors, Cell Surface; D051196:Toll-Like Receptor 3; D051197:Toll-Like Receptor 4; D051193:Toll-Like Receptors; D007371:Interferon-gamma; D011070:Poly I-C