Toll-Like Receptor (TLR)-3, but Not TLR4, Agonist Protects against Genital Herpes Infection in the Absence of Inflammation Seen with CpG DNA

• Published in: The Journal of infectious diseases 2004-11, Vol.190 (10), p.1841-1849
• Main Authors: Ashkar, Ali A., Yao, Xiao-Dan, Gill, Navkiran, Sajic, Dusan, Patrick, Amy J., Rosenthal, Kenneth L.
• Format: Article
• Language: English
• Subjects: Animals; Antivirals; Biological and medical sciences; Cell Line; Cell lines; Disease Models, Animal; Double stranded RNA; Female; Fundamental and applied biological sciences. Psychology; Genitalia; Herpes Genitalis - prevention & control; Herpes simplex virus; Herpesvirus 2, Human - immunology; Human herpesvirus 2; Infections; Infectious diseases; Interferon-gamma - metabolism; Ligands; Lipopolysaccharides - immunology; Medical sciences; Membrane Glycoproteins - agonists; Membrane Glycoproteins - genetics; Membrane Glycoproteins - immunology; Membrane Glycoproteins - metabolism; Mice; Mice, Inbred C57BL; Microbiology; Mucous Membrane - immunology; Mucous Membrane - virology; Oligodeoxyribonucleotides - administration & dosage; Poly I-C - administration & dosage; Receptors, Cell Surface - agonists; Receptors, Cell Surface - genetics; Receptors, Cell Surface - immunology; Receptors, Cell Surface - metabolism; RNA; RNA, Double-Stranded - administration & dosage; RNA, Messenger - analysis; Signal Transduction; Spleen cells; Survival Analysis; Toll-Like Receptor 3; Toll-Like Receptor 4; Toll-Like Receptors; Transcription, Genetic; Vagina - immunology; Viral Plaque Assay; Virues
• ISSN: 0022-1899; 1537-6613
• DOI: 10.1086/425079

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 doublestranded 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.