title: Treatment of intravaginal HSV-2 infection in mice: a comparison of CpG oligodeoxynucleotides and resiquimod (R-848).
abstract: The mammalian innate immune system recognizes pathogens via a series of pattern-recognition receptors such as the toll-like receptors (TLR) that interact with pathogen-associated molecular patterns (PAMPs) and lead to the rapid activation of innate immune cells. In this study, we compared the efficacy of CpG ODN (a TLR9 agonist) and resiquimod (R-848; a TLR7/8 agonist) for topical immunoprophylaxis or immunotherapy of vaginal herpes simplex virus type 2 (HSV-2) infection in mice. Efficacy against HSV infection was observed with CpG ODN but less so with R-848, even after repeated administrations. Intravaginal (IVAG) administration of CpG ODN resulted in strong local but relatively weak systemic immune activation, as determined by levels of the chemokines IP-10, MIG and I-TAC in vaginal tissue and plasma, respectively. In contrast, IVAG administration of R-848 resulted in high levels of plasma IP-10, similar to those seen after parenteral administration, but overall, weaker or shorter-lived local immune responses than obtained with CpG ODN. These findings suggest that differences in biodistribution and sites of immune activation between CpG ODN and R-848 after IVAG delivery account for differences in efficacy, and demonstrate the need for local mucosal innate activation for protection against HSV-2.
authors.affiliation: Coley Pharmaceutical Group, 340 Terry Fox Drive, Suite 200, Ottawa, Ont., Canada K2K 3A2. mmccluskie@coleypharma.com
authors.forename: Michael J
authors.initials: MJ
authors.lastname: McCluskie
authors.forename: Janna L M
authors.initials: JL
authors.lastname: Cartier
authors.forename: Amy J
authors.initials: AJ
authors.lastname: Patrick
authors.forename: Dusan
authors.initials: D
authors.lastname: Sajic
authors.forename: Risini D
authors.initials: RD
authors.lastname: Weeratna
authors.forename: Kenneth L
authors.initials: KL
authors.lastname: Rosenthal
authors.forename: Heather L
authors.initials: HL
authors.lastname: Davis
mesh_terms: D000276:Adjuvants, Immunologic / Q000008:administration & dosage / Q000627:therapeutic use*; D000818:Animals; D018899:CpG Islands; D005260:Female; D006558:Herpes Genitalis / Q000188:drug therapy* / Q000517:prevention & control / Q000821:virology; D018258:Herpesvirus 2, Human / Q000187:drug effects* / Q000472:pathogenicity; D007093:Imidazoles / Q000008:administration & dosage / Q000627:therapeutic use*; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D009838:Oligodeoxyribonucleotides / Q000008:administration & dosage / Q000627:therapeutic use*; D016896:Treatment Outcome; D014621:Vagina / Q000821:virology
chemical_list: D000276:Adjuvants, Immunologic; C408982:CPG-oligonucleotide; D007093:Imidazoles; D009838:Oligodeoxyribonucleotides; C402365:resiquimod