Natural and semisynthetic diterpenoids with antiviral and immunomodulatory activities block the ERK signaling pathway
We evaluated the effects of agonists and antagonist of toll-like receptor (TLR) 9 in comparison with a TLR3 agonist in a mouse model of herpes simplex virus type 1 (HSV-1) encephalitis (HSE). BALB/c mice received a single intranasal dose of either a TLR3 agonist (polyinosinic:polycytidylic acid; PIC), TLR9 agonists (oligodeoxynucleotides (ODNs) 1585, 1826 or 2395) or a TLR9 antagonist (ODN 2088), 1 day before and, for selected groups, 3 days after infection with HSV-1. Mice that received the pre-treatment with vehicle, PIC, ODNs 1585, 1826, 2395 and 2088 before infection had survival rates of 25%, 65%, 55%, 40%, 55% and 30%, respectively (P<0.05 for PIC and ODNs 1585 and 2395 versus vehicle). Infected mice subsequently treated with vehicle, ODNs 2395 and 2088 had survival rates of 9%, 0% and 30%, respectively (P<0.05, ODN 2088 versus other groups). The pre-treatment of mice with ODN 2395 reduced both the viral load (P<0.05 at day 5) and the production of CCL2, IL-6 and CCL5 at days 3, 4 and 5 (P<0.05 for IL-6 at day 3 and P<0.05 for CCL2 and CCL5 at day 4). Treatment of infected mice with ODN 2088 reduced the production of the same cytokines (P=0.07 for CCL2 and P=0.09 for IL-6 at day 5). Pre-treatment of mice with TLR9 agonists before infection reduces brain viral load and cytokine levels resulting in increased HSE survival rates. On the other hand, TLR9 antagonists can be helpful to control the inflammatory response that could be detrimental after infection.