Resumo

Herpes Simplex type 1 (HSV-1) is an enveloped DNA virus which can cause various human clinical manifestations, from simple cold sores to encephalitis. Approximately 70% of adults in the world are serum-positive for HSV-1. Cells of the innate immune system recognize pathogen-associated molecular patterns (PAMPs) through Toll Like Receptors (TLRs) and other receptors, orchestrating the immune response against the virus. When activated, TLRs start a signalization cascade that culminates in the activation of genes related to the innate immune defense. In previous works we showed that the immune response against HSV-1 is dependent on TLR2 and TLR9 expression and IFN gamma production in trigeminal ganglia (TG) of infected animals. In the present work we studied TLR and nitric oxide (NO) importance in HSV-1 control in the murine model. C57BL/ 6 Wild Type (WT), TLR2 knockout (KO), TLR9KO and TLR2/9KO mice were intranasally infected with 10⁶ p.f.u. of HSV-1. At day 5 post infection (dpi) mice were euthanized and TG were collected. Induced nitric oxide synthase (iNOS) expression, measured by real time PCR in mice TG, was higher in WT infected mice than in the other groups. Immunofluorescence assays of mice TG showed increased production of iNOS by F4/80 positive cells in WT infected mice, what did not occur with TLR2/9KO infected mice. Additionally, the production of NO by intraperitoneal macrophages was measured, showing that WT macrophages had higher production of NO when compared to TLR KOs, after exposure to HSV-1. In a survival assay, 100% of iNOSKO mice died with encephalitis signs after HSV-1 infection, while WT mice had only 10% of mortality. The results show that TLRs orchestrate efficiently the innate immune system, eliciting NO production by monocytes/macrophages in mice trigeminal ganglia, to control HSV-1 infection.