ACTIVATION OF THE INNATE IMMUNE RESPONSE MEDIATED BY TOLL-LIKE RECEPTORS IN A MURINE INTRANASAL MODEL OF HSV-1 INFECTION.

CAMPOS M. A.(1)

(1)Laboratory of Immunophatology, CPqRR, Fiocruz, Brazil.

Recently it is shown the importance of Toll-like receptors (TLRs) in the host response to different virus infections. MyD88 is an adaptor protein that is downstream to mediated TLR activation and is essential for the production of inflammatory cytokines. The Herpes simplex virus is related with different diseases, being one of the most frequently non-epidemic causes of encephalitis. Using in vitro techniques and knock-out mice in an intranasal model of  infection we show the importance of MyD88 and other innate immunity molecules such as IFNg, TNFrp55 and iNOS. First of all, using CHO transfected cells we show the activation of TLR2 by the HSV-1 in a dose dependent way. Despite this activation, macrophages of TLR2-/- mice induced with HSV-1 had the same TNFa  production profile that WT mice, while MyD88-/- macrophages did not produce this cytokine. To study the role for TLRs in vivo, C57BL/6, TLR2-/-, MyD88-/- and IFNg-/- four week-old mice were infected with 104p.f.u. of HSV-1. Histopathological and immunohistochemical analyses demonstrate a severe encephalitis and the presence of virus in the brain of  MyD88-/- and IFNg-/-, on the contrary of WT and TLR2-/- mice, that showed no signs of encephalitis and no presence of virus in the brain. MyD88-/- and IFNg-/- had 100% and 50% of lethality, respectively, while both the WT and TLR2-/- mice survive 100% to the infection. The HSV-1 was found in the trigeminal ganglia of all mice, which characterize effective infection of all mice with and without symptoms. To look for other molecules that may be important in the HSV-1 disease, TNFarp55-/- and iNOS-/- mice were infected in the same way, which presents 75% and 100% lethality, respectively. ELISA analyses show no differences in the production of TNFa in the sixth day post infection in mice brain or between the 1-4th day in mice serum. Our data points to a very localized infection and probably the control of the infection might be in the ganglia and also suggest the importance of the TLRs pathway and other innate immunity molecules in the intranasal model for HSV-1 encephalitis.

CORRESPONDENCE TO:

Marco Antônio da Silva Campos, Fundação Oswaldo Cruz, Centro de Pesquisas René Rachou. Av. Augusto de Lima 1715, Laboratório Imunopatologia, Barro Preto, 30190-002, Belo Horizonte, MG, Brasil, Telefone: (031) 33497700 Ramal: 142 Fax: (031) 32953115. Email: marcoasc@cpqrr.fiocruz.br