Inhibition of influenza virus-induced NF-kappaB and Raf/MEK/ERK activation can reduce both virus titers and cytokine expression simultaneously in vitro and in vivo

Influenza virus (IV) infection can cause severe pneumonia and death. Therapeutic actions are limited to vaccines and a few anti-viral drugs. These target viral functions thereby selecting resistant variants. During replication IV activates the Raf/MEK/ERK-cascade and the transcription factor NF-kappaB. Both result in virus supportive and anti-viral effects by promoting viral genome transport for virus assembly and by inducing expression of pro-inflammatory host factors. Apart from tissue damage caused by the virus lytic replication, an imbalanced overproduction of anti-viral cytokines can cause severe lung damage as observed in human H5-type IV infections. Recently we showed that inhibition of NF-kappaB activity reduces the virus titer in vitro and in vivo. We have now analyzed whether inhibition of these pathways, allows simultaneous reduction of virus titers and virus-induced cytokines. The results show that inhibition of either pathway indeed leads to decreased virus titers and cytokine expression. This was not only true for infected permanent cells or primary mouse alveolar epithelial cells, but also in infected mice. Hereby we demonstrate for the first time in vitro and in vivo that virus titers and pro-inflammatory cytokine expression can be modulated simultaneously. This could provide a new rationale of future therapeutic strategies to treat IV pneumonia.