Project 1. Modulation of TLR3-mediated innate responses to dampen excessive inflammation and inhibit viral replication

There is a pressing need to develop alternatives to annual influenza vaccines and antiviral agents licensed for RNA viruses such as influenza or Thick Borne Encephalitis (TBE) virus. Previous studies suggest that Toll-like receptor (TLR) 3-/- mice have less lung damage after influenza infection compared with wild type mice. In addition, an epidemiological study suggested that a functional TLR3 gene is a risk factor for severe TBE infection. Thus, strategies to prevent TLR3 hyper-responsiveness may constitute a therapeutic path. Alternatively, strengthening of the TLR3-mediated innate immune response may aid in more rapid clearance of virus during an acute virus infection. We recently reported that a single-stranded DNA oligonucleotide (ssODN) can inhibit TLR3-signalling (Sköld AE et al Blood. 2012 Jul 26;120(4):768-77). We will now investigate how strengthening or inhibition of TLR3-signalling will affect innate immune responses and subsequent inflammatory and anti-viral responses.