Project Summary We have developed and applied a highly automated system of random germline mutagenesis to probe TLR signaling and resistance to viral infection in mice. The search for still more proteins involved in TLR signaling will continue as we have not yet approached saturation of the genome. Moreover, we have identified a number of genes with essential functions in these processes and propose to study them further. As new and essential components of the system are identified we will seek to understand them mechanistically using tools of biochemistry, cell biology, and genetics. We will also analyze the antagonistic relationship between MyD88 and Ticam1 by placing specific markers of the inhibitory influence exercised by each adaptor protein under surveillance. We envision close collaboration with our colleagues in Seattle, Stanford, La Jolla and Sydney, with whom we have worked for many years.