Inhibition of host signalling pathways by VACV members of A46 and related families. TLRs are distributed in the plasma membrane and endosomes. When a pathogen is recognized by a TLR adaptor proteins are recruited which transmit the signal further downstream until specific transcription factors are activated and enhance the expression of genes encoding type I IFNs and pro-inflammatory cytokines. VACV proteins belonging to A46 and N1 families interfere with the TLR signalling pathway at different levels. A46 targets all known adaptor proteins: MyD88, MAL (TIRAP), TRIF and TRAM. A52 targets IRAK2 and TRAF6, intermediary between adaptors and transcription factors. K7 inhibits IRAK2, TRAF6 and also DDX3, which is part of the complex that activates transcription factor IRF3. B15 targets the IKK complex by avoiding IKKbeta phosphorylation, what eventually causes the inhibition of NF-kappaB. N1 associates with several components of the IKK complex and with TBK1, inhibiting NF-kappaB and IRF3 activation, respectively.