However, it should be noted that the host range of ranaviruses is incompletely understood at this time. The host immune system has evolved multiple ways to fight virus infection and replication. One important arm of the host immune response is the innate immune system, which recognizes molecular patterns present in many pathogens and initiates antimicrobial responses [13, 14]. An important
component of ZD1839 concentration the host response is the antiviral protein kinase PKR, which contains double-stranded (ds) RNA binding domains (RBD) and a kinase domain. PKR is activated by dsRNA, which is formed during infection by many RNA and DNA viruses, and phosphorylates the α subunit of eukaryotic translation initiation factor 2 (reviewed in ). PKR is inactive in its latent monomeric form. However, upon binding dsRNA, two PKR molecules
dimerize and undergo autophosphorylation on residue Thr446 (for human PKR) [16–18]. Activated PKR then phosphorylates eIF2α on Ser51, which subsequently acts as an inhibitor of the guanine nucleotide exchange factor eIF2B. As eIF2B normally exchanges GDP for GTP on eIF2, a step necessary for successful translation initiation, eIF2α phosphorylation leads to a general inhibition of translation initiation [19, 20]. The function of mammalian PKR and its interaction with viruses has been extensively characterized (reviewed in ). However, PKR-like molecules in ectotherms eluded molecular characterization until recently. PKR-like activity from was first described in fish cells [21, 22]. This was followed by the cloning and functional buy Pembrolizumab characterization of crucian carp and zebrafish PKR-related genes, which contain Z-DNA binding (Zα) domains instead of the dsRBDs and were hence named PKZ [23, 24]. PKZ was subsequently described in Atlantic salmon and the rare minnow [25, 26]. Recently, authentic PKR genes were described and characterized in many ectotherm species including zebrafish, pufferfish, Japanese flounder and two Xenopus species [27, 28]. Like mammalian PKR, both PKZ and PKR are induced by immunostimulation [23, 27,
28]. Phylogenetic analyses indicate that a duplication of an ancestral PKR-like gene in the fish lineage probably led to the emergence of PKR and PKZ in a fish ancestor, and might have helped to extend the spectrum of viral nucleic acids that can be recognized . Although higher vertebrates lack PKZ genes, they contain a different Zα-containing protein, termed ZBP1, which binds Z-DNA and has been implicated in the recognition of viral DNA and the induction of an antiviral response [29–31]. In order to overcome the antiviral effects of PKR many mammalian viruses encode inhibitors of PKR, which block PKR activation or activity at different steps during or following the activation process (reviewed in ).