Innate and adaptive defense mechanisms have evolved to prevent the viral entry, to inhibit virus replication and to destroy viral-derived products. The response of multicellular hosts to viral infection is supposed to originate from an ancestral defense system used to control selfish genetic elements. Although hemocytes have been recently used as an in-vitro model for studying Malacoherpesviridae infections, the propagation of these viruses is still relying almost exclusively on in-vivo experiments. In particular, dual RNA-seq and other HTS approaches have been used to investigate host’s response and the genetic basis for host’s resistance or susceptibility to Malacoherpesviridae. Nowadays, high-throughput sequencing (HTS) supports the investigation of both transcriptional and genomic landscapes, successfully disclosing such features in non-model organisms also during in-vivo infections and providing an unprecedented resolution of molecular host-pathogen interactions. (chordate) suggests a past history of intricate relationships and a possible long lasting co-evolution between these viruses and their hosts. Although the evolutionary history of Malacoherpesviridae is largely unknown and this virus family is only distantly related to vertebrate herpesviruses, the identification of Malacoherpesviridae-like sequences in the genome of Crassostrea gigas (bivalve), Capitella teleta (nematode) and Branchiostoma spp. Among the variety of potential pathogens, dsDNA viruses of the Malacoherpesviridae family represent a major issue for a number of bivalve and gastropod species, as they have greatly challenged the abalone and oyster aquaculture in the last decades. Virus abundances are especially noticeable in marine coastal ecosystems and viruses of different origin are often found in filter-feeding invertebrates such as bivalve mollusks. As a result, all cellular organisms have developed antiviral defense mechanisms and the arms race between viruses and their hosts has contributed to shape both their genomes over millions of years. Since the early life, cells have been parasitized by self-replicating elements such as viruses. The analysis of base neighbor preferences, structural features and expression profiles of molluscan ADAR1 supports the conservation of the enzyme function among metazoans and further suggested that ADAR1 exerts an antiviral role in mollusks. We report, for the first time, evidence of an extensive editing of Malacoherpesviridae RNAs attributable to host ADAR1 enzymes. The analysis of viral sequences suggested that, under the pressure of the ADAR editing, the two Malacoherpesviridae genomes have evolved to reduce the number of deamination targets. The SNV sites and their upstream neighbor nucleotide indicated the targeting of selected adenosines. SNVs occurred at low frequency in genomic hotspots, denoted by the overlapping of viral genes encoded on opposite DNA strands. Single nucleotide variation (SNV) profiles obtained by pairing RNA- and DNA-seq data from the viral infected individuals resulted to be mostly compatible with ADAR-mediated A-to-I editing (up to 97%). Accordingly, we demonstrated an extensive ADAR-mediated editing of viral RNAs. Using RNA-seq and quantitative real time PCR we demonstrated the upregulation of one ADAR1 homolog in the bivalve Crassostrea gigas and in the gastropod Haliotis diversicolor supertexta during Ostreid herpesvirus-1 or Haliotid herpesvirus-1 infection. We traced 4 ADAR homologs in 14 lophotrochozoan genomes and we classified them into ADAD, ADAR1 or ADAR2, based on phylogenetic and structural analyses of the enzymatic domain. Acting on exogenous dsRNAs, ADAR1 exerts a pro- or anti-viral role in vertebrates and Drosophila. They convert adenine into inosine in dsRNAs and thus alter both structural properties and the coding potential of their substrates. Adenosine deaminase enzymes of the ADAR family are conserved in metazoans.
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