Phosphorylcholine works not only as a pathogen-associated molecular pattern (PAMP) 10,18-20 , but also as a danger-associated molecular pattern (DAMP) 18,21-24. This phosphorylcholine-binding site of the soluble CRP is also involved in interactions with, for instance, oxidized low-density lipoprotein (LDL) 21 , nuclear materials (such as chromatin, histones, small nuclear ribonucleoproteins) 25,26 , and other compounds that may not contain phosphorylcholine but are abundant in bacteria 27 , fungi 28,29 and parasites 30,31. In mammals, CRPs are usually triggered during both viral and bacterial infections 32 , although associated serum CRP level increases are more characteristic of bacterial infections, during which they increase by 3-fold logs, while viruses induce lower but significant 10 1 serum CRP levels 2,32,33. Furthermore, the few existing studies that have analysed C-reactive-like protein (CRP) levels in fish show moderate serum level increases in response to both bacterial and viral infections, suggesting an antiviral effect for CRPs 34-36. For example, in common carp (Cyprinus carpio), the serum CRP levels increase up to 2-, 6-and 10-fold in response to Aeromonas salmonicida 37 , Aeromonas hydrophila 34 and cyprinid herpesvirus-3 (CyHV-3) 35 infections, respectively. Further positive correlations between CRP levels and viral infections have been established in fish by transcriptional analysis. For instance, significant upregulation of crp gene expression in several immune-and non-immune-related tissues of diverse fish species has been revealed in response to viruses such as CyHV-3 35 , red seabream iridovirus (RSIV) 38-40 , viral haemorrhagic septicaemia virus (VHSV) 41,42 and spring viraemia of carp virus (SVCV) 42,43. Similarly, higher transcriptional expression of crp genes was observed in common carp treated with polyinosinic:polycytidylic acid (polyI:C, a compound that mimics viral dsRNA) 36 , in DNA-vaccinated rainbow trout (Oncorhynchus mykiss) 44 and zebrafish (Danio rerio) embryos microinjected with an expression plasmid encoding the il6 gene 42 , a cytokine that is upregulated in response to viral infections in humans 45. In this sense, our recent findings show that all previously identified zebrafish CRP1-7 isoforms 46 confer isoform-dependent anti-SVCV protection in vitro and in vivo 47 and exert unexpected anti-SVCV synergistic effects 47 with 25-hydroxycholesterol (25-HOC) 48. Recombinant CRP from tongue sole (Cynoglossus semilaevis) has also been reported to enhance host resistance to RSIV infection when intraperitoneally (i.p.) co-injected with the virus inoculum 40. However, despite the great relevance for evolutionary immunology and therapeutic potential of CRPs, the underlying mechanisms for CRP antiviral effects are not yet known. The present work has been focused on these mechanistic aspects. Results CRP1-7 anti-SVCV activity targets host cells rather than the virus. Our previous studies showed that the treatment with the supernatant from epithelioma papulosum cyprinid (EPC) cells th...