Infectious Salmon Anaemia virus (ISAV) is an orthomyxovirus that causes large economic losses in Atlantic salmon ( Salmo salar L.) aquaculture. All virulent ISAV variants originally emerged from a non-virulent subtype, ISAV-HPR0. Transient ISAV-HPR0 infections are common in both freshwater and marine environments. ISAVHPR0 infects juveniles, marine salmon at on-growing sites, and broodstock salmon. The shift in virulence from ISAV-HPR0 to the virulent HPR Delta is suggested to be a stochastic event that depends on the virus's replication frequency. Therefore, reducing the capacity to maintain ISAV-HPR0 infection within individual farms may limit the risk of emerging pathogenic ISAV variants and ISA disease. The absence of infection-related clinical signs and the lack of experimental models limit our understanding of ISAV-HPR0-host interactions. We characterise the host transcriptional response to natural ISAV-HPR0 infection, using Atlantic salmon gill tissues collected on three Norwegian smolt farms. The comparison of all infected (qPCR-positive) and non-infected (qPCR-negative) individuals revealed a classic antiviral response in the gills of ISAV-HPR0 infected fish in a site-independent transcriptomic analysis. Complementary analyses showed that the response to infection varied considerably between sites. Site-specific differences could be associated with a range of factors that are challenging to control in field studies, such as fish size, the stage of infection, and the presence of additional microorganisms. Our findings enhance our understanding of how Atlantic salmon respond to ISAV-HPR0 infection, pinpointing common HPR0-induced antiviral response genes. Future studies should investigate whether these candidate genes limit virus replication in the gill for risk of novel transitions to virulence.
