Immune cell-resolved transcriptomics provides insights into the basis for variations of fish genetic resistance to...

The genetic basis of host resistance to viral infections is generally shaped by complex interactions between host genetic variations affecting antiviral immunity and the rapid evolutionary adaptability of viruses. In this study, we investigated two isogenic rainbow trout lines exhibiting extreme resistance or susceptibility to the rhabdovirus VHSV. We compared transcriptomes of the pronephros - a major lymphoid organ in fish - at steady state and following VHSV infection. By integrating bulk tissue RNA-seq with single-cell RNA-seq, we mapped the divergent transcriptomic responses of resistant and susceptible fish to specific immune cell types.

At steady state, differences in antiviral pathways were minimal. However, VHSV triggered markedly distinct transcriptomic shifts between the lines. Both resistant and susceptible fish exhibited a broad transcriptional response enriched in core type I interferon (IFN) pathway genes. However, line-specific responses were enriched in genes induced by infection independently of type I IFN. In resistant fish, lymphocyte responses included type I IFN pathway, numerous transcription factors, and various cytokine receptors. In contrast, lymphocyte responses in susceptible fish involved only a limited set of type I IFN-induced genes. Monocytic cell responses also diverged: susceptible fish upregulated IFN-induced genes, while resistant fish showed increased expression of proinflammatory genes.

This study reveals the contribution of the core set of interferon-stimulated genes conserved across vertebrates to the response of different immune cells and the response of other genes in resistant and susceptible fish. It provides a comprehensive basis for evolutionary studies of resistance to viruses in vertebrates.