The two groups of zebrafish type I interferons target different tissues, paralleling the mammalian type I: type III IFN functional division

Wiggett, H.; Porter, D.; Briolat, V.; Balaboi, T.; Abi Younes, M.; Colin, I.; Lutfalla, G.; Levraud, J.-P.

doi:10.1101/2025.11.03.686239

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bioRxiv · 10.1101/2025.11.03.686239

The two groups of zebrafish type I interferons target different tissues, paralleling the mammalian type I: type III IFN functional division

Wiggett, H.·Porter, D.·Briolat, V.·Balaboi, T.·Abi Younes, M.·Colin, I.·Lutfalla, G.·Levraud, J.-P.

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Abstract

Interferons (IFNs) are ancient cytokines that arose in jawed vertebrates [~]400-500 million years ago. IFN systems are present with conserved antiviral functions across vertebrate lineages, including zebrafish (Danio rerio). In mammals, antiviral IFNs are divided between type I interferons (IFN-I), which drive systemic responses, and type III interferons (IFN-III), which protect barrier mucosal epithelia, owing to the specific distribution of their respective receptors. Although zebrafish lack IFN-III, they have IFN-Is which subdivide into 2 groups with distinct receptors, providing a unique opportunity to study how antiviral immunity has evolved in the absence of IFN-III. Whilst previous work has suggested complementary, non-redundant roles for IFNs from these groups, the tissue specificity has not yet been resolved. As larvae, zebrafish only express one group 1 (IFN{varphi}1) and one group 2 IFN (IFN{varphi}3). Using viral infection assays and reporter transgenics, we found that IFNs from group 1 (IFN{varphi}1) and group 2 (IFN{varphi}3) are produced by distinct subsets of cells, with no detectable co-expression. To assess tissue and cell-type-specific responses to these two IFNs, we used ISG reporter fish imaging and whole-larva single cell RNA sequencing after injection of recombinant IFN{varphi}1 and IFN{varphi}3. Despite a similar core ISG response, distinct downstream ISG programs across multiple tissues and organ systems were found. In particular, barrier epithelial cells, such as enterocytes, responded more strongly to IFN{varphi}1, while myeloid cells responded more strongly to IFN{varphi}3. Our results indicate that zebrafish IFN-I families have functionally diversified their antiviral immune responses by tissue context, driven by cellular partitioning of both IFN-I production and response. These results mirror the division of labour between mammalian IFN-I and IFN-III, emphasising the evolutionary importance of tissue division of immune responses, as well as deepening our understanding of the zebrafish as a model for host-pathogen interactions.

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Wiggett, H., Porter, D., Briolat, V., Balaboi, T., Abi Younes, M., Colin, I., Lutfalla, G., Levraud, J.-P.. 2025-11-04. The two groups of zebrafish type I interferons target different tissues, paralleling the mammalian type I: type III IFN functional division. https://doi.org/10.1101/2025.11.03.686239

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