# In vivo multiscale analyses of spring viremia of carp virus (SVCV) infection: From model organism to target species

## TL;DR

Researchers developed a new model to study SVCV infection in zebrafish, revealing infection sites and immune responses, which could help in finding treatments.

## Contribution

The first reverse genetics system and recombinant SVCV for in vivo imaging, revealing new insights into SVCV infection and host immune responses.

## Key findings

- Fins are the main initial sites of SVCV infection in zebrafish and carp.
- Neutrophils are recruited to infection sites, leading to uncontrolled inflammation linked to IL1β expression.
- The route of infection affects the immune response, with bath immersion causing persistent inflammation rather than IFN activation.

## Abstract

Spring viremia of carp virus (SVCV) has a broad fish host spectrum and is responsible for a disease that generally affects juvenile fishes with a mortality rate of up to 90%. In the absence of treatments or vaccines against SVCV, the search for prophylactic or therapeutic solutions is thus relevant, particularly to identify solutions compatible with mass vaccination. In addition to being a threat to aquaculture and ecosystems, SVCV is a unique pathogen to study virus-host interactions in the zebrafish model. Establishing the first reverse genetics system for SVCV and the design of recombinant SVCV (rSVCV) expressing fluorescent or bioluminescent proteins adds a new dimension for the study of these interactions using innovative imaging techniques. The infection by bath immersion of zebrafish larvae with rSVCV expressing mCherry allows us to define the first SVCV replication sites and the host innate immune responses using different transgenic lines of zebrafish. The fins were found as the main initial sites of infection in both zebrafish and carp, its natural host. Hence, new insights into the physiopathology of SVCV infection have been described. We report that neutrophils are recruited at the sites of infection and persist up to the death of the animal leading to an uncontrolled inflammation correlated with the expression of the pro-inflammatory cytokine IL1β. Tissue damage was observed at the site of initial replication, a likely consequence of virus-induced injury or the pro-inflammatory response. Interestingly, SVCV infection by bath immersion triggers a persistent pro-inflammatory response rather than activation of the antiviral IFN signaling pathway as observed following intravenous injection, highlighting the importance of the route of infection on the progression of pathogenicity. Thus, this model of zebrafish larvae infection by rSVCV offers new perspectives to study in detail virus-host interactions and to discover new prophylactic or therapeutic solutions.

In addition to being a threat to many valuable aquaculture species, spring viremia of carp virus (SVCV) is a model pathogen used to study host immune responses for the zebrafish community. Here, we bring another dimension to these studies thanks to the generation of traceable recombinant viruses by reverse genetics enabling for the first time in vivo imaging of SVCV infection. Upon zebrafish inoculation with a recombinant SVCV expressing mCherry, we established a robust and highly reproducible model of infection based on the natural route of infection. This powerful model allows us to define the first SVCV replication sites, viral spreading, target organs as well as host responses using different transgenic lines of zebrafish. We found that the fins were the main initial sites of infection and not the gills as commonly reported. This was confirmed in carp, the natural host of SVCV. New insights into the physiopathology of SVCV infection have been described. Thus, the development of this standardized model of viral infection in zebrafish larvae opens new perspectives to better understand SVCV infection and to discover antiviral drugs and/or immunomodulating compounds assessed by in vivo high content screening while ensuring 3R compliance on animal experimentation.