A DN-mda5 transgenic zebrafish model demonstrates that Mda5 plays an important role in snakehead rhabdovirus resistance

• Overexpression of mda5 induced zebrafish IFN promoter activity and conferred protection against SHRV infection in vitro.
• A dominant negative mda5 transgenic zebrafish was generated to assess the in vivo function of mda5.
• DN-mda5 zebrafish resistance to SHRV infection is significantly reduced and leads to higher viral burden and mortality.
• Recombinant mda5 confers protection against SHRV infection in DN-mda5 zebrafish.

Melanoma Differentiation-Associated protein 5 (MDA5) is a member of the retinoic acid-inducible gene I (RIG-I)-like receptor (RLR) family, which is a cytosolic pattern recognition receptor that detects viral nucleic acids. Here we show an Mda5-dependent response to rhabdovirus infection in vivo using a dominant-negative mda5 transgenic zebrafish. Dominant-negative mda5 zebrafish embryos displayed an impaired antiviral immune response compared to wild-type counterparts that can be rescued by recombinant full-length Mda5. To our knowledge, we have generated the first dominant-negative mda5 transgenic zebrafish and demonstrated a critical role for Mda5 in the antiviral response to rhabdovirus.