Exploring zebrafish larvae as a COVID-19 model: probable SARS-COV-2 replication in the swim bladder

Animal models are essential to understand COVID-19 pathophysiology and for pre-clinical assessment of drugs and other therapeutic or prophylactic interventions. We explored the small, cheap and transparent zebrafish larva as a potential host for the SARS-CoV-2 virus. Bath exposure, as well as microinjection in the coelom, pericardium, brain ventricle, bloodstream, or yolk, did not result in detectable SARS-CoV-2 replication in wild-type larvae. However, when the virus was inoculated in the swim bladder, a modest increase in viral RNA was observed after 24 hours, suggesting a successful infection in some animals. The low infectivity of SARS-CoV-2 in zebrafish was not due to the host type I interferon response, as similar results were observed in type I interferon-deficient animals. We could not detect the induction of transcriptional type I interferon or inflammatory cytokine responses following infection. Overexpression of human ACE2 in a mosaic fashion by plasmid injection in eggs was not sufficient to increase SARS-CoV-2 infectivity. In conclusion, wild-type zebrafish larvae appear mostly non-permissive to SARS-CoV-2, except in the swim bladder, an aerial organ sharing similarities with lungs.