Given that 80% of disease-associated genes of humans have a zebrafish ortholog ( Howe et al., 2013), it is not surprising that zebrafish continue to be developed as models for human pathogens. Zebrafish is also a genetically tractable model, and thousands of mutant and reporter transgenic lines are available in fish facilities and repositories worldwide. Thus, zebrafish larvae allow live imaging of pathogen dissemination at the whole organism to subcellular scales, and in vivo molecule screens in 96-well formats. Low cost of husbandry, high fecundity, and small size and transparency at early stages are among its main advantages. The zebrafish larva is an increasingly popular model to understand host–pathogen interactions ( Torraca and Mostowy, 2018). Here, we test if zebrafish larvae can be added to the list of suitable animal models for the study of COVID-19. As a result, expanding the repertoire of animal models for any disease is always beneficial and each model may shed light to unique aspects of the pathogen–host interaction. hACE2 transgenic mice remain expensive and not readily available. Non-human primates are very expensive, require large animal facilities, and are not conducive to large-scale experiments. All these models have several advantages and disadvantages. Mice, the most widely used model for host–pathogen studies, require a transgene-mediated expression of human angiotensin-converting enzyme 2 (hACE2) to be infected ( Lutz et al., 2020), although some recent variants replicate to a significant extent in wild-type mice ( Montagutelli et al., 2021). Besides non-human primates, other mammals such as Syrian hamsters and ferrets are naturally susceptible to SARS-CoV-2 ( Muñoz-Fontela et al., 2020). Thus, it will be necessary to continue the research efforts to understand its heterogeneous pathology and develop new drugs and vaccines.Īnimal models play a central role during any pandemic since they are essential to analyzing pathology, transmission, and test vaccines and drugs. Although vaccination is finally under way, the SARS-CoV-2 virus is predicted to persist for years ( Moore et al., 2021), and its variants represent an unpredictable threat. The COVID-19 pandemic has taken an enormous toll worldwide, in both human and economic losses. 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 the mammalian lung.
A mosaic overexpression of human ACE2 was not sufficient to increase SARS-CoV-2 infectivity in zebrafish embryos or in fish cells in vitro. Low infectivity of SARS-CoV-2 in zebrafish larvae was not due to the host type I interferon response, as comparable viral loads were detected in type I interferon-deficient animals. In some animals, several variants of concern were also tested with no evidence of increased infectivity in our model. Our data suggest an abortive infection of the swim bladder. By immunohistochemistry, epithelial cells containing SARS-CoV-2 nucleoprotein were observed in the swim bladder wall. However, when the virus was inoculated in the swim bladder, viral RNA stabilized after 24 h. Bath exposure, as well as microinjection in the coelom, pericardium, brain ventricle, or bloodstream, resulted in a rapid decrease of SARS-CoV-2 RNA in wild-type larvae. We explored the small, cheap, and transparent zebrafish larva as a potential host for SARS-CoV-2. 6Université Paris-Saclay, Centre National de la Recherche Scientifique (CNRS), Institut Pasteur, Institut des Neurosciences Paris-Saclay, Gif-sur-Yvette, FranceĪnimal models are essential to understanding COVID-19 pathophysiology and for preclinical assessment of drugs and other therapeutic or prophylactic interventions.5Laboratory of Pathogen-Host Interactions (LPHI), Centre National de la Recherche Scientifique (CNRS), Université de Montpellier, Montpellier, France.4Department of Biology, University of New Mexico, Albuquerque, NM, United States.3Université Paris-Saclay, Institut National pour la Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Université Versailles Saint-Quentin (UVSQ), Virologie et Immunologie Moléculaire (VIM), Jouy-en-Josas, France.2Institut Pasteur, Unité Populations Virales et Pathogénèse, Institut Pasteur, Paris, France.1Institut Pasteur, Centre National de la Recherche Scientifique (CNRS) Unité mixte de Recherche (UMR) 3637, Unité Macrophages et Développement de l’Immunité, Paris, France.Valerio Laghi 1 Veronica Rezelj 2 Laurent Boucontet 1 Maxence Frétaud 3 Bruno Da Costa 3 Pierre Boudinot 3 Irene Salinas 4 Georges Lutfalla 5 Marco Vignuzzi 2 Jean-Pierre Levraud 1,6*
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