Animal and translational models of SARS-CoV-2 infection and COVID-19

Abstract

COVID-19 is causing a major once-in-a-century global pandemic. The scientific and clinical community is in a race to define and develop effective preventions and treatments. The major features of disease are described but clinical trials have been hampered by competing interests, small scale, lack of defined patient cohorts and defined readouts. What is needed now is head-to-head comparison of existing drugs, testing of safety including in the background of predisposing chronic diseases, and the development of new and targeted preventions and treatments. This is most efficiently achieved using representative animal models of primary infection including in the background of chronic disease with validation of findings in primary human cells and tissues. We explore and discuss the diverse animal, cell and tissue models that are being used and developed and collectively recapitulate many critical aspects of disease manifestation in humans to develop and test new preventions and treatments.

Fig. 1

ACE2 protein phylogenetic divergence and in vivo model severity. Left panel, fast minimum evolution distance tree for ACE2 protein sequences using Griphin for evolutionary distance, unsorted. Species included are Gallus gallus (Chicken), Anas platyrhynchos (Duck), Cavia porcellus (Guinea Pig), Mustela putoris furo (Ferret), Canis lupus familiaris (Dog), Felis catus (Cat), Sus scrofa (Pig), Rousettus aegyptiacus (fruitbat), Mesocricetus auratus (Golden hamster), Mus musculus (Mouse), Callithrixjacchus (Common Marmoset), Macaca mulatta (Rhesus macaque), Macaca fascicularis (Cynomolgus Macaque), Chlorocebus aethiops (African Green Monkey) and Homo sapiens. Macaques are represented as one image due to close divergence. Severity of disease is color-coded from refractory to infection (BLUE, no virus detected) to severe (RED, shedding). Common Marmoset and Guinea Pig have only been assessed for SARS-CoV, all others with SARS-CoV-2. Scale indicates 10% amino acid divergence.

Fig. 2

Comparison of disease features shared between humans with COVID-19 and mouse models of SARS-CoV-2. Both humans and mice display similar clinical signs such as weight loss and pneumonia. Severe infections are often associated with increased pro-inflammatory cytokine production, accompanied by high viral lung titres which correlates with extensive lung damage and significant pulmonary decline.

Fig. 3

Phylogeny of observed wild infections. Left panel, fast minimum evolution distance tree for ACE2 protein sequences using Grishin for evolutionary distance, unsorted. Species included are Erinaceous europaeus (in place of Erinaceous amurensis, Hedgehog), Rhinolophus sinicus (representative microbat), Nyctereutes procyonoides (Racoon Dog), Manisjavanica (Sunda Pangolin), Paguma larvata (Masked Palm Civet), Mustela putoris furo (representative ferret), Panthera tigris altaica (Siberian Tiger, in place of Bengal Tiger), Canis lupus familiaris (Dog), Neovison vison (in place of European Mink). The closest species was used where applicable due to a lack of sequence for ACE2. Right side indicates whether infection was observed for SARS-CoV, SARS-CoV-2 or SARSr-CoV (Bat SARS-Like CoVs), as indicated. Green arrows indicate where animal-animal transmission has been reported to occur.

Fig. 4

Overview of the different translational model systems used to interrogate disease mechanisms of SARS-CoV-2. Cell culture and organoid/primary cell infection studies are critical for deciphering the cellular mechanisms of SARAS-CoV-2 pathogenesis and for high-throughput identification of leading drug candidates. In vitro findings can then be directly translated to animal models such as mice, hamsters, guinea pigs and non-human primates to assess the safety and efficacy of drugs and vaccines before progressing to human clinical trials.