Animal Models of COVID-19. I. Comparative Virology and Disease Pathogenesis

Abstract

The Coronavirus Disease 2019 (COVID-19) pandemic has fueled unprecedented development of animal models to understand disease pathogenesis, test therapeutics, and support vaccine development. Models previously developed to study severe acute respiratory syndrome coronavirus (SARS-CoV) have been rapidly deployed to study SARS-CoV-2. However, it has become clear that despite the common use of ACE2 as a receptor for both viruses, the host range of the 2 viruses does not entirely overlap. Distinct ACE2-interacting residues within the receptor binding domain of SARS-CoV and SARS-CoV-2, as well as species differences in additional proteases needed for activation and internalization of the virus, are likely sources of host differences between the 2 viruses. Spontaneous models include rhesus and cynomolgus macaques, African Green monkeys, hamsters, and ferrets. Viral shedding and transmission studies are more frequently reported in spontaneous models. Mice can be infected with SARS-CoV; however, mouse and rat ACE2 does not support SARS-CoV-2 infection. Murine models for COVID-19 are induced through genetic adaptation of SARS-CoV-2, creation of chimeric SARS-CoV and SARS-CoV-2 viruses, use of human ACE2 knock-in and transgenic mice, and viral transfection of wild-type mice with human ACE2. Core aspects of COVID-19 are faithfully reproduced across species and model. These include the acute nature and predominantly respiratory source of viral shedding, acute transient and nonfatal disease with a largely pulmonary phenotype, similar short-term immune responses, and age-enhanced disease. Severity of disease and tissue involvement (particularly brain) in transgenic mice varies by promoter. To date, these models have provided a remarkably consistent template on which to test therapeutics, understand immune responses, and test vaccine approaches. The role of comorbidity in disease severity and the range of severe organ-specific pathology in humans remains to be accurately modeled.

Figure 1

Pulmonary histopathology at 3 and 5 days post infection (dpi) with SARS-CoV-2 (10³ TCID₅₀). A–C: 3 dpi. Histopathology is characterized by broncho-interstitial pneumonia centered on bronchioles and adjacent parenchyma (A), corresponding to distribution of viral antigen (C). Bronchiolar epithelial necrosis is accompanied by efflux of neutrophils and macrophages into bronchiolar lumen (B). D–F: 5 dpi. Worsened broncho-interstitial pneumonia results in regional parenchymal consolidation (D), and progressive bronchiolitis is accompanied by syncytial epithelial cells (arrows, E).Viral immunoreactivity is most prominent in alveolar epithelial cells (F). Hematoxylin and eosin (A, B, D, E); immunohistochemistry using GenScript U864YFA140–4/CB2093 NP-1 at a 1:1000 dilution (C, F); Bar = 50 μm (A, C, D), 20 μm (B, E, F). Panel reconstructed from Rosenke K, Meade-White K, Letko M, Clancy C, Hansen F, Liu Y, Okumura A, Tang-Huau TL, Li R, Saturday G, Feldmann F, Scott D, Wang Z, Munster V, Jarvis MA, Feldmann H. Defining the Syrian hamster as a highly susceptible preclinical model for SARS-CoV-2 infection. Emerg Microbes Infect. 2020 Nov 29:1–36. doi: 10.1080/22221751.2020.1858177. PMID: 33251966. Permissions obtained under Creative Commons CC BY license (https://creativecommons.org/licenses/by-nc-nd/4.0/).