Pathogenesis and virulence of coronavirus disease: Comparative pathology of animal models for COVID-19

Figures & data

Figure 1. Structure and genomic organization of SARS-CoV-2. The virion (a) consists of an unsegmented, positive ssRNA genome complexed with the nucleocapsid protein (n). Envelope-associated structural proteins include the trimeric spike (s), membrane (m), and envelope (e) proteins. Open reading frames (ORF) 1a and 1b are directly translated into the numerous nonstructural proteins (nsps) that form the replicase-transcriptase complex, including the RdRp. The remaining structural and accessory proteins (3a through 10) are derived from subgenomic mRnas (b). For additional information on coronavirus replication strategies, please see ref [9].

Figure 2. Lung pathology in mice infected with SARS-CoV-2. a-c K18-hACE2 mouse infected with 5 × 10⁴ pfu SARS-CoV-2 WA10 that died on day 7. At low magnification (a), approximately 70% of the lung is hypercellular and there are multiple discrete foci of inflammation (arrows). The normal pulmonary architecture is obscured due to haemorrhage (arrow), oedema (stars), and inflammation (b). The alveolar and bronchiolar exudate is largely composed of neutrophils and there is rare type II pneumocyte hyperplasia (arrow) (c). (d-f) 6-week-old BALB/c mouse infected with 1 × 10⁴ pfu SARS-CoV-2 MA10 that was euthanized on day 4. There is minimal change at low magnification (d). There are occasional areas of hypercellularity (e) where septa are mildly thickened due to congestion and increased lymphocytes and macrophages (f).

Table 1. Summary of animal models of COVID-19.

	Details	Clinical Signs	Pathology	Pros	Cons	Main Uses
Mice
K18-hACE2	Express hACE2 under epithelial promoter K18	Weight loss, lethargy, anosmia, dyspnoea, and death	Interstitial pneumonia, oedema, type II pneumocyte hyperplasia, vasculitis, syncytial cells	Dose-dependent clinical signs and mortality Lethal model	Viral encephalitis may be cause of death	Vaccine and therapeutic testing [120,160,216–218] Pathogenesis [219–223]
mAce2-hACE2	hACE2 driven by endogenous murine Ace2 promoter	Mild weight loss and ruffled fur	Moderate interstitial pneumonia with bronchiolar degeneration	No evidence of brain infection	Overall mild disease	Not frequently used
HFH4/FOXJ1-hACE2	Lung ciliated epithelium-specific promoter	Variable; asymptomatic or weight loss, dyspnoea, and neurologic signs prior to death	Interstitial pneumonia with hyaline membranes and thrombi	Some features of human disease like hyaline membranes and thrombosis	Viral encephalitis as the cause of death	Not frequently used
mAce2-hACE2 knockin	hACE2 replaces mAce2 with expression directed by endogenous mAce2 promoter	Weight loss only in older mice	Mild interstitial pneumonia and haemorrhage	Targeted gene insertion, so expression levels may be more physiologic mAce2 not present	High levels of virus in brain	Pathogenesis [224,225]
Adenovirus or AAV hACE2 transduction	Non-replicating viral vector transiently transduces expression of hACE2	Mild or no weight loss	Mild to moderate pneumonia with congestion	Various mouse strains can be transfected Less costly than generating transgenic mice	Ectopic hACE2 expression is possible	Vaccine and therapeutic testing [98,226–228] Pathogenesis [109,229]
C57BL/6 and BALB/c	Infected with mouse adapted SARS-CoV-2 (MA10)	Dose- and age-dependent weight loss and death	Interstitial pneumonia, bronchiolar epithelial necrosis, alveolitis, hyaline membranes, and oedema	Can infect different mouse strains Less costly than generating transgenic mice	Variability between mouse strains RBD mutations could impact therapeutics targeting spike protein	Vaccine and therapeutic testing [103,107,136,230,231]
C57BL/6, BALB/c, 129	Wildtype laboratory mice can be infected with variants of concern (Alpha, Beta, Gamma, and Omicron)	Weight loss seen with Alpha, Beta, and Delta infections; Omicron infections are asymptomatic with limited weight change	Alpha and Beta: Mild to moderate interstitial pneumonia and haemorrhage Omicron: Milder and less frequent interstitial inflammation	Natural infection with clinically applicable isolates No encephalitis Display similar variant-specific severity to people	Disease less severe than in transgenic mice Cannot compare to ancestral strains or Delta variant of SARS-CoV-2	Pathogenesis and severity of new variants [112,135,138,143]
Others
Ferret	N/A	Sneezing, cough, lethargy, increased temperature May also be asymptomatic Not lethal	Suppurative bronchiolitis and peribronchiolitis and BALT hyperplasia; interstitial pneumonia less common Suppurative and lymphohistiocytic rhinitis and/or tracheitis	Naturally susceptible to SARS-CoV and SARS-CoV-2 Transmission to naïve ferrets	High viral loads in URT, but not in LRT	Good for transmission modelling and testing mucosal vaccines [160–163]
Syrian hamster	N/A	Lethargy, hunching, ruffled fur, tachypnoea, and weight loss, anosmia and ageusia Not lethal	Rhinitis and suppurative tracheobronchitis Interstitial pneumonia and oedema with syncytia Endotheliitis	Increased disease with age and male sex Naturally susceptible SARS-CoV and SARS-CoV-2	Fewer reagents and tools available	Vaccine and therapeutic testing [232–237] Pathogenesis [172,238,239]
Roborovski dwarf hamster	N/A	Dyspnea, snuffling, fever, lethargy, hunching, weight loss, and death	Necrotizing alveolitis with oedema, hyaline membranes, and haemorrhage	Dose-dependent disease, can model both mild/moderate and severe lethal disease Smaller than Syrian hamsters and easier to handle	Fewer reagents and tools available	Vaccine and therapeutic testing, although less frequently than other models [155,237,240]
NHP	N/A	Asymptomatic or decreased appetite, hunching, piloerection, increased temperature, and mild weight loss	Interstitial pneumonia centred on terminal bronchioles with BALT hyperplasia and occasional hyaline membranes and syncytia Type II pneumocyte hyperplasia	Antemortem imaging Age-dependent increase in disease Worse disease in baboons and aged AGMs	Generally mild, non-lethal disease Expensive Ethical concerns	Vaccines and therapeut-ics [144–146,214,215] Immunology studies [200,202,241,242]

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Data Availability statement

Data reported in the figure and table in this article have been deposited in a recognized data repository (Figshare.com) with a digital object identifier: 10.6084/m9.figshare.24348958