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Literature detail

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

Caroline J Zeiss1 Susan Compton1 Rebecca Terilli Veenhuis2
Affiliations 2 institutions
  1. Department of Comparative Medicine, Yale University School of Medicine, New Haven, Connecticut, USA.
  2. Department of Comparative Medicine, John Hopkins School of Medicine, Baltimore, Maryland, USA.
PMID 33836527 2021 ILAR J eng ppublish
PubMed DOI Browse context

Article

Publication summary

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.

COVID-19 Severe acute respiratory syndrome-related coronavirus Angiotensin-Converting Enzyme 2 Animals Chlorocebus aethiops Cricetinae Disease Models, Animal Ferrets Mice Mice, Transgenic Models, Animal Peptidyl-Dipeptidase A Rats Receptors, Virus SARS-CoV-2

Structured evidence records

Evidence records

9 total
Host Range Experiment 5 records
Host Range Experiment Extraction confidence 0.90
Key finding

Experimental infection studies found that SARS-CoV infects mice, but the ACE2 receptor from mice and rats does not permit SARS-CoV-2 infection.

Virus
SARS-CoV
Location
Not specified
Supporting text

Mice can be infected with SARS-CoV; however, mouse and rat ACE2 does not support SARS-CoV-2 infection.

Method
experimental infection
Experimental system
in vivo animal experiment
Host Range Experiment Extraction confidence 0.90
Key finding

SARS-CoV-2 infection in mice can be achieved experimentally using human ACE2 knock-in or transgenic mice or through viral adaptation and chimeric virus approaches.

Virus
SARS-CoV-2
Location
Not specified
Supporting text

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.

Method
genetic adaptation; chimeric virus construction; viral transfection
Experimental system
in vivo animal experiment
Host Range Experiment Extraction confidence 0.90
Key finding

Multiple animal species including macaques, African Green monkeys, hamsters, and ferrets have been experimentally shown to support SARS-CoV-2 infection and transmission, serving as spontaneous infection models.

Virus
SARS-CoV-2
Location
Not specified
Supporting text

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.

Method
experimental infection; transmission study
Experimental system
in vivo animal experiment
Host Range Experiment Extraction confidence 0.90
Key finding

Hamsters were experimentally infected with SARS-CoV-2 and used in viral shedding and transmission studies demonstrating host susceptibility.

Virus
SARS-CoV-2
Host
Cricetinae
Location
Not specified
Supporting text

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.

Method
experimental infection; transmission study
Experimental system
in vivo animal experiment
Host Range Experiment Extraction confidence 0.90
Key finding

Ferrets can be experimentally infected with SARS-CoV-2 and have been used for viral shedding and transmission assays indicating host susceptibility.

Virus
SARS-CoV-2
Location
Not specified
Supporting text

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.

Method
experimental infection; transmission study
Experimental system
in vivo animal experiment
Molecular Adaptation 2 records
Molecular Adaptation Extraction confidence 0.80
Key finding

Differences in ACE2-binding residues and variation in host proteases contribute to the divergent host ranges of SARS-CoV and SARS-CoV-2.

Virus
SARS-CoV-2
Host
Not specified
Location
Not specified
Supporting text

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.

Genes or proteins
ACE2; receptor binding domain
Receptors
ACE2
Host factors
proteases
Mechanism types
receptor_binding; cell_entry; host_factor_interaction; host_range
Molecular Adaptation Extraction confidence 0.80
Key finding

SARS-CoV-2 can be adapted to infect mice through genetic modification or by expressing human ACE2, demonstrating molecular adaptation enabling infection of new hosts.

Virus
SARS-CoV-2
Host
Not specified
Location
Not specified
Supporting text

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.

Genes or proteins
ACE2
Receptors
human ACE2
Mechanism types
receptor_binding; host_range; genetic_adaptation
Receptor Usage 2 records
Receptor Usage Extraction confidence 0.95
Key finding

SARS-CoV and SARS-CoV-2 both utilize ACE2 as a receptor, but differences in ACE2-binding residues correlate with differences in host range.

Virus
SARS-CoV-2
Host
Not specified
Location
Not specified
Supporting text

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 are likely sources of host differences between the 2 viruses.

Receptors
ACE2
Receptor Usage Extraction confidence 0.95
Key finding

Mouse and rat ACE2 are incompatible with SARS-CoV-2 entry, while expression of human ACE2 in mice confers susceptibility.

Virus
SARS-CoV-2
Location
Not specified
Supporting text

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, use of human ACE2 knock-in and transgenic mice, and viral transfection of wild-type mice with human ACE2.

Receptors
ACE2