Animal models of SARS-CoV-2 infectionThe World Health Organization (WHO) assembled a global panel of experts in early 2020 to share knowledge about appropriate animal models for the study of COVID-19. One outcome of that panel was a September 2020 publication in Nature1 describing the then-current state of COVID-19 animal research. The panel reviewed in detail mouse models, Syrian hamsters, ferrets and non-human primates, along with some information on less-commonly used models such as mink and poultry.
Ferrets and hamsters have been long used to study respiratory infectious diseases and are useful in SARS-CoV-2 research. From a logistical standpoint, these are models which are already familiar to scientists with established respiratory disease programs, but for researchers pivoting to COVID-19 research, there may be challenges in housing and working with these species as many institutions have limited or no housing for these species, particularly at higher biosafety levels . And while these models have been extraordinarily helpful in the development of the currently-available vaccines and therapeutics, they may not be as useful for studies directed at understanding the impact of co-morbidities and genetic risk factors on disease progression and outcomes. For that type of work, the mouse has unparalleled value as a model organism.
The power of the mouse as a model organism
Beyond a vaccine — how hACE2 mice can uncover the mysteries of COVID-19Age and certain co-morbidities have emerged as risk factors for poor outcomes in COVID-19, but the mechanisms involved are not yet clear. A mechanistic understanding of disease is often the required first step for development of a new therapeutic, as it allows identification of potential drug targets. It is this type of research where mouse models shine. At a basic level, mutant models can elucidate the role of cell surface receptors on viral entry and how particular immune cells react in either helpful or adverse ways. Perhaps more interestingly, mice can clarify how genetic and other risk factors are involved in COVID-19 pathogenesis. How does disease differ in an obese mouse versus a lean mouse? How do various human APOE isoforms contribute to disease outcomes? These are all questions which genetically engineered mice will help answer in the coming years.
hACE2 mice as SARS-CoV-2 infection modelsA particular subset of genetically engineered mice has already been widely used in SARS-CoV-2 infection studies: mice expressing human ACE2. ACE2 is the cell surface receptor involved in SARS-CoV-2 viral entry, and the binding affinity of SARS-CoV-2 spike protein to human ACE2 is much higher than to mouse ACE2. In general, normal laboratory mice are not susceptible to infection by SARS-CoV-2 whereas mice expressing human ACE2 are.
In the human population, COVID-19 disease in response to SARS-CoV-2 infection can range from asymptomatic, to relatively mild, to severe/lethal. Mouse models which can replicate this range of disease response are needed. Several unique human ACE2 transgenic mouse strains have been generated and are now being used in COVID-19 research to better understand mechanisms of infection and to develop therapeutics. Taconic Biosciences distributes two strains, hACE2 AC70 and hACE2 AC22, which represent independent founder lines carrying the same ubiquitously expressed transgene encoding human ACE2 cDNA . While AC70 is an incredibly sensitive lethal model of SARS-CoV-2 infection, with a lethal dose of >10 virions, AC22 is a lethality resistant model in which the majority of mice develop clinical illness after intranasal infection with 105 TCID50 of SARS-CoV-2 (US_WA-1/2020) and then recover, with some proportion of mice exhibiting lethal infection. Additional research is underway to further explore the viral dose response of AC22.
|Susceptibility to SARS-CoV-2|
|hACE2 Strain||Taconic model #||Nomenclature||Transgene Location||Transgene Copy Number||SARS-CoV-2 Dose (US_WA-1/2020)||Mortality||Survival (days post-infection)||Clinical Signs||Site of Viral Replication||Sex Differences||Other Information|
|AC70||18222||B6;C3-Tg(CAG-ACE2)70Ctkt||X chromosome||1||103-106 TCID50||100%||4-5||Severe weight loss, lethal infection||Primarily lung and brain||Minimal sex differences observed|
|101 TCID50||100%||6-10||Moderate-severe weight loss, lethal infection||Primarily lung and brain||LD50: 3 TCID50|
ID50: 0.5 TCID50
|AC22||18225||B6;C3(C)-Tg(CAG-ACE2)22Ctkt||an unplaced scaffold region, presumably on chromosome 10||~30-40||105 TCID50||30-40%||7||Moderate weight loss, lethal infection in some mice||Primarily lung and brain||ID50: 101.5 TCID50|
These two models are complementary and can support a range of COVID-19 studies. Lethal infection models such as AC70 or K18-hACE2 mice (infected above a threshold dose) are useful for clear readouts on challenge studies to evaluate prophylactic vaccines. AC70 mice may also be useful for assessment of therapeutic efficacy, though the rapid onset of morbidity and mortality (~5-7 days after infection) may in some cases not provide sufficient time for a therapy to impact the course of disease or even to assess target engagement. Mortality in these mice may result from infection and inflammation in the brain3 rather than respiratory illness, the latter of which is the most common direct cause of death in COVID-19 patients4,5.
Mice which exhibit sublethal infection may be more appropriate for certain types of studies. Of note, the majority of people infected with COVID-19 do not die, but rather recover from infection, sometimes with long-term sequelae. Mice with sublethal infection may be useful to investigate the recovery process in detail, tissue by tissue. Public health systems now face what could be an epidemic of patients suffering from long-term post-COVID-19 symptoms6, and research is needed to understand this syndrome and treat it effectively. This may be one emerging application for mouse models of sublethal SARS-CoV-2 infection.