An Overview of Mouse Models for COVID-19

COVID-19 is rapidly spreading around the globe and constitutes a global health crisis. This disease is caused by the SARS-CoV-2 virus, a coronavirus related to the SARS-CoV virus which caused the global SARS outbreak in 2003^1,2.

Preclinical research on SARS may provide insight into useful animal models for COVID-19 research, and much of the information presented below is based on studies of SARS. While there is little information on COVID-19 studies in animal models, this is a rapidly evolving area of research and new preprints are coming out daily.

COVID-19 Disease Models

Genetically Engineered Models (GEMs)

SARS-CoV-2 uses the ACE2 protein to enter cells³. In vitro studies showed that ACE2 from many species facilitated entry into HeLa cells, but mouse ACE2 did not¹. This poses a challenge for mouse studies of COVID-19, and there is one report that SARS-CoV-2 cannot replicate in the outbred ICR mouse stock following intranasal inoculation.

Human ACE2 Expression

Transgenic mice expressing human ACE2 are likely to be critical for animal studies of COVID-19. Bao et al. reported that transgenic hACE2 mice developed clinical illness following SARS-CoV-2 infection, including weight loss and interstitial pneumonia⁴.

Ace2 Knockout

Acute respiratory distress syndrome (ARDS) is a serious complication of COVID-19 and present in a large percentage of COVID-19 deaths⁵. ACE2 is protective against ARDS. Binding of viral spike SARS protein to ACE2 in mice downregulates ACE2 expression. Loss of ACE2 expression is associated with severe lung failure. Ace2 knockout mice have been used in ARDS and SARS research and may be useful for study of COVID-19-related ARDS^6,7.

Tmprss2 Knockout

TMPRSS2 is involved in SARS-CoV-2 entry into cells. Inhibition of this protein may constitute a treatment/prophylaxis mechanism. Tmprss2 knockout mice may be useful in studying COVID-19 disease pathogenesis¹⁰.

Stat1 Knockout

Stat1 knockout mice support SARS-CoV viral replication in the lungs and develop progressive lung disease including diffuse interstitial pneumonia with inflammation and systemic spread to other organs. These mice may be useful to study COVID-19 disease pathogenesis and antiviral treatments^1,8,9,10.

Standard Mouse Strains

Mouse-adapted SARS strains induce clinical illness in BALB/c mice, with similar disease characteristics as seen in humans. When mouse-adapted SARS-CoV-2 isolates become available, inbred mice may be useful for studies of vaccines, antiviral drugs and disease pathogenesis¹¹.

Inbred mice have been used extensively in SARS studies. Young inbred mice such as BALB/c, C57BL/6 and 129S6 support viral replication of SARS-CoV and may be useful for COVID-19 vaccine and antiviral studies even without supporting development of disease. They may also be useful in studying immune responses to infection¹².

In contrast to young mice, 12-14 month old BALB/c mice develop clinical illness including patchy interstitial pneumonia following SARS infection and may be useful to model the age-related mortality increase seen in humans seen in COVID-19¹³. Aged C57BL/6 and 129S6 mice may also be useful to study age-related mortality increases, but with lower viremia compared to BALB/c based on SARS research¹⁴.

C57BL/6 mice have been used in various models of acute lung injury, and these models may be useful for studies directed at treating ARDS associated with COVID-19.

State of COVID-19 Vaccine Research

A number of vaccine candidates for COVID-19 are under investigation, with phase 1 clinical trials underway already.

In many cases, new vaccines are based on in silico epitope predictions which may need to be validated in animal models prior to use in humans. Preclinical studies involving rationally-designed vaccines is complicated by differences between species in the antigens presented by major histocompatibility complex (MHC) proteins. MHC is called human leukocyte antigen (HLA) in humans.

The human population carries a wide variety of HLA genes which can be divided into supertypes based on similar antigen binding. Mice which carry human HLA genes are useful in vaccine discovery and development because they better model the human response to vaccines compared to wild type mice and even non-human primates.

Humanized immune system mice offer a small animal model engrafted with human immune cells. Immunodeficient NOG mice engrafted with human peripheral blood mononuclear cells (model huPBMC-NOG) have been used to study SARS vaccine response. Humanized immune system mice may be useful for studies into human immune system response to infection and/or vaccine response.

COVID-19 Research Landscape Evolving Daily

The scientific community has jumped into action with the goal of understanding SARS-CoV-2 and finding treatments and vaccines for the COVID-19 pandemic. With many cities, states, provinces, and countries on virtual lockdown to slow the spread COVID-19, the race is on to identify approved and investigational drugs with efficacy against this disease and to develop a vaccine.

Expect the research landscape to change on a daily basis as new results are reported. Taconic Biosciences supports COVID-19 research through subsidized distribution of specialty transgenics including an Ace2 knockout mouse as well as discounts on other key models to facilitate this important research.

References:

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9. Frieman, M. B.; Chen, J.; Morrison, T. E.; Whitmore, A.; Funkhouser, W.; Ward, J. M.; Lamirande, E. W.; Roberts, A.; Heise, M.; Subbarao, K.; Baric, R. S. SARS-CoV Pathogenesis Is Regulated by a STAT1 Dependent but a Type I, II and III Interferon Receptor Independent Mechanism. PLoS Pathogens. 2010, 6 (4).

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