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Mouse model of SARS-CoV-2 reveals inflammatory role of type I interferon signaling
Benjamin Israelow1,2, Eric Song1, Tianyang Mao1
1Department of Immunobiology, Yale University School of Medicine, New Haven, CT.
Abstract:
Severe acute respiratory syndrome-coronavirus 2 (SARS-Cov-2) has caused over 13,000,000 cases of coronavirus disease (COVID-19) with a significant fatality rate. Laboratory mice have been the stalwart of therapeutic and vaccine development; however, they do not support infection by SARS-CoV-2 due to the virus's inability to use the mouse orthologue of its human entry receptor angiotensin-converting enzyme 2 (hACE2). While hACE2 transgenic mice support infection and pathogenesis, these mice are currently limited in availability and are restricted to a single genetic background. Here we report the development of a mouse model of SARS-CoV-2 based on adeno-associated virus (AAV)-mediated expression of hACE2. These mice support viral replication and exhibit pathological findings found in COVID-19 patients. Moreover, we show that type I interferons do not control SARS-CoV-2 replication in vivo but are significant drivers of pathological responses. Thus, the AAV-hACE2 mouse model enables rapid deployment for in-depth analysis following robust SARS-CoV-2 infection with authentic patient-derived virus in mice of diverse genetic backgrounds.
Insights
A new AAV-hACE2 mouse model allows for robust SARS-CoV-2 infection, mimicking COVID-19 pathology. This model enables diverse genetic backgrounds for accelerated therapeutic and vaccine research against SARS-CoV-2.
Area of Science:
- Virology
- Immunology
- Pathology
Background:
- Severe acute respiratory syndrome-coronavirus 2 (SARS-CoV-2) causes COVID-19, a disease with high fatality rates.
- Traditional laboratory mice are not susceptible to SARS-CoV-2 due to differences in the ACE2 receptor.
- Existing transgenic mouse models are limited in availability and genetic diversity.
Purpose of the Study:
- To develop a novel, readily available mouse model for SARS-CoV-2 infection.
- To investigate SARS-CoV-2 pathogenesis and host responses in a susceptible mouse model.
- To facilitate rapid research into therapeutics and vaccines for COVID-19.
Main Methods:
- Adeno-associated virus (AAV)-mediated expression of human angiotensin-converting enzyme 2 (hACE2) in mice.
- Infection of AAV-hACE2 mice with patient-derived SARS-CoV-2.
- Analysis of viral replication and pathological findings.
- Investigation of type I interferon responses.
Main Results:
- AAV-hACE2 mice efficiently support SARS-CoV-2 replication.
- These mice exhibit pathological features consistent with human COVID-19.
- Type I interferons were found to drive pathology rather than control viral replication in vivo.
Conclusions:
- The AAV-hACE2 mouse model provides a versatile platform for studying SARS-CoV-2.
- This model allows for rapid research deployment across diverse mouse genetic backgrounds.
- Findings highlight the role of interferons in COVID-19 pathogenesis.
