A mouse model of lethal respiratory dysfunction for SARS-CoV-2 infection.

Area of Science:

• Virology
• Infectious Diseases
• Animal Models

Background:

• The COVID-19 pandemic necessitates animal models to study severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and develop treatments.
• Existing rodent models often display mild pulmonary disease, with mortality linked to central nervous system (CNS) dysfunction.

Purpose of the Study:

• To isolate and characterize SARS-CoV-2 variants capable of replicating specific COVID-19 disease manifestations in animal models.
• To establish models for testing novel vaccines and therapeutics against SARS-CoV-2.

Main Methods:

• Infection of transgenic mice expressing human angiotensin I-converting enzyme 2 (hACE2) with wild-type SARS-CoV-2.
• Full genome sequencing and plaque morphology analysis of SARS-CoV-2 isolates from infected mouse brains and lungs.
• Intranasal inoculation of distinct brain and lung SARS-CoV-2 isolates into new hACE2 mouse cohorts.

Main Results:

• Wild-type SARS-CoV-2 infection proved lethal in hACE2 transgenic mice.
• Genetic and plaque morphology differences were observed between SARS-CoV-2 isolated from the lungs versus the brains of infected mice.
• Lung-derived isolates caused lethal pulmonary infection, while brain-derived isolates caused lethal CNS infection in new mice.

Conclusions:

• SARS-CoV-2 can evolve into distinct variants with tropism for either pulmonary or CNS tissues.
• These isolated variants provide valuable tools for modeling specific aspects of COVID-19 in mice.
• The study highlights the potential of using these distinct viral variants for preclinical testing of vaccines and therapeutics.