Human ACE2 Gene Replacement Mice Support SARS-CoV-2 Viral Replication and Nonlethal Disease Progression

Area of Science:

• Virology
• Immunology
• Genetics

Background:

• Mouse models expressing human ACE2 are crucial for SARS-CoV-2 research.
• Existing models often exhibit nonphysiological ACE2 regulation, leading to severe infections and atypical viral spread.
• This limits their utility for studying host responses and long-term effects.

Purpose of the Study:

• To develop and characterize a novel ACE2 gene replacement (ACE2-GR) mouse model.
• To investigate SARS-CoV-2 infection dynamics and disease presentation in ACE2-GR mice.
• To provide a more physiologically relevant model for SARS-CoV-2 research.

Main Methods:

• Genomic engineering to replace the mouse Ace2 locus with the human ACE2 gene locus, creating ACE2-GR mice.
• Infection of ACE2-GR mice with SARS-CoV-2.
• Assessment of viral replication, disease severity, and central nervous system (CNS) involvement.

Main Results:

• ACE2-GR mice successfully support SARS-CoV-2 viral replication.
• Infection in ACE2-GR mice results in mild disease, unlike more severe outcomes in other models.
• No detectable central nervous system (CNS) involvement was observed in ACE2-GR mice following infection.

Conclusions:

• The ACE2-GR mouse model provides a more physiologically accurate representation of SARS-CoV-2 infection.
• This model exhibits reduced disease severity and lacks CNS pathology compared to transgenic models like K18-hACE2.
• ACE2-GR mice are a valuable tool for studying SARS-CoV-2 immune responses and long-term consequences.