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Mutations in nonstructural proteins essential for pathogenicity in SARS-CoV-2-infected mice
Ruangang Pan1, Pengfei Li1, David K Meyerholz2
1Department of Microbiology and Immunology, University of Iowa, Iowa City, Iowa, USA.
Journal of Virology
|June 18, 2024
Summary
Mutations in the spike protein and nonstructural proteins of SARS-CoV-2 are essential for severe disease in mice. Understanding these changes helps in studying COVID-19 pathogenesis.
Area of Science:
- Virology
- Immunology
- Pathogenesis
Background:
- Severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2) causes COVID-19, leading to significant illness and death.
- Studying COVID-19 pathogenesis in humans is challenging, necessitating the use of animal models.
- Mice are generally resistant to SARS-CoV-2, but adapted strains and variants can infect them, often requiring passage for virulence.
Purpose of the Study:
- To investigate the specific viral mutations responsible for increased virulence of mouse-adapted SARS-CoV-2.
- To elucidate the roles of structural (spike) and nonstructural protein mutations in SARS-CoV-2 pathogenesis in mice.
Main Methods:
- Engineered recombinant SARS-CoV-2 viruses with subsets of mutations from a mouse-adapted strain (rSARS2-MA30N501Y).
- Assessed viral virulence in mice infected with engineered viruses.
- Analyzed innate immune responses and viral tropism using lineage tracking.
Main Results:
- SARS-CoV-2 variants with only spike protein mutations caused mild infections in mice.
- Virulence required additional mutations in nonstructural proteins (nsp4 and nsp8).
- Virulent virus infections showed delayed innate immune responses and altered tissue tropism compared to attenuated viruses.
Conclusions:
- Maximal virulence of SARS-CoV-2 in mice requires mutations in both the spike protein and nonstructural proteins.
- Spike protein mutations, while necessary for mouse adaptation, are insufficient for full virulence.
- These findings enhance understanding of SARS-CoV-2 adaptation and pathogenesis in experimental models.
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