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Updated: Sep 5, 2025
Dissecting Innate Immune Signaling in Viral Evasion of Cytokine Production
Published on: March 2, 2014
Characterization of SARS-CoV-2 Spike mutations important for infection of mice and escape from human immune sera
Raveen Rathnasinghe1,2,3,4, Sonia Jangra1,3, Chengjin Ye5
1Department of Microbiology, Icahn School of Medicine at Mount Sinai New York, New York, NY, USA.
Abstract:
Due to differences in human and murine angiotensin converting enzyme 2 (ACE-2) receptor, initially available SARS-CoV-2 isolates could not infect mice. Here we show that serial passaging of USA-WA1/2020 strain in mouse lungs results in "mouse-adapted" SARS-CoV-2 (MA-SARS-CoV-2) with mutations in S, M, and N genes, and a twelve-nucleotide insertion in the S gene. MA-SARS-CoV-2 infection causes mild disease, with more pronounced morbidity depending on genetic background and in aged and obese mice. Two mutations in the S gene associated with mouse adaptation (N501Y, H655Y) are present in SARS-CoV-2 variants of concern (VoCs). N501Y in the receptor binding domain of viruses of the B.1.1.7, B.1.351, P.1 and B.1.1.529 lineages (Alpha, Beta, Gamma and Omicron variants) is associated with high transmissibility and allows VoCs to infect wild type mice. We further show that S protein mutations of MA-SARS-CoV-2 do not affect neutralization efficiency by human convalescent and post vaccination sera.
Insights
Researchers adapted SARS-CoV-2 for mouse infection, creating mouse-adapted SARS-CoV-2 (MA-SARS-CoV-2). These adapted viruses, with mutations like N501Y, can infect mice and show reduced neutralization by human sera.
Area of Science:
- Virology
- Infectious Diseases
- Genetics
Background:
- Initial SARS-CoV-2 strains could not infect mice due to differences in the ACE-2 receptor.
- Mouse models are crucial for studying viral pathogenesis and testing therapeutics.
Purpose of the Study:
- To develop a mouse-adapted SARS-CoV-2 (MA-SARS-CoV-2) for research.
- To investigate the genetic changes associated with mouse adaptation.
- To assess the impact of these adaptations on viral infectivity and neutralization.
Main Methods:
- Serial passaging of the USA-WA1/2020 SARS-CoV-2 strain in mouse lungs.
- Genetic sequencing to identify mutations in MA-SARS-CoV-2.
- Infection studies in mice to evaluate disease severity.
- Neutralization assays using human convalescent and post-vaccination sera.
Main Results:
- MA-SARS-CoV-2 was generated with mutations in S, M, and N genes, including a 12-nucleotide insertion in the S gene.
- Infection caused mild disease, with increased severity in aged, obese, or genetically susceptible mice.
- Key mutations (N501Y, H655Y) found in MA-SARS-CoV-2 are also present in SARS-CoV-2 variants of concern (VoCs).
- The N501Y mutation facilitates VoC infection in wild-type mice.
- MA-SARS-CoV-2 S protein mutations did not significantly affect neutralization by human sera.
Conclusions:
- MA-SARS-CoV-2 provides a valuable model for studying SARS-CoV-2 infection in mice.
- Mutations conferring mouse adaptation, like N501Y, are relevant to highly transmissible SARS-CoV-2 variants.
- The study highlights the potential for viral adaptation and the importance of ongoing surveillance.
