Mouse-Adapted SARS-CoV-2 Viruses for Accurate ARDS Modeling
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Solution Overview
Problem
Current mouse models for SARS-CoV-2 infection do not accurately replicate the human disease course, particularly in terms of age-dependent susceptibility and pulmonary lesions associated with acute lung injury and ARDS, as they fail to efficiently target nasal epithelia and alveolar pneumocytes.
Innovation Solution
Development of mouse-adapted SARS-CoV-2 viruses with specific amino acid substitutions in the spike protein, nsp4, nsp7, nsp8, nsp9, and ORF6 proteins, along with the incorporation of a nanoluciferase reporter sequence in place of wildtype ORF7, to enhance binding to murine ACE2 and replicate human-like infection parameters.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If transgenic mouse lines expressing hACE2 are used to generate SARS-CoV-2 mouse models, then productive infection can be achieved, but the model fails to accurately replicate human disease course and pulmonary lesions
Solution Approach 1:
The patent applies parameter changes by introducing specific amino acid substitutions in the spike protein (Q493K, Q498Y, P499T) and other nonstructural proteins to adapt SARS-CoV-2 for efficient murine infection. These parameter changes in viral protein sequences enable the virus to use mACE2 as receptor while maintaining human-like disease pathology, thus resolving the contradiction between infection productivity and disease accuracy.
2Loss of time
If adenovirus or adeno-associated virus vectors are used for transduction, then transgenic mouse lines can be generated quickly, but the model produces fatal encephalitis rather than severe lung disease
Solution Approach 1:
The patent extracts and eliminates the harmful effect of fatal encephalitis by using mouse-adapted SARS-CoV-2 that specifically targets respiratory epithelia and alveolar pneumocytes. The virus adaptations ensure selective tropism for lung tissue through modified spike protein binding to mACE2, removing the unwanted encephalitic phenotype while maintaining rapid model generation capabilities.
3Measurement precision
If standard laboratory mice are used, then the model should reproduce human disease course accurately, but conventional SARS-CoV-2 cannot efficiently infect them due to receptor incompatibility
Solution Approach 1:
The patent applies parameter changes by introducing specific amino acid substitutions in the spike protein (Q493K, Q498Y, P499T) and other nonstructural proteins to adapt SARS-CoV-2 for efficient murine infection. These parameter changes enable the virus to use mACE2 as receptor while maintaining human-like disease pathology, thus resolving the contradiction between infection productivity and disease accuracy.
4Measurement precision
If mouse-adapted SARS-CoV-2 with multiple amino acid substitutions is developed, then accurate reproduction of human-like infection parameters is achieved, but the viral complexity increases
Solution Approach 1:
The patent systematically applies parameter changes through targeted amino acid substitutions in key viral proteins (spike, nsp4, nsp7, nsp8, nsp9, ORF6) to achieve mouse adaptation. While this increases sequence complexity, the changes are focused and functionally directed toward specific goals: enabling mACE2 binding and reproducing human-like pulmonary pathology, thus justifying the complexity increase through significant gains in model accuracy.
Data Source
AI summary
This invention relates to SARS-CoV-2 viruses adapted with nanoluciferase reporter molecules and mouse-adapted SARS-CoV-2 viruses, compositions including the same and methods of use thereof.