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Convergent evolution in nucleocapsid facilitated SARS-CoV-2 adaptation for human infection
Kumari G Lokugamage1, Yiyang Zhou1,2, R Elias Alvarado1
1Department of Microbiology and Immunology, The University of Texas Medical Branch, Galveston, Texas, USA.
Journal of Virology
|June 12, 2025
Summary
Three SARS-CoV-2 nucleocapsid protein mutations (R203K + G204R, R203M, T205I) enhance human cell infection and viral fitness. These mutations show distinct phosphorylation patterns and reduced replication in bat cells, indicating adaptation for human transmission.
Area of Science:
- Virology
- Molecular Biology
- Genomics
Background:
- SARS-CoV-2 variants of concern (VOCs) acquired mutations in the nucleocapsid (N) protein's 203-205 region.
- Previous work showed R203K + G204R mutations enhance N phosphorylation, viral fitness, and pathogenesis.
Purpose of the Study:
- Investigate the effects of R203M and T205I mutations on SARS-CoV-2 infection.
- Determine how these mutations impact viral replication, fitness, and phosphorylation patterns.
Main Methods:
- Used reverse genetics to introduce R203M and T205I mutations into the WA-1 strain.
- Infected human and bat cells (expressing human ACE2) with mutant SARS-CoV-2 strains.
- Analyzed viral replication, lung pathology, and N protein phosphorylation.
Main Results:
- R203M and T205I mutants enhanced SARS-CoV-2 replication and fitness in human cells.
- These mutants caused moderate lung pathology, distinct from R203K + G204R.
- All three mutations induced unique N phosphorylation patterns.
- In bat cells, these mutations reduced viral replication and N phosphorylation.
Conclusions:
- The R203K + G204R, R203M, and T205I mutations are products of convergent evolution, adapting SARS-CoV-2 for human infection.
- Distinct N phosphorylation patterns correlate with observed phenotypic differences.
- These mutations are critical for SARS-CoV-2's expansion in human populations and may drive future zoonotic outbreaks.
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