Journal
ELIFE
Volume 11, Issue -, Pages -Publisher
eLIFE SCIENCES PUBL LTD
DOI: 10.7554/eLife.74153
Keywords
COVID-19; SARS-CoV-2; variant of concern; B; 1; 1; 7; single-molecule fluorescence in situ hybridisation; early replication; smFISH; Human; Viruses
Categories
Funding
- Wellcome Trust [209412/Z/17/Z, 091911/B/10/Z, 107457/Z/15/Z, 200838/Z/16/Z]
- Medical Research Council [MC_UU_12014/12, MR/R022011/1, MR/L019434/1, MR/R021562/1, MC_UU_12014/10]
- Chinese Academy of Medical Sciences [2018-I2M-2-002]
- University of Oxford
- James Martin 21st Century Foundation
- Leverhulme Trust
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Despite extensive research, early replication events of SARS-CoV-2 are still poorly understood. This study used smFISH to quantify viral RNA and found that SARS-CoV-2 genomic RNA has a long lifespan in cells and replication varies significantly between cells. Additionally, the B.1.1.7 variant exhibits slower replication kinetics than the Victoria strain, suggesting a novel mechanism contributing to its higher transmissibility.
Despite an unprecedented global research effort on SARS-CoV-2, early replication events remain poorly understood. Given the clinical importance of emergent viral variants with increased transmission, there is an urgent need to understand the early stages of viral replication and transcription. We used single-molecule fluorescence in situ hybridisation (smFISH) to quantify positive sense RNA genomes with 95% detection efficiency, while simultaneously visualising negative sense genomes, subgenomic RNAs, and viral proteins. Our absolute quantification of viral RNAs and replication factories revealed that SARS-CoV-2 genomic RNA is long-lived after entry, suggesting that it avoids degradation by cellular nucleases. Moreover, we observed that SARS-CoV-2 replication is highly variable between cells, with only a small cell population displaying high burden of viral RNA. Unexpectedly, the B.1.1.7 variant, first identified in the UK, exhibits significantly slower replication kinetics than the Victoria strain, suggesting a novel mechanism contributing to its higher transmissibility with important clinical implications.
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