Dataset Information

Spike protein cleavage-activation mediated by the SARS-CoV-2 P681R mutation: a case-study from its first appearance in variant of interest (VOI) A.23.1 identified in Uganda.

ABSTRACT: The African continent like all other parts of the world with high infection/low vaccination rates can, and will, be a source of novel SARS-CoV-2 variants. The A.23 viral lineage, characterized by three spike mutations F157L, V367F and Q613H, was first identified in COVID-19 cases from a Ugandan prison in July 2020, and then was identified in the general population with the additional spike mutation P681R at the S1/S2 cleavage site to comprise lineage A.23.1 by September 2020 with subsequent spread to 26 other countries. The P681R spike substitution of A.23.1 is of note as it increases the number of basic residues in the sub-optimal SARS-CoV-2 spike protein furin cleavage site; as such, this substitution may affect viral replication, transmissibility, or pathogenic properties. The same P681R substitution has also subsequently appeared in B.1.617 variants, including B.1.617.2 (Delta). Here, we performed assays using fluorogenic peptides mimicking the S1/S2 from A.23.1 and B.1.617 and observed significantly increased cleavability with furin, compared to sequences derived from the original Wuhan-Hu1 S1/S2. We performed cell-cell fusion and functional infectivity assays using pseudotyped particles harboring SARS-CoV-2 spike proteins and observed an increase in transduction for A.23.1-pseudotyped particles compared to Wuhan-Hu-1. However, these changes in activity were not reproduced in the original Wuhan-Hu-1 spike bearing only the P681R substitution. Our findings suggest that while A.23.1 has increased furin-mediated cleavage linked to the P681R substitution-which may affect viral infection and transmissibility-this substitution alone needs to occur on the background of other spike protein changes to enable its full functional consequences.

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SUBMITTER: Lubinski B

PROVIDER: S-EPMC8259907 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:This work is to demonstrate that high quality cone beam CT images can be generated for a volume of interest (VOI) and to investigate the exposure reduction effect, dose saving, and scatter reduction with the VOI scanning technique. The VOI scanning technique involves inserting a filtering mask between the x-ray source and the breast during image acquisition. The mask has an opening to allow full x-ray exposure to be delivered to a preselected VOI and a lower, filtered exposure to the region outside the VOI. To investigate the effects of increased noise due to reduced exposure outside the VOI on the reconstructed VOI image, we directly extracted the projection data inside the VOI from the full-field projection data and added additional data to the projection outside the VOI to simulate the relative noise increase due to reduced exposure. The nonuniform reference images were simulated in an identical manner to normalize the projection images and measure the x-ray attenuation factor for the object. Regular Feldkamp-Davis-Kress filtered backprojection algorithm was used to reconstruct the 3D images. The noise level inside the VOI was evaluated and compared with that of the full-field higher exposure image. Calcifications phantom and low contrast phantom were imaged. Dose reduction was investigated by estimating the dose distribution in a cylindrical water phantom using Monte Carlo simulation based Geant4 package. Scatter reduction at the detector input was also studied. Our results show that with the exposure level reduced by the VOI mask, the dose levels were significantly reduced both inside and outside the VOI without compromising the accuracy of image reconstruction, allowing for the VOI to be imaged with more clarity and helping to reduce the breast dose. The contrast-to-noise ratio inside the VOI was improved. The VOI images were not adversely affected by noisier projection data outside the VOI. Scatter intensities at the detector input were also shown to decrease significantly both inside and outside the VOI in the projection images, indicating potential improvement of image quality inside the VOI and contribution to dose reduction both inside and outside the VOI.

Dataset Information

Spike protein cleavage-activation mediated by the SARS-CoV-2 P681R mutation: a case-study from its first appearance in variant of interest (VOI) A.23.1 identified in Uganda.

Graphical abstract

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