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Belgian and German researchers have shown how the glycoprotein peak of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is fine-tuned based on human airway temperature and protease conditions, which in turn improves viral transmission and the consequent pathology. Their study is available on bioRxiv * prepress server.
The rapid advancement of SARS-CoV-2, the causative agent of the coronavirus disease pandemic (COVID-19), is linked to copious replication in the upper airways, which is not the case with other highly pathogenic human coronaviruses such as SARS -CoV- 1 and MERS-CoV.
Furthermore, since SARS-CoV-2 is characterized by abundant replication in the nose, it is possible that its spike glycoprotein (which mediates viral entry into host cells) is somehow adapted for this colder compartment.
The transmembrane serine protease 2 (TMPRSS2) in the host is a prominent actor in cleaving the full-length spike glycoprotein and S2 activation, which in turn broadens the cellular or tissue trophism of the putative viral agent.
It is important to note that within months of circulation among humans, SARS-CoV-2 has acquired a spike mutation known as D614G, which is increasingly recognized as a possible cause of increased viral transmission. More specifically, the D614G mutation was detected relatively early in the pandemic.
Therefore, in a recent tour de force paper, a research group led by Dr Manon Laporte of the University of Leuven in Belgium revealed the characteristics of the SARS-CoV-2 glycoprotein, which is responsible for the optimization of the virus towards different regions. of the respiratory tract.
Methodological approach
“We hypothesized that coronavirus spiked glycoproteins could show temperature dependence, in relation to the temperature required for optimal virus replication,” state the study authors. “The temperature gradient in the human respiratory tract is a plausible key factor in determining whether a virus replicates preferentially in the upper or lower airways,” they add.
To study it, the researchers first produced murine leukemia virus (MLV) particles containing spike glycoproteins of highly pathogenic SARS-CoV-1, SARS-CoV-2 and MERS-CoV, but also the common cold coronavirus HCoV-229E. . Pseudovirus production was performed at 33 ° C and 37 ° C.
Then they addressed how the entry of SARS-CoV-2 is controlled by host proteases cleaving the glycoprotein extended S1 / S2 cycle or S2 ‘site. Consequently, they analyzed the entry behavior of different loop deletion mutants and evaluated which of the 18 families of human type II transmembrane proteases (including TMPRSS2) act as peak coronavirus activators.
Finally, the researchers investigated the temperature and protease dependence of the SARS-CoV-2 D614G mutant in order to assess how these peak characteristics might be associated with virus transmissibility.
Structure of the SARS-CoV-2 spike trimer, based on PDB 6ZGE (81), in which we modeled the cleavage ring using SWISS-MODEL (82). The amino acids shown in magenta have been replaced or eliminated, to create three mutants of the S1 / S2 cycle. The inset on the right shows the D614 residue, forming a hydrogen bond with the T859 residue in the S2 subunit of another protomer.
Temperature gradient and protease activators
In this study, the researchers revealed that the common cold virus HCoV-229E replicates much more efficiently at 33 ° C and 35 ° C than at 37 ° C and (specifically) 39 ° C. Similarly, SARS-CoV-2 was reported to prefer 33 ° C to 37 ° C, while SARS-CoV-1 showed the opposite profile.
Furthermore, the SARS-CoV-2 spike glycoprotein was efficiently activated by TMPRSS13, along with the previously identified TMPRSS2 host cell protease, which broadens the known cell tropism of SARS-CoV-2.
TMPRSS13 was found to be an effective spike activator for virulent coronaviruses, but not the common cold virus HCoV-229E. Furthermore, activation by these proteases requires pre-cleavage of the S1 / S2 cleavage loop, and both the furin motif and the extended loop length have been found to be critical in gaining entry of the virus into epithelial cells. of the airways.
Finally, the researchers demonstrated that the D614G mutation in SARS-CoV-2 has the propensity to increase the stability of the spike glycoprotein and its expression at 37 ° C, which also promotes virus entry via the activation of cathepsin B / L (i.e. a family of cysteine protease lysosomes).
Appreciating the behavior of the emerging spike mutants
“In this study, we recognized two characteristics of the SARS-CoV-2 spike protein, namely, compatibility with variable temperature in the human respiratory tract and a well-regulated protease activation mechanism, which could be two determinants of high transmissibility and virulence of this virus, “the study authors conclude in this bioRxiv paper.
Their approach to engaging pseudoviruses with spikes of SARS-CoV-1, MERS-CoV, and HCoV-229E has opened the door for noticing similarities and interpreting the results from a much broader perspective.
In conclusion, these insights will further elucidate the host-coronavirus interaction and adaptation and (at least in the short term) could prove very valuable for understanding the behavior of emerging SARS-CoV-2 spike mutants.
*Important Notice
bioRxiv publishes preliminary scientific reports that are not peer-reviewed and therefore should not be considered conclusive, guide clinical practice / health-related behavior, or treated as consolidated information.
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