BREAKING! Study Shows Newer Omicron Subvariants Spotting H655Y Mutation Like BA.2, BA.2.12.1, BA.4, BA.5 And BA.2.75 Have Decreased Fusogenicity!

SARS-CoV-2 Variants: A new study by American researchers from Ohio State University-USA and University of Texas Medical Branch-USA has found that newer Omicron variants or sub-lineages possessing the H655Y mutation tend to display lower fusogenicity with possible implications for lower risk of disease severity initially upon infection.


 
However, such variants and sub-lineages possessing the H655Y mutation also tend to exhibit a higher preference of using endosomal entry pathways to gain access into host cells.
 
At present, besides the BA.1.1 Omicron variant, the newer BA.2, BA.2.12.1, BA.4, BA.5 and BA.2.75. variants and sub-lineages spot the H655Y mutation.
 
The rapid spread and strong immune evasion of the SARS-CoV-2 Omicron subvariants has raised serious concerns for the global COVID-19 pandemic.
 
Interesting, these new SARS-CoV-2 Variants exhibit reduced fusogenicity and increased endosomal entry pathway utilization compared to the ancestral D614G variant, the underlying mechanisms of which remain elusive.
 
The study team demonstrated showed that the C-terminal S1 mutations of the BA.1.1 subvariant, H655Y and T547K, critically govern the low fusogenicity of Omicron.
 
Importantly, the H655Y mutation also dictates the enhanced endosome entry pathway utilization.
 
Mechanistically, both the T547K and H655Y mutations likely stabilize the spike trimer conformation, as shown by increased molecular interactions in structural modeling as well as reduced S1 shedding.
 
However, the H655Y mutation also significantly determines the low fusogenicity and high dependence on the endosomal entry pathway of other Omicron subvariants, including BA.2, BA.2.12.1, BA.4/5 and BA.2.75.
 
The study findings uncover mechanisms governing Omicron subvariant entry and provide insights into altered Omicron tissue tropism and pathogenesis.
 
The study findings were published on a preprint printer and are currently being peer reviewed.
https://www.biorxiv.org/content/10.1101/2022.10.15.512322v1
 
It should be noted that although the H655Y  mutation critically govern the low fusogenicity of these newer Omicron variants and sub-lineages, we at this stage do not have the full understanding of the pathogenesis of these new variants and sub-lineages and are hence not aware of what mid or long-term effects and medical conditions they can cause.
 
The key finding of this study is that the altered entry route preference of Omicron is largely determined by the key H655Y mutations.
 
To date, it has been well established that SARS-CoV-2 is capable of utilizing either endosomal entry mediated by Cat L/B or plasma membrane entry mediated by TMPRSS2.
 
It has been found however, SARS-CoV-2 entry in primary lung epithelial cells and lung-derived cell lines such as Calu-3 cell is largely TMPRSS2 dependent, likely occurring on the plasma membrane.
 
Interestingly, following its emergence, the Omicron variant BA. 1 has been shown to have a distinct entry profile, utilizing predominantly the endosomal entry pathway exhibiting poor replication in lower airway derived primary cells and Calu-3 cells as well as displaying reduced disease severity.
https://pubmed.ncbi.nlm.nih.gov/35082449/
 
https://pubmed.ncbi.nlm.nih.gov/35075452/
 
https://pubmed.ncbi.nlm.nih.gov/35062015/
 
The study team found that the H655Y 276 mutation governs BA.1.1 entry through endosomes, as suggested by the significant increase in viral infectivity observed in HEK293T-ACE2 cells but substantial reduction in viral infectivity in Calu-3 cells, and by the increased sensitivity of H655Y bearing variants to E64d, yet with decreased sensitivity to Camostat.
 
The impact of H655Y on in vivo virus tropism and pathogenicity however remains to be investigated.
 
Should the altered entry route preference introduced by the H655Y mutation is responsible for the enhanced nasopharynx tropism and reduced pathogenicity of the Omicron subvariants, any reversion of the H655Y mutation in future variants would be of great concern, as such a variant may exhibit enhanced pathogenicity.
 
Hence careful monitoring this reversion mutation in the pandemic is warranted.
 
It is already known that membrane fusion is critical for entry of all enveloped viruses.
 
The study team found that reversion mutations K547T and Y655H significantly promoted BA.1.1 S-mediated cell-cell fusion whereas forward mutations T547K and H655Y slightly impaired the D614G S-mediated cell-cell fusion, indicating that these two residues critically determine the low fusogenicity of BA.1.1.
 
Surprisingly, the study team found no evidence that T547K and H655Y affect S processing of BA.1.1 in cell lysates.
 
Rather, reversion mutations K547T and Y655H strongly promote S1 shedding in the presence of sACE2, indicating that T547K and H655Y mutations, especially the latter, critically stabilize the BA.1.1 S conformation.
 
The study findings correlated with the structural modelling that T547K appears to stabilize the close conformation of S protein, which is also supported by a recent study reporting an extra hydrogen bond between the tyrosine residue at position 655 in S1 and the threonine residue at position 696 in S2 of BA.1.
https://www.biorxiv.org/content/10.1101/2022.03.21.485084v1
 
Subsequent structural analyses, including comparisons between K547T/Y655H reversion mutants and the parental BA.1.1 or other Omicron subvariants by cryogenic electron microscopy (cryo-EM) or crystallography, are needed to further elucidate the role of T547K and/or H655Y in Omicron subvariant S conformation.
 
The study team stressed that it is important to note that H655Y mutation has been found to be associated with SARS-CoV-2 infection in index cats and minks.
https://pubmed.ncbi.nlm.nih.gov/33635912/
 
https://pubmed.ncbi.nlm.nih.gov/35150638/
 
Also, the H655Y mutation appears to have arisen independently multiple times in human population, and is a lineage-defining mutation for the Gamma (P.1) SARS-CoV-2 variant in addition to the Omicron subvariants.
https://pubmed.ncbi.nlm.nih.gov/35150638/
 
Significantly, H655Y is present in all predominant Omicron sub-lineages, including BA.1.1, BA.1, BA.2, BA.2.12.1 and more recent BA.4/5 and BA.2.75, indicating that H655Y likely improves fitness and the ability to adapt to new hosts, including humans, cats, minks, and others.
 
Such a hypothesis is supported by a recent report demonstrating an enhancement of virus infectivity in mice for H655Y-containing viruses.
https://biologydirect.biomedcentral.com/articles/10.1186/s13062-022-00325-x
 
The study findings along with other recent reports, together suggest that the occurrence of mutations at position 655 in S protein of current and future SARS-CoV-2 variants needs to be closely monitored.
 
Furthermore, in vivo examinations of the impact of the H655Y mutation on virus tropism and pathogenicity are critical and need to be investigated, as any reversion of the H655Y mutation could generate new concern for the course of the COVID-19 pandemic as novel Omicron subvariants continue to emerge.
 
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