A large multinational group of researchers has shown how the Omicron variant of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has gained exceptional immune evasion properties but also a much lower propensity to enter cells such as those in lung alveoli, resulting in its reduced pathogenicity. Their paper is currently released as an unedited version of the manuscript prior to publication in the journal Nature.

The Omicron variant of SARS-CoV-2 initially detected in South Africa in November 2021 during the ongoing coronavirus disease 2019 (COVID-19) pandemic, spread around the world at a ferocious pace, and is known to carry more than 30 mutations in its spike glycoprotein.

Moreover, the Omicron variant has been linked to a rather rapid increase in case numbers, with recent data demonstrating substantial re-infection rates and vaccine ‘breakthrough’ potential, probably due to a successful evasion of neutralizing antibody responses.

On the other hand, recent findings suggest (somewhat paradoxically) that there is also a reduced disease severity in individuals infected with the Omicron variant when compared to the Delta variant of concern. The pertinent question then is – does that mean SARS-CoV-2 is evolving into a milder virus?

In this Nature paper, the large international research group explored biological properties of Omicron variant of concern with particular focus on spike-mediated evasion of neutralizing antibodies, increased receptor binding affinity, as well as a shift in tropism away from cells expressing TMPRSS2 and reduced ability to generate syncytia (or fused cells).

Appraising neutralization and cell entry

One of the critical questions in this study was whether antibodies developed after vaccinations are able to neutralize Omicron. For that purpose, the researchers have synthesized codon-optimized spike expression plasmids for spike glycoproteins for both Delta and Omicron variants of concern.

Then they have generated pseudovirus particles by co-transfecting the spike expression plasmids with a lentivirus, which represents an efficient method for the delivery of transgenes for research purposes. Many different cell lines were used to explore the propensity for cell entry, as well as the action of certain drugs.

In order to confirm the loss of neutralizing activity against the Omicron variant following the second vaccine dose, the researchers have used a live virus experimental system for comparing Delta and Omicron variants against serum specimens taken four weeks after the second dose of BioNTech/Pfizer (BNT162b2) vaccine.

Lower affinity for the cell receptor

The study has highlighted that spike glycoprotein in Omicron SARS-CoV-2 variant comes with a higher affinity for angiotensin-converting enzyme 2 (ACE2) cell receptor (which is pivotal for cell entry) in comparison to the Delta variant of concern.

Furthermore, there is a marked change of antigenicity due to a cornucopia of mutations, which results in significant evasion of monoclonal antibodies used for treatment, but also vaccine-elicited polyclonal neutralizing antibodies after two doses. Still, mRNA vaccination as a third vaccine dose in a way rescues and broadens this neutralization process.

The defect for Omicron pseudovirus to enter specific cell types in an effective manner has been correlated with higher cellular RNA expression of TMPRSS2 (Transmembrane Serine Protease 2), while a knock-down of TMPRSS2 influenced Delta entry to a much greater extent than Omicron.

More specifically, the replication process was similar for Omicron and Delta variants in human nasal epithelial cultures; however, in lower airway organoids, lung cells, and intestinal cells, Omicron showed much lower replication potential.

Drug inhibitors that target specific entry pathways demonstrated that the Omicron spike glycoprotein does not efficiently utilize TMPRSS2 protease, which actually promotes cell entry via plasma membrane fusion. This means this variant depends more on cell entry via the endocytic pathway.

The need for complex molecular insights

In summary, the Omicron SARS-CoV-2 variant has gained immune evasion properties, but at the same time compromised cell entry in TMPRSS2 expressing cells (primarily those in alveoli), as well as the ability to form syncytia or cell fusion – a combination characteristically linked to reduced ability to cause a severe disease.

“Our data showing tropism differences for Omicron in organoid systems and human nasal epithelial cultures are limited by the fact that they are in vitro systems, albeit using primary human tissue”, state study authors in this Nature paper.

“It should also be noted that levels of TMPRRS2 may impact ACE2, particularly as TMPRSS2 has been implicated in ACE2 cleavage, and our effect sizes were impacted by ACE2 expression”, they emphasize.

Most importantly, the experience with the Omicron variant has clearly shown that any predictions regarding replication and tropism based only on gene sequence can be misleading; thus, a comprehensive molecular understanding of the tropism change will be pivotal as novel SARS-CoV-2 variants continue to emerge.

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