Unlocking the secrets of Omicron: study reveals how unique spike mutations enable enhanced infectivity and resistance to immune barrier

NewsGuard 100/100 Score

In a recent study posted to the bioRxiv* preprint server, researchers reported that the increased transmissibility of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) Omicron variant is not due to its immune evasive abilities alone, but due to alternate mechanisms of cellular entry that allow it to evade the interferon-induced antiviral factors.

Study: Omicron Spike confers enhanced infectivity and interferon resistance to SARS-CoV-2 in human nasal tissue. Image Credit: angellodeco/Shutterstock.comStudy: Omicron Spike confers enhanced infectivity and interferon resistance to SARS-CoV-2 in human nasal tissue. Image Credit: angellodeco/Shutterstock.com

*Important notice: bioRxiv publishes preliminary scientific reports that are not peer-reviewed and, therefore, should not be regarded as conclusive, guide clinical practice/health-related behavior, or treated as established information.

Background

Cellular entry of SARS-CoV-2 occurs when the viral spike protein binds to the angiotensin-converting enzyme-2 (ACE-2) receptor, altering the confirmation of the spike protein and activating cleavage by serine proteases such as transmembrane serine protease 2 (TMPRSS2) or matrix metalloproteinases (MMPs).

This cleavage allows the spike protein to trigger the viral membrane to fuse with the cell membrane, releasing viral contents into the host cell.

The Omicron (BA.1) variant emerged after the worldwide efforts to complete primary vaccinations were well underway. The Omicron variant and its sub-variants rapidly replaced the existing dominant variants and exhibited numerous novel mutations in the receptor binding domain of the spike protein.

These novel mutations improved ACE-2 receptor binding and allowed the evasion of the neutralizing antibodies elicited by coronavirus disease 2019 (COVID-19) vaccines, potentially increasing the transmissibility of the Omicron variant.

However, the Omicron variant has also been thought to utilize cellular entry pathways different from the previous SARS-CoV-2 variants.

About the study

In the present study, the researchers compared the abilities of the Omicron variant, Delta variant, and the ancestral SARS-CoV-2 variant (USA-WA1/2020) to invade human nasal epithelial cells cultured in the air-liquid interface (ALI).

Pooled nasal epithelial cells obtained from three donors were cultured as submerged monolayers to propagate the cells in an undifferentiated or basal state. Immunofluorescence staining was used to confirm the undifferentiated state of the cells.

The nasal epithelial cell monolayers were then inoculated with the ancestral, Omicron, and Delta SARS-CoV-2 variants, and quantitative reverse transcription polymerase chain reaction (qRT-PCR) was carried out at multiple time points to measure the viral ribonucleic acid (RNA) and quantify viral replication.

Additionally, the pseudostratified, three-dimensional architecture of nasal epithelia was recreated in vivo by culturing the pooled nasal epithelial cells from 14 donors in ALI.

The presence of stratified nuclei and mature cilia on the surface of the tissue confirmed the differentiated status of the cells.

These ALI-cultured nasal epithelial cells were also inoculated with the ancestral, Omicron, and Delta SARS-CoV-2 variants, and viral levels in the supernatant of the culture medium in which the inoculated cells were grown were quantified to confirm infection.

To determine the subcellular location of spike-mediated cellular entry of the Omicron variant, aloxistatin (E64d), a protease inhibitor, was used to prevent the cathepsin-mediated entry of SARS-CoV-2 in the endolysosomes.

Similarly, camostat mesylate, a serine protease inhibitor, was also used individually and in combination with E64d to determine the viral entry route of the Omicron variant.

Furthermore, undifferentiated nasal epithelial cells were treated with type-I interferon (IFN-β) and type-III interferon (IFN-λ) and challenged with the ancestral and Omicron SARS-CoV-2 variants to determine whether the mutated Omicron spike proteins enabled the virus to evade the interferon-induced antiviral state.

Results

The results indicated that the Omicron variants BA.1 and BA.2 showed higher infectivity of nasal epithelial cells than the ancestral and Delta variants of SARS-CoV-2. This was partly explained by the increased adherence of the Omicron virions to the nasal epithelial cell surface.

Additionally, the study also showed that the entry of the Omicron variant into the nasal epithelial cell is independent of TMPRSS2 or any other serine proteases and instead utilizes cellular MMPs to enter the host cell.

Furthermore, the spike protein-mediated infection of the nasal epithelial cells by the Omicron variant was seen to evade the antiviral state induced by IFN-β and IFN-λ, suggesting that viral entry into the host cell using MMPs might be enabling the evasion of the interferon-induced antiviral state.

Although the Omicron BA.1 variant showed higher replication in the undifferentiated nasal epithelial cells than the ancestral and Delta variants of SARS-CoV-2, in the undifferentiated small airway or lung epithelial cells, the Omicron variant did not replicate, while the ancestral SARS-CoV-2 variant has similar replication kinetics in both nasal and lung epithelial cell cultures.

This suggested that the growth advantage of the Omicron variant due to the novel mutations in the spike proteins was specific for the upper airway epithelial cells.

The role of the novel spike protein mutations in the increased infectivity of nasal tissue was confirmed when a recombinant ancestral SARS-CoV-2 encoding the spike protein from the Omicron BA.1 variant showed higher infectivity of nasal epithelial cells than the ancestral variant encoding the WA.1 or Delta spike protein.

Conclusions

Overall, the findings indicated that the increased transmissibility of the SARS-CoV-2 Omicron variant could be attributed only partially to the higher adherence of the viral spike protein to the ACE-2 receptor or the ability to evade vaccine-induced immunity.

The increased ability of the Omicron variant to invade nasal epithelial cells and the resistance to the interferon-induced antiviral state potentially enabled by the dependence on MMPs rather than serine proteases could also be driving the increased transmittance of the SARS-CoV-2 Omicron variant.

*Important notice: bioRxiv publishes preliminary scientific reports that are not peer-reviewed and, therefore, should not be regarded as conclusive, guide clinical practice/health-related behavior, or treated as established information.

Journal reference:
Dr. Chinta Sidharthan

Written by

Dr. Chinta Sidharthan

Chinta Sidharthan is a writer based in Bangalore, India. Her academic background is in evolutionary biology and genetics, and she has extensive experience in scientific research, teaching, science writing, and herpetology. Chinta holds a Ph.D. in evolutionary biology from the Indian Institute of Science and is passionate about science education, writing, animals, wildlife, and conservation. For her doctoral research, she explored the origins and diversification of blindsnakes in India, as a part of which she did extensive fieldwork in the jungles of southern India. She has received the Canadian Governor General’s bronze medal and Bangalore University gold medal for academic excellence and published her research in high-impact journals.

Citations

Please use one of the following formats to cite this article in your essay, paper or report:

  • APA

    Sidharthan, Chinta. (2023, May 11). Unlocking the secrets of Omicron: study reveals how unique spike mutations enable enhanced infectivity and resistance to immune barrier. News-Medical. Retrieved on June 14, 2024 from https://www.news-medical.net/news/20230511/Unlocking-the-secrets-of-Omicron-study-reveals-how-unique-spike-mutations-enable-enhanced-infectivity-and-resistance-to-immune-barrier.aspx.

  • MLA

    Sidharthan, Chinta. "Unlocking the secrets of Omicron: study reveals how unique spike mutations enable enhanced infectivity and resistance to immune barrier". News-Medical. 14 June 2024. <https://www.news-medical.net/news/20230511/Unlocking-the-secrets-of-Omicron-study-reveals-how-unique-spike-mutations-enable-enhanced-infectivity-and-resistance-to-immune-barrier.aspx>.

  • Chicago

    Sidharthan, Chinta. "Unlocking the secrets of Omicron: study reveals how unique spike mutations enable enhanced infectivity and resistance to immune barrier". News-Medical. https://www.news-medical.net/news/20230511/Unlocking-the-secrets-of-Omicron-study-reveals-how-unique-spike-mutations-enable-enhanced-infectivity-and-resistance-to-immune-barrier.aspx. (accessed June 14, 2024).

  • Harvard

    Sidharthan, Chinta. 2023. Unlocking the secrets of Omicron: study reveals how unique spike mutations enable enhanced infectivity and resistance to immune barrier. News-Medical, viewed 14 June 2024, https://www.news-medical.net/news/20230511/Unlocking-the-secrets-of-Omicron-study-reveals-how-unique-spike-mutations-enable-enhanced-infectivity-and-resistance-to-immune-barrier.aspx.

Comments

The opinions expressed here are the views of the writer and do not necessarily reflect the views and opinions of News Medical.
Post a new comment
Post

While we only use edited and approved content for Azthena answers, it may on occasions provide incorrect responses. Please confirm any data provided with the related suppliers or authors. We do not provide medical advice, if you search for medical information you must always consult a medical professional before acting on any information provided.

Your questions, but not your email details will be shared with OpenAI and retained for 30 days in accordance with their privacy principles.

Please do not ask questions that use sensitive or confidential information.

Read the full Terms & Conditions.

You might also like...
Antenatal COVID-19 vaccination shown to be safe for pregnant women and their babies