Omicron Mutation: The Evolution of Omicron Subvariant Allowing Efficient Lung Cell Infection

by François Dupont
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Omicron subvariant

Scientists have made a significant discovery regarding a mutation in the Omicron BA.5 subvariant, which enables it to effectively infect lung cells. This development has concerning implications, particularly for high-risk groups, as it could lead to more severe disease outcomes. The study underscores the need for continuous monitoring of the evolution of Omicron subvariants.

There is a possibility that future SARS-CoV-2 variants may regain the capacity to infect the lower respiratory tract.

Currently, Omicron-derived virus variants account for the majority of global SARS-CoV-2 infections. Compared to its predecessors, Omicron generally causes less severe disease. This is primarily attributed to its reduced ability to infect lung cells and, consequently, its lower frequency of causing pneumonia. However, an international team of researchers, including scientists from the German Primate Center – Leibniz Institute for Primate Research, has discovered a mutation in the spike protein of the Omicron subvariant BA.5. This mutation enables the virus to efficiently infect lung cells once again.

This study provides evidence that Omicron subvariants may evolve in a manner that allows them to regain the ability to effectively infect the lungs and cause severe illness in high-risk patients and individuals with inadequate immunity. The findings have been published in the journal Nature Communications.

Omicron Subvariants: BA.1 and BA.2

During the first half of 2022, the BA.1 and BA.2 Omicron subvariants dominated the COVID-19 pandemic. In comparison to the Delta variant and other strains, these subvariants demonstrated a reduced ability to infect lung cells. However, the infectivity of the BA.5 subvariant, which surpassed other Omicron subvariants in the autumn of 2022, was initially uncertain. Markus Hoffmann and Stefan Pöhlmann from the German Primate Center led a team of researchers who demonstrated that, due to a mutation in the spike protein, BA.5 can infect lung cells much more efficiently than its predecessors.

Model of the spike protein of the Omicron subvariant BA.5, highlighting the H69Δ/V70Δ mutation responsible for increased lung cell entry. Credit: Markus Hoffmann

Impact of Spike Protein Mutations

The researchers discovered that the spike protein of the BA.5 Omicron subvariant undergoes more efficient cleavage compared to earlier strains. Moreover, the spike protein of BA.5 facilitates the virus’s entry into lung cells and enhances cell fusion efficiency. The team employed “pseudo-viruses” as a safe model to examine how the virus penetrates lung cells.

Markus Hoffmann, the lead author of the study, explains, “We found that BA.5 has acquired a mutation that allows the virus to enter lung cells more efficiently than the previously dominant Omicron subvariants. Therefore, the ongoing evolution of Omicron subvariants might generate viruses in the future that spread efficiently to the lower respiratory tract, potentially causing severe disease in patients without sufficient immune protection.” The altered properties of Omicron BA.5 are due to a critical mutation known as “H69Δ/V70Δ.”

Infection biologist Dr. Markus Hoffmann (left) and Prof. Dr. Stefan Pöhlmann, head of the Infection Biology Unit at the German Primate Center (DPZ) – Leibniz Institute for Primate Research. Credit: Karin Tilch

Confirmation with Real Virus and Further Studies

To validate these findings, Christian Drosten’s team at the Virology Department of Charité – Berlin University Hospital conducted additional experiments using real viruses. These tests confirmed that BA.5 strain viruses efficiently infect lung cells, corroborating the results from Göttingen. In order to determine whether Omicron BA.5 also infects lung cells in living organisms, researchers at the University of Iowa compared the lungs of mice infected with BA.5 to those infected with other subvariants. They discovered that BA.5 replicated up to 1000 times more efficiently in the lungs of mice compared to earlier Omicron subvariants.

Lastly, experiments performed on ferrets at the Friedrich-Loeffler-Institut in Greifswald – Insel Riems, Germany, revealed that the BA.5 subvariant spreads more efficiently in the upper respiratory tract than previous virus variants.

“Taken together, these findings suggest that, similar to other Omicron subvariants, BA.5 is highly contagious and has additionally acquired the ability to efficiently infect lung cells,” says Stefan Pöhlmann, head of the Infection Biology Unit at the German Primate Center. “Therefore, close monitoring of the further evolution of Omicron subvariants is necessary to quickly identify variants with an increased risk potential.”

Reference: “Omicron subvariant BA.5 efficiently infects lung cells” by Markus Hoffmann, Lok-Yin Roy Wong, Prerna Arora, Lu Zhang, Cheila Rocha, Abby Odle, Inga Nehlmeier, Amy Kempf, Anja Richter, Nico Joel Halwe, Jacob Schön, Lorenz Ulrich, Donata Hoffmann, Martin Beer, Christian Drosten, Stanley Perlman, and Stefan Pöhlmann, 13 June 2023, Nature Communications. DOI: 10.1038/s41467-023-39147-4

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Frequently Asked Questions (FAQs) about Omicron subvariant

What is the significance of the Omicron BA.5 mutation?

The Omicron BA.5 mutation is significant because it enables the virus to efficiently infect lung cells. This has implications for disease severity, particularly in high-risk groups.

How does the BA.5 subvariant compare to its predecessors?

Compared to earlier Omicron subvariants, BA.5 has regained the ability to infect lung cells more efficiently. This could potentially lead to more severe illness, especially in individuals with inadequate immune protection.

What are the implications of the study’s findings?

The findings highlight the need for ongoing monitoring of Omicron subvariants’ evolution. It is crucial to identify variants with increased risk potential, as they may spread more effectively to the lower respiratory tract and cause severe disease.

How did the researchers determine the impact of the spike protein mutations?

The researchers used “pseudo-viruses” as a safe model to study how the BA.5 variant penetrates lung cells. They discovered that the spike protein of BA.5 undergoes more efficient cleavage, facilitating the virus’s entry into lung cells and increasing cell fusion efficiency.

Were the findings validated with real viruses and living organisms?

Yes, additional experiments with real viruses confirmed that BA.5 strain viruses efficiently infect lung cells. Furthermore, studies on mice and ferrets demonstrated BA.5’s increased replication in the lungs and its efficient spread in the upper respiratory tract.

What should be done in response to these findings?

The study emphasizes the importance of closely monitoring the further evolution of Omicron subvariants. This will help in quickly identifying variants with an increased risk potential and implementing necessary measures to mitigate their impact.

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