Virus uses same entry pathway into lung cells as earlier Covid-19 variants
Mutations in the spike protein of the Pirola variant of the SARS-CoV-2 variant facilitate entry into lung cells
Even after the end of the pandemic, Covid-19 continues to pose a serious health threat. Most individuals have established robust immune protection and do not develop severe disease, but the infection can still lead to marked and sometimes long-lasting disease symptoms. In the late summer of 2023, a new SARS-CoV-2 variant emerged, BA.2.86 (Pirola), which differs markedly in its genetics from all previously circulating variants.
A team of researchers from the German Primate Center – Leibniz Institute for Primate Research (DPZ, Göttingen), have worked together with partners at Charité (Berlin), Hannover Medical School, Helmholtz Center for Infection Research (Braunschweig) and the team led by Prof. Dr. Hans-Martin Jäck, head of the Department of Molecular Immunology at Universitätsklinikum Erlangen, FAU, to investigate the biological properties of the Pirola variant.
The researchers discovered that the Pirola variant, in contrast to all previously circulating Omicron variants, enters lung cells with high efficiency and uses the cellular enzyme TMPRSS2 for entry, thereby exhibiting surprising parallels to variants Alpha, Beta, Gamma and Delta that circulated during the first years of the pandemic. Although the improved entry into lung cells might indicate that the virus is more aggressive, production of new, infectious viral particles in infected cells was reduced, possibly limiting its spread and pathogenic potential.
Finally, the researchers reported that the Pirola variant is resistant against all therapeutic antibodies and efficiently evades antibody responses in vaccinated individuals with and without breakthrough infection. However, the virus was appreciably inhibited by antibodies elicited by the new mRNA vaccine adapted to the XBB.1.5 variant. In summary, the results show that even four years after the start of the pandemic, the virus is still capable of profound changes and can reacquire properties which may promote the development of severe disease.
The spread of SARS-CoV-2 is associated with the constant emergence of new viral variants. These variants have acquired mutations in the spike protein, which allow evasion of neutralizing antibodies in vaccinated and convalescent individuals. The emergence of viral variants started with the Alpha variant followed by the Beta, Gamma and Delta variants.
At the end of 2021, the Omicron variant became globally dominant, which, based on genome sequence, differed markedly from previously circulating variants. However, the virus had to pay a price for this massive change. The Omicron variant can evade neutralizing antibodies effectively and is transmitted with high efficiency but it has lost the ability to efficiently use a host cell enzyme, the protease TMPRSS2, for lung cell entry. As a consequence, the Omicron variant induces pneumonia less frequently.
Pirola: A quantum leap in SARS-CoV-2 evolution
Descendants of the Omicron variant dominated globally until the end of the year 2023. New variants frequently differed from their predecessors by only a few mutations and there was evidence that viruses circulating in 2023 had only limited options to evade antibody pressure in the human population. Therefore, the discovery of a new SARS-CoV-2 Omicron subvariant, Pirola (BA.2.86), which, based on genome sequence, strongly differed from other circulating viruses drew a lot of attention. The Pirola variant, like the Omicron variant, likely arose in immunocompromised patients and presents a quantum leap in SARS-CoV-2 evolution.
The spike protein of the Pirola variant harbors more than 30 mutations relative to its precursor variant, BA.2, and it is largely unknown how these mutations affect the biological properties of the virus. A team of researchers from the German Primate Center (DPZ) led by Markus Hoffmann and Stefan Pöhlmann addressed this question jointly with the research groups of Christian Drosten (Charité, Berlin), Georg Behrens (Hannover Medical School), Luka Cicin-Sain (Helmholtz Centre for Infection Research, Braunschweig) and Hans-Martin Jäck (FAU, Erlangen).
Pirola can infect lung cells more efficiently…
The researchers discovered that the Pirola variant, in contrast to all previously circulating Omicron subvariants, enters lung cells with high efficiency, using TMPRSS2. Further, they demonstrated that mutations S50L and K356T in the spike protein of the Pirola variant are important for the highly efficient lung cell entry.
… but replicates less well than its predecessors
SARS-CoV-2 infected cells produce new virus particles many of which, but not all, are able to infect new cells. The researchers provided evidence that cells infected by the Pirola variant are less well able than cells infected with previous variants to produce intact viral particles.
Therapeutic antibodies are ineffective against Pirola
Recombinantly produced neutralizing antibodies were used successfully for COVID-19 prophylaxis and therapy. However, due to the emergence of viral variants with mutations in the antibody binding sites, most of those antibodies are not active against currently circulating variants. The present study shows that the Pirola variant is no exception – none of the tested antibodies were able to neutralize the virus.
New, adapted vaccine protects against Pirola
The Pirola variant was also able to evade antibodies induced by vaccination or infection but with less efficiency than the contemporaneously circulating Eris variant (EG.5.1). However, antibodies induced by vaccination with the new XBB.1.5-adapted vaccine were able to appreciably inhibit both the Pirola and the Eris variant.to original publication
Prof. Dr. Hans-Martin Jäck
Department of Molecular Immunology at Universitätsklinikum Erlangen
Phone: +49 9131 85 35912