– Findings show key mutations and evolution of U.K. SARS-CoV-2 compared to earlier lineages account for upregulation of innate immune antagonists, which hamper immune response and allow for increased viral replication and duration of infection –
SAN FRANCISCO, Calif. and LONDON, June 07, 2021 (GLOBE NEWSWIRE) — In a study published online in bioRxiv today, scientists at UCSF QBI and the University College, London reported new findings on the viral replication and pathogenesis of the B.1.1.7 U.K. coronavirus strain. In the paper titled, Evolution of Enhanced Innate Immune Evasion by the SARS-CoV-2 B.1.1.7 UK Variant, scientists described specific mutations that increase the transmissibility, enhance efficiency of host invasion, inhibit host immune response and possibly increase mortality. Importantly, these effects are connected to mutations in the virus that are not in Spike. While the B.1.1.7 variant fortunately remains sensitive to vaccine and infection-induced neutralizing antibodies, the mutations of this variant suggest [rapid] and evolved adaptation to the human host which increase the variant’s ability to survive and thrive in humans.
The study was led by the laboratories of Nevan Krogan, Ph.D., Director of the Quantitative Biosciences Institute (QBI) at the School of Pharmacy at UC San Francisco, Senior Investigator at Gladstone Institutes, and Professor Greg Towers and Dr. Clare Jolly at University College London (UCL) in London, England, among others.
“With the B.1.1.7 SARS-CoV-2 variant becoming the most prevalent coronavirus variant in the world, we sought to uncover the biological mechanisms and cellular machinery fueling its replication, transmissibility and pathogenesis,” said Dr. Krogan, who founded the QBI Coronavirus Research Group (QCRG). “We discovered that the U.K. variant has evolved rapidly with over 20 key mutations from earlier viral lineages and that these mutations, including those not in the Spike protein, have rendered this variant more infectious and capable of suppressing human host immune response. Our data reveal how the SARS-CoV-2 B.1.1.7 lineage has adapted to the host by enhancing its ability to evade the host innate immune response and increase expression of key viral innate antagonists. Furthermore, our data highlight that certain changes in protein expression levels, namely Orf9b, may have significant impact on the virus-host interaction. In identifying the key pathway and proteins responsible for pathogenesis, we have uncovered druggable targets with high therapeutic value. This has important implications for management of the ongoing pandemic.”
Professor Towers based at UCL Division of Infection & Immunity added, “We believe the B.1.1.7 variant’s ability to suppress the host immune response contributes to its transmission advantage, as has been observed for HIV, and other pandemic viruses. We hypothesize that more effective innate immune antagonism permits enhanced transmission through reduced and delayed host responses which otherwise protect cells from infection.”
Clare Jolly, Ph.D., associate professor at UCL Division of Infection & Immunity commented, “We believe our model captures the earliest interactions between the virus and airway epithelial cells, in which the virus outpaces the innate response through a combination of antagonism and evasion. These are key findings that could support identification and development of effective therapeutics against this more infectious strain.”
Remarkably, viral replication of B.1.1.7 in vitro is similar to earlier SARS-CoV-2 viral lineages. However, QBI and University of College researchers discovered striking differences with respect to the host response to these viruses. Using a combination of abundance proteomics, phosphoproteomics, mRNA sequencing as well as viral assays, they have found that B.1.1.7 isolates more effectively suppress host innate immune responses in human airway epithelial cells. Furthermore, they observed that the viral proteins Orf9b, Orf6 and N, are more highly expressed at both the RNA and protein levels in cells infected with B.1.1.7 compared to earlier SARS-CoV-2 lineages. This upregulation of Orf9b subgenomic RNA (sgRNA) expression has been linked to a mutation in B.1.1.7, suggesting a new and unique way that this virus is evolving to alter the expression of sgRNAs. Researchers found that expression of Orf9b alone suppresses innate immune responses. From previous studies conducted at QBI and published in Science, Cell and Nature, the scientists uncovered an interaction with the host protein TOM70, a mitochondrial protein required for the activation of MAVS, an RNA sensing adaptor and identified phosphorylation sites. In this present study, researchers showed that this interaction is regulated by this phosphorylation and is also required for the suppression of the innate immune response. In summary, the mutations in B.1.1.7 outside of Spike were found to allow the virus to more effectively antagonize host innate immune responses through upregulation of specific sgRNA synthesis and expression of key innate immune antagonists, increasing the likelihood of successful B.1.1.7 transmission and likely increasing in vivo replication and duration of infection. Importantly, the authors have created an experimental pipeline that is also being used to study the other variants, efforts that will allow a deeper understanding of how SARS-CoV-2 mutates to better attack its host and ultimately how it can be combatted.
About QBI: The Quantitative Biosciences Institute (QBI) is a University of California organized research
About UCSF: The University of California, San Francisco (UCSF) is exclusively focused on the health sciences and is dedicated to promoting health worldwide through advanced biomedical research, graduate-level education in the life sciences and health professions, and excellence in patient care. UCSF Health, which serves as UCSF’s primary academic medical center, includes top-ranked specialty hospitals and other clinical programs, and has affiliations throughout the Bay Area. Learn more at ucsf.edu or see our Fact Sheet.
About Gladstone Institutes: To ensure our work does the greatest good, Gladstone Institutes focuses on conditions with profound medical, economic, and social impact—unsolved diseases. Gladstone is an independent, nonprofit life science research organization that uses visionary science and technology to overcome disease. It has an academic affiliation with UC San Francisco. Learn more at gladstone.org.
Authorship and funding: This work was funded by grants from the National Institute of Mental Health and the National Institute of Allergy and Infectious Diseases, both part of the National Institutes of Health; the Defense Advanced Research Projects Agency; the Center for Research for Influenza Pathogenesis; the Centers of Excellence for Influenza Research and Surveillance of the National Institute of Allergy and Infectious Diseases; the Centers of Excellence for Integrative Biology of Emerging Infectious Diseases of the Agence Nationale de la Recherche (France); F. Hoffmann-LaRoche AG; Vir Biotechnology, Centre for Integrative Biological Signalling Studies (CIBSS), European Research Council (ERC) and QCRG philanthropic donors. Shokat is a Howard Hughes Medical Institute investigator. A complete list of authors and full funding information is available in the bioRxiv paper.
About UCL – London’s Global University
UCL is a diverse community with the freedom to challenge and think differently. Our community of more than 41,500 students from 150 countries and over 12,500 staff pursues academic excellence, breaks boundaries and makes a positive impact on real world problems. We are consistently ranked among the top 10 universities in the world and are one of only a handful of institutions rated as having the strongest academic reputation and the broadest research impact. We have a progressive and integrated approach to our teaching and research – championing innovation, creativity and cross-disciplinary working. We teach our students how to think, not what to think, and see them as partners, collaborators and contributors. For almost 200 years, we are proud to have opened higher education to students from a wide range of backgrounds and to change the way we create and share knowledge. We were the first in England to welcome women to university education and that courageous attitude and disruptive spirit is still alive today.
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Find out how UCL is helping lead the global fight against COVID-19 www.ucl.ac.uk/covid-19-
|Sylvia Wheeler, Wheelhouse LSA||Kristen Bole, UCSF Office of Communications|
|Aljanae Reynolds, Wheelhouse LSA|
|Julie Langelier, Gladstone Communications|