UCSF QBI, University College London, and Mount Sinai Identify Shared Molecular Mechanisms Across SARS-CoV-2 Variants that Allow Virus to Thrive Despite Vaccination
- Findings show viral proteins outside of Spike across Alpha, Beta, Gamma, Delta and Omicron SARS-CoV-2 variants are responsible for innate immune suppression and escape from human immune system barriers - Elucidation of common evolutionary thread provides key biologic target against future COVID-19 variants and other pandemics
In a study published online in CELL today, scientists at UCSF QBI, University College London and the Icahn School of Medicine at Mount Sinai reported breakthrough findings on convergent evolutionary mechanisms shared by COVID-19 variants, allowing them to overcome both adaptive and innate immune system barriers. In the paper titled, SARS-CoV-2 Variants Evolve Convergent Strategies to Remodel the Host Response, scientists carried out an unprecedented, systematic comparative study using the most infectious COVID-19 variants, namely Alpha, Beta, Gamma, Delta and Omicron to identify specific viral mutations responsible for hijacking a common host pathway, thereby leading to increased transmissibility, infectivity and survival. Specifically, they discovered a convergence in potent suppression of interferon-stimulated genes through several viral proteins, including Orf6 and Orf9b, which serve as innate immune antagonist proteins capable of blocking innate host immune response.
The study, 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, was a collaborative effort that involved 16 institutions in six countries, including University College London (UCL) in London, England (Greg Towers and Clare Jolly) and Icahn Mount Sinai (Adolfo Garcia-Sastre and Lisa Miorin) among others.
Separately yesterday, Dr. Krogan received special recognition as the recipient of the first-ever “Discovery | Innovation | Health Prize” from Research!America for his “trailblazing efforts to address future pandemic threats” and acknowledgement of his approach to building global collaborations in advance of future health threats as a preemptive strategy to protect human life, health, and opportunity. The award, which included a $200,000 prize, is intended to provide support for his vision for progress against pandemic threats.
“Unfortunately, we continue to see new mutations and strains of SARS-CoV-2 despite innovations in new vaccines,” said Dr. Krogan, who founded the QBI Coronavirus Research Group (QCRG). “We evaluated each of the viral variants in isolation and discovered that there was a common mechanism involving several viral proteins, including Orf6 and Orf9b, that potently suppresses innate immunity. This finding is consistent with our investigation of early SARS-CoV-2 variants where certain viral proteins were highly expressed in infected cells which helped the virus infect our cells. With our additional research across SARS-CoV-2 variants, we now see this as a crucial finding that, if targeted effectively, could be turned into a significant vulnerability for this virus, which also has important implications for management of future pandemics.”
In a second paper titled “Impact of SARS-CoV-2 Orf6 and its variant polymorphisms on host responses and viral pathogenesis” also published today in Cell Host & Microbe, the researchers further detailed the role of Orf6 in subverting important pathways involved in the host antiviral response.
“In this study we found that Orf6 is a major SARS-CoV-2 innate immune antagonist by selectively interfering with nucleocytoplasmic trafficking through direct interactions with the nuclear pore complex”, said Lisa Miorin, PhD, Assistant Professor Department of Microbiology at Mount Sinai. “We show that the absence of ORF6, or the introduction of ORF6 loss-of-function mutations, significantly influences the host antiviral responses resulting in SARS-CoV-2 attenuation in animal models.”
Adolfo García-Sastre, PhD, Professor of Medicine (Infectious Diseases),Microbiology and Pathology, Molecular and Cell Based Medicine and Director of the Global Health and Emerging Pathogens Institute at Mount Sinai added, “These observations provide a potential new way to address viral pandemics by targeting a common pathway that the virus uses for infectivity, a different approach from vaccines that are created to target mutated Spike proteins within individual variants. By investigating the variant’s ability to suppress the host immune response we have uncovered what appears to be a mechanism that viruses use that can be exploited.”
Mehdi Bouhaddou, PhD, Assistant Professor Department of Microbiology, Immunology, and Molecular Genetics at the University of California, Los Angeles (UCLA) who contributed to the research during his prior post-doctoral fellowship at UCSF commented, “Similar to treatment regimens for HIV, we believe the future approach to managing pandemics will require a drug combination cocktail. Here, this could include a combination of vaccines and antiviral innovations to target the virus. Specifically, combination therapy approaches to target the adaptive immune response (e.g., vaccines, antibody treatments) and another inhibiting viral innate immune antagonist proteins (e.g., Orf6 and Orf9b) or activating the innate immune response, could be the most effective. Perhaps with this approach, we may be able to get ahead of viruses before they reach pandemic levels.”
To understand the effect of viral mutations on viral replication and cellular responses, the researchers systematically studied the five SARS-CoV-2 variants of concern during infection in human airway epithelial cells. Their analysis pinpointed cellular pathways that are similarly modulated across variants during infection and represent putative targets for pan-coronavirus antivirals. They observed most of the variants improve their ability to inhibit the host innate immune response, which likely contributed to variant dominance by improving transmission. They reason this reflects a strong selection imposed by the human innate immune system on the virus, whose ancestor likely adapted to evade innate immunity in a non-human species. The researchers concluded that a major force in shaping SARS-CoV-2 virus-host adaptations is related to evasion of innate and adaptive responses, a finding that has also been shown in research evasion of innate immune responses in HIV.
About QBI: The Quantitative Biosciences Institute (QBI) is a University of California organized research unit reporting through the UCSF School of Pharmacy. QBI fosters collaborations across the biomedical and the physical sciences, seeking quantitative methods to address pressing problems in biology and biomedicine. Motivated by problems of human disease, QBI is committed to investigating fundamental biological mechanisms, because ultimately solutions to many diseases have been revealed by unexpected discoveries in the basic sciences. Learn more at qbi.ucsf.edu.
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 the Mount Sinai Health System: Mount Sinai Health System is one of the largest academic medical systems in the New York metro area, with more than 43,000 employees working across eight hospitals, more than 400 outpatient practices, more than 300 labs, a school of nursing, and a leading school of medicine and graduate education. Mount Sinai advances health for all people, everywhere, by taking on the most complex health care challenges of our time—discovering and applying new scientific learning and knowledge; developing safer, more effective treatments; educating the next generation of medical leaders and innovators; and supporting local communities by delivering high-quality care to all who need it.
Through the integration of its hospitals, labs, and schools, Mount Sinai offers comprehensive health care solutions from birth through geriatrics, leveraging innovative approaches such as artificial intelligence and informatics while keeping patients’ medical and emotional needs at the center of all treatment. The Health System includes approximately 7,400 primary and specialty care physicians; 13 joint-venture outpatient surgery centers throughout the five boroughs of New York City, Westchester, Long Island, and Florida; and more than 30 affiliated community health centers. Hospitals within the System are consistently ranked by Newsweek’s® “The World’s Best Smart Hospitals” and by U.S. News & World Report's® “Best Hospitals” and “Best Children’s Hospitals.” The Mount Sinai Hospital is on the U.S. News & World Report's® “Best Hospitals” Honor Roll for 2023-2024.
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.
We are UCL.
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Find out how UCL is helping lead the global fight against COVID-19 www.ucl.ac.uk/covid-19-research
About the Mount Sinai Health System
Mount Sinai Health System is one of the largest academic medical systems in the New York metro area, with 48,000 employees working across eight hospitals, more than 400 outpatient practices, more than 600 research and clinical labs, a school of nursing, and a leading school of medicine and graduate education. Mount Sinai advances health for all people, everywhere, by taking on the most complex health care challenges of our time—discovering and applying new scientific learning and knowledge; developing safer, more effective treatments; educating the next generation of medical leaders and innovators; and supporting local communities by delivering high-quality care to all who need it.
Through the integration of its hospitals, labs, and schools, Mount Sinai offers comprehensive health care solutions from birth through geriatrics, leveraging innovative approaches such as artificial intelligence and informatics while keeping patients’ medical and emotional needs at the center of all treatment. The Health System includes approximately 9,000 primary and specialty care physicians and 11 free-standing joint-venture centers throughout the five boroughs of New York City, Westchester, Long Island, and Florida. Hospitals within the System are consistently ranked by Newsweek’s® “The World’s Best Smart Hospitals, Best in State Hospitals, World Best Hospitals and Best Specialty Hospitals” and by U.S. News & World Report's® “Best Hospitals” and “Best Children’s Hospitals.” The Mount Sinai Hospital is on the U.S. News & World Report® “Best Hospitals” Honor Roll for 2024-2025.
For more information, visit https://www.mountsinai.org or find Mount Sinai on Facebook, Twitter and YouTube.
