SAN FRANCISCO, Oct. 25, 2022 (GLOBE NEWSWIRE) — Researchers at the UCSF QBI Coronavirus Research Group (QCRG) have uncovered how the SARS-CoV-2 variants of concern (VOC) differ in their ability to manipulate human cells on a molecular level during infection. They have discovered variant specific differences in viral RNA and protein levels, including viral proteins N, Orf6, and Orf9b, and how specific mutations are responsible for changing viral protein levels during infection with each variant. They have also revealed how mutations in the variants change protein-protein interactions between viral and host proteins. This highly collaborative work, which also included scientists at the University of College London, Icahn School of Medicine at Mount Sinai, and Texas Biomedical Research Institute, highlighted how holistic approaches utilizing proteomics and genomics can reveal cellular changes at the protein and RNA level during infection. “What is exciting to me is how we are integrating different kinds of molecular ‘omics’ data together using computational tools and using it to understand how SARS-CoV-2 is evolving. The methodology and insights we are developing can be applied to understanding other viruses and diseases in the future,” said Mehdi Bouhaddou, a QBI Postdoctoral Fellow in Nevan Krogan’s laboratory and co-first author on the research featured in a paper that appeared on Oct. 21, 2022, on bioRxiv.
The results paint a more complete picture of how specific variants evade our innate immune system. The mechanistic approach not only suggests better treatments for future variants but also enhances our future pandemic preparedness.
“Using these approaches, we can pinpoint what specific mechanisms we can successfully target to develop therapies against all the variants. But it also tells us as long as the virus continues to transmit in the population it will continue to evolve and adapt to humans – an example of that being Omicron and its subvariants. This is important because viruses only live in the host, so as long as it’s transmitting it will continue to adapt,” said Lorena Zuliani-Alvarez, PhD, QBI Lead Senior Scientist and co-senior author on the paper.
Convergence and Divergence
Since 2020, SARS-CoV-2 has arced an evolutionary trajectory through several different VOCs including Alpha, Beta, Gamma, Delta, and Omicron but when cell response to infection is examined both conserved and divergent biological pathways are observed.
Conserved, or things that remained common despite mutation, included the regulation of translation, or how proteins are made in cells. This pathway with conserved regulation across the variants has made it a practical target for inhibiting the virus across all VOCs utilizing the translational inhibitor plitidepsin, a compound developed by PharmaMar and in clinical trials for COVID-19. Conversely, changes in the inflammatory response were most divergent, or different, across the VOCs. When examining specific variants, they found that Alpha and Beta, but not Omicron BA.1, could suppress the innate immune system, impeding what is often referred to as our first line of defense. This modulation in the inflammatory response is linked specifically to the decreased production of the protein interferon, which is responsible for inhibiting viral replication and aiding in clearing the infection. The researchers discovered many of these differences correlated with the expression and mutation status of the viral protein Orf6.
Orf6 and Omicron
Orf6 is an accessory protein that can suppress the interferon response. It does this by blocking the transport of transcription factors into the nucleus, inhibiting production of not only interferon but also interferon stimulated genes. While it was clear there were different levels of Orf6 expressed by different VOCs, there were also different amounts of Orf6 expressed by each Omicron subvariant. BA.1 and BA.2 infections lead to the greatest production of interferon, your innate immune system working, while BA.5 evolved to suppress it by upregulating expression of Orf6. BA.4 also upregulated Orf6, but additionally contained a mutation that reduced its ability to inhibit a key host protein complex called the nuclear pore. This demonstrates that VOCs have evolved to fine-tune both viral protein expression and their interactions with host proteins in a way that can manipulate our innate and adaptive immune responses, – highlighting a likely reason for increased transmission in humans.
QBI’s integrative approach enables the rapid evaluation of emerging viral mutations and their mechanistic consequences on viral replication. “Our goal was to understand how mutations that were naturally occurring in the SARS-CoV-2 variants affected the course of infection. We found many examples of how mutations in the virus changed the host molecular response in human cells. For example, inflammatory response is drastically different across variants, with ramifications for clinical symptoms and transmission. By understanding more about how SARS-CoV-2 is evolving, we hope to be better prepared for new variants and future pandemics of emerging viruses because we are getting a sense for the things this virus is changing over time,” explains Nevan Krogan, director of QBI at the School of Pharmacy at UCSF and senior investigator at Gladstone Institutes. With these insights the research will pave the way to discover broad antivirals that can target existing and upcoming VOCs.
Lorena Zuliani-Alvarez, PhD is the co-senior author along with Nevan Krogan, PhD. First author Mehdi Bouhaddou, PhD is a Postdoctoral fellow in the Krogan Lab. For further author information please see the study.
Academic and private sector scientists from UCSF, QBI’s Coronavirus Research Group (QCRG) Gladstone Institutes, University College London, Icahn School of Medicine at Mount Sinai, Texas Biomedical Research Institute, University of Glasgow, Wellcome Sanger Institute, Francis Crick Institute, ETH Zurich, MIT, and Tel Aviv University, and other institutions as well as the companies PharmaMar and Synthego participated in the research.
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; F. Hoffmann-LaRoche; Vir Biotechnology, Centre for Integrative Biological Signalling Studies (CIBSS), European Research Council (ERC) and QCRG philanthropic donors.
About the Quantitative Biosciences Institute (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.
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