The study of the worrisome variants gives us insights into the evolution of SARS-CoV-2. We now have an idea of the proteins which mutate most frequently and of the biological consequences of these mutations “, Mehdi Bouhaddou, PhD
December 29, 2021 – By Robin Marques – The Alpha variant of SARS-CoV-2 – the first variant of concern – evolved with mutations that allowed it to suppress the immune system more effectively early response to infection, new study by scientists at UC San Francisco finds Institute of Quantitative Biosciences (QBI) and University College London.
COVID electron micrograph – Credit: NIH
The researchers found that the variant sped up production of a protein that it uses to suppress immune stimulating signals from infected cells. The mutations responsible for this change likely help the Alpha variant escape immune detection and speed up its transmission, and similar mutations exist in Omicron. The findings are reported in the Dec. 23 issue of Nature.
The team, led by senior authors Nevan Krogan, PhD, UCSF, and Claire Jolly and Greg Towers, PhD, University College London, found that the increased infectivity of Alpha resulted from mutations outside of the spike, the proteins that have attracted many the attention of scientists since the start of the pandemic. Spike, which the virus uses to enter its host’s cells, is essential for infection and is the target of all available COVID-19 vaccines. But this is just one of the many tools the virus uses to manipulate its host.
As scientists closely monitored mutations in the region for spikes of new variants – Omicron has over 30 of them – Krogan stressed that changes in other regions could have a big impact as well.
“The spike mutations allow the virus to enter cells more efficiently. But what about once the virus gets into the cells? There may be other mutations that allow it to replicate further, ”said Krogan, who also heads UCSF’s QBI and its Coronavirus Research Group (QCRG).
After being first detected in the UK in late 2020, Alpha quickly spread around the world, suggesting it was significantly more transmissible than the original virus.
But experiments in Towers’ lab indicated that the new variant did not reproduce any faster than its predecessor. Looking for an explanation, the QCRG investigated whether the new variant interacted differently with the cells it infected.
The team, which also included researchers from the Massachusetts Institute of Technology (MIT), the European Molecular Biology Laboratory (EMBL) and the Icahn School of Medicine at Mount Sinai, compared the impact of the variant on host cells to that of the virus isolated at the start of the pandemic. .
To do this, postdoctoral researcher Mehdi Bouhaddou, PhD, Lorena Zuliani-Alvarez, PhD, Principal Scientist at QBI, both co-lead authors of the study, measured the activity of each gene and monitored protein levels in laboratory-grown cells infected with the virus . They also studied the state of protein phosphorylation – an assay that detects chemical changes that can temporarily adjust protein function.
Using this data to compare the response to Alpha infection and the original virus, the researchers found that many of the significant differences involved the innate immune response, the body’s first line of defense against pathogens. Many genes involved in rallying this defense were hardly activated in the presence of the SARS-CoV-2 Alpha variant.
Additionally, the team found that cells infected with Alpha contained high amounts of three viral proteins known to help the virus evade the body’s immune response. Other experiments have shown that one of them, called Orf9b, accomplishes this task by attaching itself to a protein that activates genes that boost the immune system.
The results suggest that it may be possible to help the immune system fight SARS-CoV-2 by developing drugs that block this interaction and offer a potential strategy for doing so.
Alpha has since been overtaken by new variants whose mutations stimulate even more aggressive transmission. “The virus will continue to evolve and adapt to the host, and each time it will adapt better and better,” Zuliani-Alvarez said.
The Delta and the Omicron both appear to be cousins of Alpha, each having mutations in two of the three regions studied by the team, suggesting that they could have similar effects on the innate immune system.
The results demonstrate the value of understanding the full scope of changes that shape the behavior of viral variants. “Studying the worrisome variants gives us insights into the evolution of SARS-CoV-2,” Bouhaddou said. “Now we have an idea of which proteins mutate most frequently and the biological consequences of those mutations. I think it helps us prepare for what might happen next. “
The University of California at San Francisco (UCSF) focuses exclusively on the health sciences and is dedicated to promoting health around the world through advanced biomedical research, higher education in the sciences of life and health professions and excellence in patient care. UCSF Health, which serves as UCSF’s main academic medical center, includes top-ranked specialist hospitals and other clinical programs, and has affiliations throughout the Bay Area.
About QBI: The Quantitative Biosciences Institute (QBI) encourages collaborations between the biomedical and physical sciences, in the search for quantitative methods to solve pressing problems in biology and biomedicine. Motivated by the problems of human disease, QBI is committed to studying fundamental biological mechanisms, because ultimately solutions to many diseases were revealed through unexpected discoveries in basic science. Learn more aboutqbi.ucsf.edu.