It’s been more than a year since the mysterious virus we now know as SARS-CoV-2 was first detected in Wuhan, China. The pandemic has since had a devastating toll—around the world, there have been more than 97 million documented infections, and more than 2 million deaths from COVID-19, the disease caused by the virus.
As cases continue to climb around the globe, there remains a pressing need for better therapeutics to combat the disease. “We have very few therapies that actually decrease the negative outcomes in people with COVID,” says Dr. Brent Richards, BSc’96, MSc’06, PGME’06, a professor in the Department of Medicine at McGill University. The ability to find effective drugs depends on the answer to one key question: What causes some patients to fall severely ill with COVID-19, while others experience only mild symptoms—or no symptoms at all?
To answer this crucial question, Richards, along with an international group of scientists, carried out a study aimed at pinpointing proteins within the bloodstream that influence how well people fare after getting infected with SARS-CoV-2. They used Mendelian randomization, a technique that utilizes the known genetic variation in a population to try to pinpoint causal effects. First, the group used data which identified the genetic determinants of the levels of 931 circulating proteins in the genomes of more than 28,000 people without SARS-CoV-2 infections. Then, they examined the genomic data from thousands of patients and more than a million healthy individuals of European ancestry to assess whether the level of any of these proteins was associated with disease severity or susceptibility in COVID-19 patients.
These analyses revealed that high levels of a protein known as OAS1 was associated with both lower susceptibility to COVID-19 infection and less severe disease. The findings were posted as a preprint—meaning the manuscript has not been peer-reviewed—on medRxiv last December, and has since been provisionally accepted by Nature Medicine.
When the team dug deeper, they discovered evidence that this protection was linked to a form of OAS1 that people with European ancestry inherited from Neanderthals, and has been favoured by natural selection. “For almost anybody who’s alive today, this is the first time that we’ve dealt with a pandemic. But our ancestors’ genomes have been dealing with pandemics for millennia, and we’ve inherited those genomes,” says Dr. Sirui Zhou, a postdoctoral fellow at McGill University who led the study. “We are actually reasonably well designed to be able to fight viruses—and this is one of the mechanisms that we use.”
Evidence from prior studies suggests that this protective form of OAS1 existed in ancestral humans, Homo sapiens, who migrated out of Africa approximately 50,000 to 70,000 years ago. But, for reasons scientists haven’t yet discovered, when these people left Africa, they lost the variant of the gene encoding for the protective form of the protein. However, Neanderthals, who at the time were living in Europe and Asia also possessed this genetic variant—and reintroduced it to our ancestors when the two met and mated.
Prior research had also shown that OAS1 helps the body fight infections from RNA viruses—a group of viruses that includes coronaviruses such as SARS-CoV-2 and influenza viruses such as the seasonal flu. “In the setting of a SARS-CoV-2 infection, this is a predominant mechanism whereby the body influences whether or not you end up with an asymptomatic infection or intubated in the ICU,” Richards says.
One of the biggest upsides of the group’s findings, according to Richards, is the fact that because the role OAS1 plays in viral defence was previously known, there are already drugs in development that target this protein. Although there isn’t a specific drug that is currently being used for other diseases that can be easily repurposed to treat COVID-19, a fair amount of work has been done to identify therapies that could act on the OAS1 pathway, he adds. “That may save us years of drug development.”
The group is now working on conducting similar analyses with larger samples of individuals and in people from different backgrounds—as the sample assessed in their study predominantly consisted of people with European ancestry. At the same time, they are also working with drug companies to help them apply the findings from their study to aid drug development for COVID-19.
Even as vaccinations begin in Canada and elsewhere in the world, the search for effective therapeutics remains essential. “While we are all excited about vaccines, it’s become increasingly clear that vaccine rollout to many parts of the world will be slow, and there will be some people who contract COVID infections despite vaccines being disseminated in the population,” Richards says. “It's very important that we have therapies for these individuals in order to prevent them from the worst consequences of COVID, which include ending up in the ICU on a ventilator, or death.”