Neanderthal-derived proteins may reduce the severity of COVID-19

Researchers at the Lady Davis Institute (LDI) at the Jewish General Hospital have discovered that elevated levels of the OAS1 protein are associated with reduced mortality and less serious illnesses requiring ventilation among patients with COVID-19. The use of drugs that increase OAS1 levels can be investigated to try to improve these outcomes. The findings are published today in Physical Medicine.

“Our analysis shows evidence that OAS1 has a protective effect against COVID-19 susceptibility and severity,” explains Dr. Brent Richards, a senior researcher at the LDI’s Center for Clinical Epidemiology and Professor of Medicine, Human Genetics, Epidemiology and Biostatistics at McGill University. . “This is a very exciting development in the race to identify potential therapies to treat patients, as there are already preclinical therapies that promote OAS1 and its effect against SARS-CoV-2 infection can be investigated.”

It is understandable that a lot of effort is put into the development of vaccines. With hundreds of millions of people already infected worldwide, it is important not to delay the search for disease-specific therapies, as few such therapies have been identified. Given the prevalence of vaccine hesitation in the community and uncertainty about how long any vaccine will be protective, COVID-19 is likely to be a global problem for years to come. The need for therapeutic treatments will therefore continue.

Researchers in Dr. Richards’ laboratory examined proteins that could be detected in peripheral blood as a potential target. The challenge was to determine which proteins play a causal role in the progression of diseases, as their levels can also be influenced by COVID-19 itself or other confusing factors. Recent advances in proteomic technology – that is, the ability to isolate and measure hundreds of circulating proteins simultaneously – combined with genetic analyzes through Mendelian randomization (MR), make it possible to fine-tune the proteins that have influenced COVID-19, to disrupt, rather than to influence. vice versa.

From genetic determinants of 931 circulating proteins, dr. Sirui Zhou, a postdoctoral fellow at the LDI and first author of the paper, finds that an increase in OAS1 levels is associated with reduced COVID-19 death or ventilation, hospitalization and susceptibility to 14,134 COVID-19 cases and 1, 2 million controls. The results were consistent in multiple sensitivity analyzes. They measured OAS1 levels in 504 patients with different COVID-19 outcomes than the Biobanque Québec COVID-19, and found that increased OAS1 levels in patients after infection were associated with protection against very severe COVID-19, hospitalization, and susceptibility.

“The protective effect was particularly great,” shows dr. Zhou, “such that we observed a 50% decrease in the chance of very severe COVID-19 per standard deviation increase in OAS1 circulation levels. It is interesting that for non-African peoples this protective effect was probably inherited from a Neanderthal -derived form of OAS1 called p46. ‘

This form of OAS1 probably originated with people of European descent tens of thousands of years ago through crossbreeding with Neanderthals. Evolutionary pressures have slowly increased the prevalence of this form of OAS1, so that it is now observable in more than thirty percent of people of European descent. It is likely that the form of the protein served as protection against earlier pandemics.

Since drug development, even in the accelerated environment of pandemic research, takes time, it is particularly exciting that molecules that can increase OAS1 activity are currently in preclinical development to eventually be used in clinical trials.

“Our recommendation is that the drugs that cause elevated OAS1 levels should be further investigated for their effect on COVID-19 outcomes so that we can better treat infected patients,” Dr. Richards said.