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

Researchers at the Lady Davis Institute (LDI) at Jewish General Hospital found that increased levels of the OAS1 protein are associated with reduced mortality and less severe illness that requires ventilation among patients with COVID-19. The use of drugs that increase OAS1 levels can be explored to try to improve these results. The results are published today in Nature Medicine.

“Our analysis shows evidence that OAS1 has a protective effect against the susceptibility and severity of COVID-19,” explains Dr. Brent Richards, senior researcher at the LDI Clinical Epidemiology Center 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 for treating patients because there are already therapies in preclinical development that increase OAS1 and could be explored for its effect against SARS-CoV-2 infection.”

Understandably, a lot of effort is being invested in vaccine development. However, with hundreds of millions of people already infected worldwide, it is important not to neglect the search for disease-specific therapies, since few of these therapies have been identified. In addition, given the prevalence of vaccine hesitation in the community and uncertainty over how long any vaccine will prove to be protective, COVID-19 is likely to be a global problem in the years to come. Thus, the need for therapeutic treatments will continue.

Researchers in Dr. Richards’ lab explored detectable proteins in peripheral blood as a potential target. The challenge was to determine which proteins play a causal role in the progression of the disease, since their levels can also be influenced by COVID-19 itself or other confounding factors. Recent advances in proteomic technology, that is, the ability to isolate and measure hundreds of circulating proteins at once, combined with genetic analyzes through Mendelian randomization (MR) make possible the delicate work of unraveling which proteins have affected the adverse results of COVID-19, instead of vice versa.

From genetic determinants of 931 circulating proteins, Dr. Sirui Zhou, postdoctoral fellow at LDI and first author of the article, found that the increase in OAS1 levels was associated with reduced death or ventilation by COVID-19, hospitalization and susceptibility in up to 14,134 COVID-19 cases and 1.2 million controls. The results were consistent across multiple sensitivity analyzes. They started measuring OAS1 levels in 504 patients with different results from COVID-19 from the Biobanque Québec COVID-19 and found that increased levels of OAS1 in post-infection patients were associated with very severe protection against COVID-19, hospitalization and susceptibility .

“The protective effect was particularly great,” says Dr. Zhou, “so that we observed a 50% decrease in the chances of very serious COVID-19 due to an increase in standard deviation in the levels of OAS circulation. , this protective effect is probably inherited in a Neanderthal-derived form of OAS1 called p46. “

This form of OAS1 probably emerged in people of European descent through crossing with Neanderthals tens of thousands of years ago. Evolutionary pressure has slowly increased the prevalence of this form of OAS1, so that it is now detectable in more than thirty percent of European descendants. It is likely that the shape of the protein served as protection against previous pandemics.

As drug development, even in the fast-paced environment of pandemic research, takes time, it is particularly stimulating that molecules that can increase OAS1 activity are currently in preclinical development for eventual implantation in clinical trials.

“Our recommendation is that drugs that trigger increased levels of OAS1 should be further studied for their effects on the results of COVID-19 so that we can better treat infected patients,” said Dr. Richards.