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

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

“Our analysis shows that OAS1 has a protective effect against the sensitivity and severity of COVID-19,” says Dr. Brent Richards, principal investigator at the Center for Clinical Epidemiology at LDI and professor of medicine, human genetics, d 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 therapies in preclinical development that stimulate OAS1 and could be explored for their effect against infection. by SARS-CoV-2. “

Naturally, a lot of effort is invested in vaccine development. However, with hundreds of millions of people already infected around the world, it is important not to overlook the search for disease-specific therapies as few of these therapies have been identified. Additionally, given the prevalence of vaccine reluctance in the community and the uncertainty over how long a vaccine will prove to be protective, COVID-19 will most likely be a global problem for 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, as their levels may also be influenced by COVID-19 itself or other confounding factors. Recent advances in proteomics technology – that is, the ability to isolate and measure hundreds of circulating proteins at once – combined with genetic analyzes by Mendelian randomization (MR) make possible the delicate work of unravel proteins affected by the adverse effects of COVID-19, rather than vice versa.

From the genetic determinants of 931 circulating proteins, Dr. Sirui Zhou, postdoctoral researcher at ILD and first author of the article, found that increased levels of OAS1 were associated with reduced mortality or breakdown by COVID-19, hospitalization and susceptibility up to 14,134 cases of COVID-19 and 1.2 million controls. The results were consistent in several sensitivity analyzes. They measured the levels of OAS1 in 504 patients with different COVID-19 results from COVID-19 from Biobanque Quebec and found that the increase in OAS1 levels in post-infection patients was associated with a protection against very severe COVID-19, hospitalization and sensitivity.

“The protective effect was particularly strong,” Dr. Zhou points out, “so we observed a 50% decrease in the likelihood of very severe COVID-19 by increasing the standard deviation of circulating OAS1 levels. Interestingly, for non-Africans, this protective effect is likely inherited from a Neanderthal-derived form of OAS1 called p46. “

This form of AEO1 likely arose in people of European descent through crossbreeding with Neanderthals tens of thousands of years ago. Progressive pressure has slowly increased the prevalence of this form of AEO1, so that it is now detectable in over 30% of people of European descent. It is likely that the form of the protein served as protection against past pandemics.

Given that 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 for eventual deployment. in clinical trials.

“Our recommendation is that drugs that trigger an increase in OAS1 levels be further studied for their effect on COVID-19 outcomes so that we can better treat infected patients,” said Dr Richards.