Gene that determines severity of COVID-19 discovered

Individuals with a specific version of the OAS1 gene have natural antiviral defences against SARS-CoV-2, resulting in less severe COVID-19 disease.

The work led by researchers from the MRC-University of Glasgow Centre for Virus Research showed that, while some people can express a more protective 'prenylated' version of the OAS1 enzyme, other people express a version of this gene which does not detect SARS-CoV-2, and without this anti-viral response the virus spreads unchecked within the body. Prenylation is the addition of a single molecule of lipid to a protein. In the case of OAS1, the prenylated version is able to detect invading SARS-CoV-2 and trigger an interferon immune response while the other version is not.

'We know viruses adapt, and even SARS-CoV-2 has likely adapted to replicate in the animal reservoir(s) in which it circulates. Cross-species transmission to humans exposed the virus SARS-CoV-2 to a new repertoire of antiviral defences, some of which SARS-CoV-2 may not know how to evade' said Professor Sam Wilson from the University of Glasgow and senior author of the study.

Publishing their study in Science, the scientists analysed the genetic information of nearly 500 patients who had been hospitalised with COVID-19 and found that the absence of prenylated OAS1 generally led to worse disease outcomes. Patients without prenylated OAS1 had a 1.6 times higher chance of admission to ICU or of dying from the disease.

Previous work had already identified OAS1 in a genome-wide association study to be linked to different disease outcomes of COVID-19 (see BioNews 1076), but this work has now uncovered the mechanism by which the prenylated OAS1 is able to contribute to a better immune defence during SARS-CoV-2 infection.

As the origin of SARS-CoV-2 is still unknown, the virus' sensitivity to prenylated OAS1 could be further evidence that the virus originated in horseshoe bats. These animals are one of very few mammals that do not possess prenylated OAS1 at all. Thus, a virus evolving in these animals is less likely to develop an escape strategy against it.

Dr Simon Clarke, associate professor in Cellular Microbiology at the University of Reading who was not involved in the study, said: 'This change alters a gene which makes OAS1, allowing it to get to parts of an infected cell where it can more easily detect the presence of the coronavirus. In doing that, it can better activate the cell's defences against the virus.'

The study authors caution however that future variants of the virus might escape the prenylated OAS1 mediated defence as SARS-CoV-1 has done in the past.

Professor Wilson explained: 'What our study shows us is that the coronavirus that caused the SARS outbreak in 2003 learned to evade prenylated OAS1. If SARS-CoV-2 variants learn the same trick, they could be substantially more pathogenic and transmissible in unvaccinated populations. This reinforces the need to continually monitor the emergence of new SARS-CoV-2 variants.'

OAS1 now adds to the growing list of genetic variants previously identified to affect severity of SARS-CoV-2 infection (see BioNews 1099 and 1103).