Inheritance of Neanderthal genes might explain why some people have stronger immunity to SARS-CoV-2
A new study has revealed key insights into the natural human antiviral defences against SARS-CoV-2, the virus that causes COVID-19.
Versions of a gene known as OAS1, inherited from Neanderthals on chromosome 12 protect cells from viral invasion. The key to the protective properties lies in the ability of the version of the gene to 'express' the addition of a lipid molecule to certain proteins, a process known as 'prenylation'. Prenylated lipo-proteins of this nature evolved to create an 'alarm system' that detect invaders and are involved in the process of activating our natural immune systems. The Neantherdal link means that these protective genes are more prevalent in people of European ancestry.
The research, published in the journal Science and led by a team of scientists at the MRC-University of Glasgow, Centre for Virus Research, sheds new light on why some people are naturally more resistant to serious SARS-CoV-2 infection – and how, in the future, the coronavirus might overcome this resistance.
Understanding the natural anti-viral response
Although the method of transmission is still not clear, COVID-19 is spread from person to person after the virus, shed by an infected person, infects the cells of a new host. Once infected, our cells try to fight off the invading virus and scientists already know that this works better is some people, making their experience of the disease less severe. However, until now, that anti-viral response – and its effect on the virus SARS-CoV-2 has not been well-understood.
In the study, the scientists reveal that some people have a version of the gene, called OAS1, that potently inhibits SARS-CoV-2. The study showed that, while some people can express a more protective ‘prenylated’ version of the OAS1 gene, other people express a version of this gene which does not detect SARS-CoV-2.
NB OAS1 should not be confused with the other immunological concept of original antigenic sin (OAS). Although both types of OAS can have a profound impact on our responses to vaccines and disease.
Lipid coat alarm sensors
Inside cells, coronaviruses hide and replicate inside vesicles coated with lipid (fat). Prenylation is the addition of a single molecule of lipid (fat) to a protein – and it’s this technical difference that allows prenylated OAS1 to ‘seek and destroy’ the invading virus by first ‘sounding the alarm’.
The study found that, in hospitalised patients, expression of a prenylated version of this gene was associated with protection from severe COVID-19, which suggests this antiviral defence is a major component of a protective antiviral response; and is likely to have offered protection to many people during the course of the pandemic.
Bad OAS1 had worse outcomes
The study also found that hospitalized COVID-19 patients with the ‘bad’ form of OAS1 had worse clinical outcomes compared to those who expressed the protective prenylated version of OAS1. Severe disease was significantly more frequent with ICU admission or death being approximately 1.6 times more likely in these patients.
Interestingly, the researchers also found that, approximately 55 million years ago, there was a removal of this protective gene in horseshoe bats (the presumed source of SARS-CoV-2), so SARS-CoV-2 never had to adapt to evade this defence.
As the protective prenylated OAS1 gene is widespread in animals, the billions of people that lack this protective gene could make humans particularly vulnerable to the spill over of coronaviruses from horseshoe bats.
Repertoire of natural anti-viral defences
Sam Wilson (pictured above) said: “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".
Concerning questions over the impact of Neanderthal ancestry on the nature of immune responses, Dr Wilson says, "The answer is that human ancestry is complicated and both [factors for risk and protection] are probably true. The Neanderthal haplotype from chromosome 3 is likely a risk factor whereas the allele of OAS1, inherited from Neanderthals (which is prenylated), on chromosome 12 is protective. Modern humans could have either, both or neither of these regions inherited from Neanderthals".
The study, ‘A Prenylated dsRNA Sensor Protects Against Severe COVID-19,’ is published in Science. The study was predominantly funded by the Medical Research Council, Wellcome, and UKRI.