Are some people resistant to COVID-19? Genetics are on the hunt.

After dodging COVID-19 multiple times during the pandemic, flight attendant Angeliki Kaoukaki wondered if she was a medical abnormality. But she may be among a small group of people who might have genetic resistance to the virus. Scientists are now trying to understand how such resistance to COVID-19 might work – and whether the trait can be used to develop new drugs against the disease.

Kaoukaki had previously worked with other cabin crew members who tested positive without getting sick themselves. Then, in July 2021, Kaoukaki’s partner contracted a severe case of COVID-19 with a high fever and excruciating pain that lasted almost 10 days. Kaoukaki showed no symptoms despite the couple isolating for two weeks in their one-bedroom apartment in Athens, Greece.

She continued to test negative on multiple rapid PCR and antigen tests, and a test she took 23 days after her partner was confirmed infected revealed no antibodies in her blood.

“Every day I heard [from doctors] that you might have COVID,” she says, “but I kept testing negative.”

Although both are vaccinated, Her partner contracted COVID-19 again during the Omicron wave in January. Kaoukaki isolated with him for five days and again showed no symptoms and continued to test negative for the virus. Then she began to search for an explanation.

A online article led her to Evangelos Andreakos, an immunologist at the Biomedical Research Foundation of the Academy of Athens. He is part of an international consortium called the COVID Human Genetic Efforts looking for genetic variations that could reveal why some people never get COVID-19.

Although Andreakos and his colleagues didn’t expect to find many such individuals for their study, they were overwhelmed by emails from at least 5,000 volunteers worldwide with stories similar to Kaoukaki’s. Using saliva samples from 20 percent of the people who met their study criteria, Andreakos and his team will scan the protein-coding regions of genes in their DNA to detect any mutations missing from the genetic sequences of patients with severe or moderate cases of COVID-19. The hope is that some of these people will hold the secret of COVID-19 resistance.

“We assume that this is a rare population,” says Andreakos. “But there are precedents.”

Resistance to other viral infections

It has long been assumed that the outcome of an infection depends on the genetic properties of the pathogen.

“There used to be a tendency to look at the pathogen more in terms of severity – it’s a severe pathogen or a mild pathogen,” says the molecular virologist Johann Nordgren at the Swedish University of Linköping. Relatively little attention has been paid to a host and whether its genes affect its ability to fight off infection, he says.

In the last two decades, however, scientists have carried out so-called Genome-Wide Association Studies to identify specific genes or regions of DNA that may be associated with specific diseases. They do this by comparing the genetic sequences of infected people with those of healthy people and looking for correlations between mutations and resistance.

In 1996, a molecular biologist made this method possible Stephen O’Brien and his colleagues too discovers a rare genetic mutation which protects against the human immunodeficiency virus that causes AIDS.

Most people have a protein receptor found primarily on the surface of certain immune cells called chemokine receptor 5 or CCR5. This receptor allows HIV to attach to and enter the cell. But O’Brien’s team discovered that some people have a mutation that produces a defective receptor.

To be resistant, an individual needs two copies of this so-called delta 32 mutation – one from each parent. A single copy can still allow the virus to infect cells, although it slows the patient’s road to developing AIDS.

“Delta 32 was a hell of an example that convinced people that genetics matter and that it’s possible to have genetic resistance,” says O’Brien.

Scientists have also identified a mutation in another gene that confers resistance certain norovirus strains which are one of the leading causes of acute gastroenteritis worldwide. This mutation prevents norovirus from entering the cells that line the human digestive tract.

“In other words, you either make the port that the virus uses to get into the cell or you don’t,” he says Lisa Lindesmith, a norovirus researcher at the University of North Carolina at Chapel Hill. “If you don’t do this, it doesn’t matter how much virus we can give you, you won’t get infected.”

While genetic resistance to viral infection is not widespread, the fact that it occurs at all has sparked interest in similar mutations in people exposed to COVID.

Genetic basis for COVID-19 resistance

The COVID Human Genetic Effort began recruiting volunteers last year, with a focus on healthcare workers who have been exposed to the virus but have not become infected and healthy adults living in households with a spouse or partner who has became ill and moderately or severely ill COVID-19 symptoms such as Kaoukaki.

The scientists hypothesized that if these individuals were repeatedly exposed and still escaped infection, they were more likely to carry a mutation that confers resistance to the virus.

A promising target is the gene that encodes the human ACE2 receptor and those that regulate its expression on cell surfaces. The SARS-CoV-2 virus that causes COVID-19 needs to bind to ACE2 in order to enter and infect cells. A mutation that alters its structure and expression could block the virus from binding and prevent infection.

So far, ACE2 seems to be our best bet, he says Jean Laurent Casanova, a geneticist at Rockefeller University who is part of the COVID Human Genetic Effort. Genetic variations that allow ACE2 to function normally but disrupt its interaction with the virus — “those would be good candidate genes,” he says.

However, it is possible that there are other biological factors besides the ACE2 receptor that could explain why some people have not developed a SARS-CoV-2 infection.

Some people may possess robust immune systems that produce antiviral proteins called type I interferons, which limit the virus’ replication in human cells. They are the body’s first line of defense and appear before antibodies against the virus are formed.

Another hypothesis is that immune cells called memory T cells, which may have formed in previously emerged coronaviruses such as those that cause the common cold, help limit SARS-CoV-2 infection in certain patients.

In 2020, before the vaccine launch, one to learn found a greater presence of memory T cells in healthcare workers who were exposed to the virus but did not develop COVID-19.

The memory T cells may have cleared the virus very quickly in some people. But it is no guarantee that these people will be protected from future infections. “In fact, we know that some got infected with more infectious variants and/or perhaps a higher dose of the virus,” he says Mala Mainia viral immunologist at University College London and one of the study authors.

If her study provides evidence of genetic resistance, Casanova hopes the information could be used to develop therapeutics for COVID-19, similar to those CCR5 Inhibitors developed to treat HIV infection. But decisions to develop these therapies, says Casanova, will depend on the type of mutant genes discovered.

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