Published by National Geographic, April 7, 2022

Thousands of people repeatedly exposed to the virus never got sick. Scientists hope their DNA may hold clues to new kinds of treatments.

After dodging COVID-19 several times during the pandemic, flight attendant Angeliki Kaoukaki wondered if she was a medical anomaly. But she’s possibly among a small group of people who might have genetic resistance to the virus. Scientists are now racing to understand how such resistance to COVID-19 could work—and whether the trait can be harnessed to develop new drugs against the disease.

Kaoukaki had already worked alongside other cabin crew members who tested positive without getting sick herself. Then in July 2021 Kaoukaki’s partner contracted a severe case of COVID-19 with high fever and unbearable pain that lasted nearly 10 days. Kaoukaki showed no symptoms, despite the fact that the pair isolated together for two weeks in their studio apartment in Athens, Greece.

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

“Every day I heard [from doctors] that maybe you have COVID,” she says, “but again and again, I tested negative.”

Despite both being vaccinated, her partner got 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. That’s when she began hunting for an explanation.

An 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 Effort that has been looking for genetic variations that might 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 with emails from at least 5,000 volunteers worldwide with stories similar to Kaoukaki’s. Using saliva samples from the 20 percent of people who met their study criteria, Andreakos and his team will be scanning the protein-coding regions of genes in their DNA to spot any mutations that are absent in the genetic sequences from patients who had severe or moderate cases of COVID-19. The hope is that some of these people harbor the secret to COVID-19 resistance.

“We expect it to be a rare population,” Andreakos says. “But there are precedents.”

Resistance to other viral infections For a long time, the outcome of any infection was assumed to depend on the genetic traits of the pathogen.

“There used to be a tendency to more think about the pathogen in terms of severity—it’s a severe pathogen or a mild pathogen,” says molecular virologist Johan Nordgren at Sweden’s Linköping University. Relatively less attention was paid to a host and whether their genes affect their ability to fight off an infection, he says.

In the last two decades or so, though, scientists have been conducting so-called genome-wide association studies to identify certain genes or regions of DNA that may be linked to specific diseases. They do this by comparing the genetic sequences of infected individuals with those who are healthy and seeking correlations between mutations and resistance.

In 1996 this method enabled molecular biologist Stephen O’Brien and his colleagues to discover a rare genetic mutation that protects against the human immunodeficiency virus that causes AIDS.

Most people have a protein receptor present primarily on the surface of certain immune cells called the chemokine receptor 5, or CCR5. This receptor allows HIV to bind with 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 down the patient’s trajectory to developing AIDS.

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

Scientists have also tracked down a mutation in a different gene that confers resistance to certain norovirus strains that are a major cause of acute gastroenteritis worldwide. This mutation prevents noroviruses from entering the cells lining the human digestive tract.

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

While genetic resistance to viral infections isn’t widespread, the fact that it happens at all has ignited interest in similar mutations in COVID-exposed individuals.

Genetic underpinnings to COVID-19 resistance The COVID Human Genetic Effort started recruiting volunteers last year,
with a focus on healthcare workers who were exposed to the virus but didn’t get infected, and healthy adults living in a household with a spouse or partner who got sick and experienced moderate or severe COVID-19 symptoms, like 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.

One promising target is the gene that codes for the human ACE2 receptor and those that regulate its expression on cell surfaces. The SARS-CoV-2 virus that causes COVID-19 must bind to ACE2 to enter cells and infect them. A mutation that alters its structure and expression might block the virus from binding and prevent infection.

So far, ACE2 seems to be our best bet, 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—”these would be good candidate genes,” he says.

It’s possible, though, that there are other biological factors aside from the ACE2 receptor that could explain why some people didn’t develop a SARS-CoV-2 infection.

Some people may possess a robust immune system that produces antiviral proteins called type I interferons, which limit the virus from replicating in human cells. They’re the body’s first line of defense and appear even before antibodies form against the virus.

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

In 2020, prior to the vaccine rollout, one study found greater presence of memory T cells in healthcare workers who were exposed to the virus but who didn’t develop COVID-19.

The memory T-cells may have cleared the virus very quickly for a few people. But it’s no guarantee these people will be protected from future infections. “In fact, we know some have gone on to get infected with more infectious variants and/or perhaps with a higher dose of the virus,” says Mala Maini, a viral immunologist at the University College London and one of the study authors.

If their study does turn up clues to genetic resistance, Casanova hopes that information could be used to develop therapeutics against COVID-19, similar to the CCR5 inhibitors designed to treat HIV infections. But decisions to develop these therapies, Casanova says, will depend on the nature of the mutated genes discovered.