A little-known gene may explain why some people never get COVID-19
This gene’s high activity in the nose seems to help protect people from the infection
Relatively few people have never had COVID-19. A study that tried to infect people on purpose — and in some cases failed — found a genetic clue to what may protect some of us.
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If you’ve never had COVID-19, you’re not alone. Others, too, have dodged the infected for more than four years. And some may have achieved this with some help from a newly discovered immune response. That’s the finding of a new study.
In that study, people volunteered to get infected with the virus — yes, on purpose. And some never get sick. Their protection now appears to be linked to the activity of a little-studied immunity gene.
The new data suggest that people in whom this gene is unusually active can better resist infection by SARS-CoV-2. That’s the coronavirus that causes COVID-19.
This study gives the most detailed look yet at how the immune system responds to that virus. It works differently in some people, and that appears to help explain why some got sick with COVID and others didn’t.
Researchers shared their unexpected findings June 19 in Nature.
A ‘challenge’ and then a surprise
Scientists in the United Kingdom conducted the study in 2021. It was at the height of the pandemic. They recruited 36 young, healthy volunteers. None had yet gotten COVID-19 or a vaccine against it. The virus was released into each volunteer’s nose. This type of study is called a challenge trial. Here, it challenged the body by exposure to the virus.
The first goal was to learn how much virus it takes to kick-start an infection.
Sixteen of the recruits also had more extensive tests. Researchers tracked a wide range of immune responses in their blood and the lining of their noses. The team measured many aspects of immunity and at many points in time — both before and after someone had been exposed. The researchers hoped to uncover details of when and where different immune reactions begin.
But there was a problem. Only six of the 16 got sick.
“Initially, we were very bummed,” recalls study leader Rik Lindeboom. It seemed “like, we’re wasting all these experiments on people that we didn’t actually infect.” A biologist, Lindeboom works at the Netherlands Cancer Institute in Amsterdam.
But then his team realized it had stumbled across a “unique opportunity,” he says. Here was a chance to ask: How do some people exposed to the virus manage to fend it off?
A quick, local response
No one knows exactly how many people have dodged COVID-19. But by the end of 2023, about 1 in 8 Americans likely hadn’t caught the virus. That estimate comes from the U.S. Centers for Disease Control and Prevention.
Challenge trials are controversial. Some experts question the ethics of choosing to give people something that can cause disease.
But “you can’t underplay how valuable this kind of information is,” says Jill Hollenbach. She studies the genetics of the immune system at the University of California, San Francisco. She did not take part in the new work. But she points out that challenge trials allow researchers to track people from the moment they encounter a disease-causing agent.
“It’s so rare,” she notes, “that we get to see a snapshot of what’s actually happening in early infection.”
Recruits in the 2021 trial who got sick — showed symptoms — developed a strong immune reaction in their noses within five days of exposure. This brought in high levels of certain proteins. Called interferons, they help signal a viral threat. This brings in cells that can go on to fight the infection.
Those who didn’t get sick responded either of two other ways.
The seven who never tested positive for the virus had widespread, but subtle, changes. These changes affected immune cells called monocytes and MAIT cells.
Three other people got brief infections in their nose. But their bodies quickly shut it down and they never felt sick. These people showed a strong immune reaction in their noses within one day of exposure. It brought in high levels of interferons — about the same levels as it took the sick group to mount in five days. In the people who would become sick, it now appears that those extra days gave the virus time to multiply and spread.
A swift response at the site of infection may be key to preventing the virus from getting a foothold, Lindeboom says.
Another finding surprised his team. Interferon activity showed up in the blood of sick people before it showed up in their noses.
“That’s the exact opposite of what we had hypothesized,” Lindeboom says. After all, the virus was delivered via the nose.
“Your immune system is capable of sensing that something is happening,” he says. It now looks like it may inform “the body — before the cells that are actually affected know about it.”
Lucky break
Lindeboom isn’t sure why some people who didn’t get sick showed a brief infection and others did not. But these groups shared one difference from people who developed symptoms. It involved the gene HLA-DQA2. It turns on in specialized immune cells that help alert the body to invading microbes.
Before exposure to the COVID virus, this gene was more active in people who didn’t get sick than in those who later did. Scientists aren’t sure exactly what this gene does. But earlier work by others has linked it to milder cases of COVID-19.
Perhaps the gene’s activity helps signal someone’s risk of getting sick, says Akiko Iwasaki. If true, she says, it “may be able to predict who is susceptible to infection.” An immunologist at Yale University, Iwasaki didn’t work on the study but she did write about it in Nature.
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Of course, much has changed since this study took place in 2021. Today, nearly everyone has some immunity to the virus. That’s because most people have had COVID-19, a vaccine against it or both. So our immune responses today would likely differ from those seen in the study, Iwasaki says.
Also of note, the study was pretty small. A larger, more diverse group of people might show a broader range of immune responses.
For whatever reason, those in this study who were able to mount a quick immune response seemed to avoid getting sick. Says Hollenbach, “It’s a lucky break for those people.”
Now that nearly everyone has some immunity to COVID-19, it will be much harder to do similar studies. “That’s what makes this study so unique,” says Lindeboom. “We’ll hopefully never be in the position to do this kind of study for SARS-CoV-2 again.”
