One in five people who contract the COVID-19 virus don’t get sick. A gene variant may explain why

SARS-CoV-2 kills some of the people it infects and makes many others miserable. But a fortunate few skate through a bout of COVID-19 without suffering symptoms. One key to avoiding illness, according to a new study, is a version of a particular immune system gene that only some people carry. When individuals with this gene variant are exposed to common coronaviruses that cause colds, the research shows, they gain protection against SARS-CoV-2.

“I love this paper,” says immunologist Shane Crotty of the La Jolla Institute for Immunology, who wasn’t connected to the research. The study, he says, provides “the strongest genetic evidence to date” that people who come down with the cold-causing coronaviruses produce immune cells that can fight off SARS-CoV-2.

About 20% of people infected with SARS-CoV-2 say they don’t feel ill, but researchers haven’t uncovered why they remain symptom-free. At the top of the list of potential protectors are human leukocyte antigen (HLA) genes, which encode proteins that help the body fight off pathogens. If a virus sets up shop in one of our cells, HLA proteins on the cell’s surface display shards of the invader’s proteins, alerting the immune system. T cells—which recognize and “remember” pathogens—then kill the infected cell, short-circuiting the virus’ replication.

HLA genes come in thousands of varieties, many of which influence how vigorously people’s immune systems combat particular viruses. For example, HIV-infected people with a certain HLA-B version have extremely low levels of the virus and don’t show symptoms, whereas patients with another HLA-B type rapidly develop AIDS. Whether particular HLA variants affect the severity of SARS-CoV-2 infection wasn’t clear, however.

In the early months of the pandemic, immunogeneticist Jill Hollenbach of the University of California, San Francisco, and colleagues wanted to investigate whether particular HLA versions led to asymptomatic COVID-19. But because of lockdowns, bringing subjects into the lab for such a study was impossible. Instead, the researchers came up with a contact-free procedure, enlisting a group of nearly 30,000 people who had signed up to donate bone marrow and thus had already undergone tests to determine their HLA complement. The participants downloaded a cellphone app and used it to record any symptoms, even mild ones like a runny nose or scratchy throat, that persisted for at least 3 days.

Of the more than 1400 subjects who tested positive for SARS-CoV-2 during the study, 136 reported that they did not feel sick. Twenty percent of the symptom-free group sported the same version of the HLA-B gene, known as HLA-B*15:01, the team reports today in Nature. In contrast, only 9% of the subjects who reported symptoms on the app carried this HLA variant. Participants with two copies of HLA-B*15:01—one inherited from each parent—received even more protection. They were eight times less likely to suffer symptoms than were people with other HLA-B varieties.

To determine how the HLA-B variant was forestalling symptoms, the scientists turned to blood samples collected from other people before the pandemic. In 75% of blood donors with HLA-B*15:01, T cells recognized a snippet of SARS-CoV-2’s spike protein, which enables the virus to enter cells. The T cells seemed raring to fight the virus—even though the subjects had never encountered it before.

But the blood donors probably had been infected by seasonal coronaviruses, widespread relatives of SARS-CoV-2 that give us colds. The team discovered that T cells from the subjects with HLA-B*15:01 also reacted aggressively to a fragment of the spike protein from two of the seasonal coronaviruses. This fragment is almost identical to the snippet of SARS-CoV-2’s spike protein that the researchers had tested. The results suggest that when people with the HLA-B variant came down with colds caused by seasonal coronaviruses, they obtained a degree of immunity against similar coronaviruses, including SARS-CoV-2.

The HLA-B variant doesn’t prevent people from becoming infected with SARS-CoV-2, says the study’s lead author Danillo Augusto, a geneticist now at the University of North Carolina, Charlotte. But, “The response is fast enough to clear the virus before the person starts having symptoms.”

Researchers still need to work out how the variant revs up the response to these coronaviruses, Hollenbach says. “There’s something going on there that’s generating very effective T cells.” HLA-B*15:01 is relatively common, accounting for about 10% of HLA-B variants in people of European descent, meaning that many people could be benefitting from its defenses. Hollenbach adds that the findings may help researchers craft new vaccines or treatments for COVID-19.

The work is the first to demonstrate that exposure to seasonal coronaviruses can prime T cells to battle SARS-CoV-2, says immunologist Andrea Sant of the University of Rochester Medical Center, who also wasn’t connected to the research. “We have been hoping for something like this. Now we’ve learned that the T cells are there and that they can protect.”

By Mitch Leslie