A few individuals have never received COVID-19. Perhaps due to a mysterious gene

It’s possible that a recently identified immune response is to blame for those who have avoided COVID-19 for longer than four years.

Researchers report on June 19, in Nature, that participants with elevated activity of a little-studied immune gene called HLA-DQA2 did not survive infection following exposure to SARS-CoV-2 in a study where volunteers were purposefully infected with the coronavirus. The research provides an unparalleled and in-depth examination of the immune system’s reaction to the coronavirus, and how variations in that reaction may account for the differences in illness outcomes between individuals.

The findings originate from a challenge trial in which 36 young, healthy unvaccinated volunteers who had never contracted COVID-19 through their nostrils were exposed to the virus by scientists in the United Kingdom during the pandemic’s peak in 2021 (SN: 2/18/21). Although the original purpose of the study was to determine the minimum amount of virus required to initiate an infection, 16 subjects undertook additional testing. A comprehensive understanding of the precise moment and location at which distinct immune players activate was made possible by the researchers’ tracking of the activities of numerous immune players in the blood and nasal lining, both prior to and following exposure.

There was a snag, though: out of the sixteen volunteers, only six fell ill.

“At first, we were really disappointed because we thought we were wasting all these tests on people who weren’t really infected,” explains biologist Rik Lindeboom of the Netherlands Cancer Institute in Amsterdam. Afterwards, he claims, he and his associates recognized they had discovered a “unique opportunity” to comprehend how some individuals who received an infectious dosage of the virus were able to fight it off. The number of people who have avoided COVID-19 is unknown. The latest projection from the U.S. By the end of 2022, almost one in four Americans, according to the Centers for Disease Control and Prevention, might not have contracted the virus.

Challenge trials are debatable since some specialists disagree with the morality of purposefully infecting individuals with a pathogen (SN: 5/27/20). However, Jill Hollenbach, an immunogeneticist at the University of California, San Francisco who was not involved in the study, believes that “you can’t underplay how valuable this kind of information is.” Because challenge trials allow researchers to follow participants from the moment they come into contact with the virus, she adds, “it’s so rare that we get to see a snapshot of what’s actually happening in early infection.”

In Lindeboom’s trial from 2021, those who stayed healthy fell into two categories. While three people experienced brief nasal infections that their bodies swiftly healed, leaving them healthy, seven people never tested positive for the virus. Researchers detected extensive, albeit subtle, alterations in immune cells known as MAIT cells and monocytes in the former group. Within a day of exposure, the transiently infected people developed a strong immune response in their noses known as an interferon response. Interferons aid in identifying a viral threat and draw anti-infection cells.

On the other hand, it took an average of five days for ill individuals to trigger the same interferon response in their noses, which allowed the virus to multiply and spread. According to Lindeboom, the disparity implies that quick, focused action at the infection site could aid in preventing SARS-CoV-2 from spreading.

Surprisingly, interferon activity was detected in the blood of sick participants before it was in their nostrils. Considering that the virus was spread by the nose, Lindeboom states, “that’s the exact opposite of what we had hypothesized.” “Your immune system has the ability to detect abnormalities and notify the body of them before the afflicted cells become aware of them.”

Lindeboom is unsure of the reason behind why some people who stayed healthy had a short infection while others did not. However, prior to exposure, both groups showed higher activation of the HLA-DQA2 gene in specialized immune cells that aid in warning the immune system about infections, in contrast to those who experienced symptoms. Although earlier study connected this gene to milder COVID-19 outcomes, scientists are still unsure of exactly what this gene accomplishes.

“Looking at their gene signature for this specific gene may allow us to predict who is susceptible to infection,” says Yale University immunologist Akiko Iwasaki, who was not involved in the work but wrote about it in Nature.

Naturally, since these challenge trials were held in 2021, a lot has transpired. According to Iwasaki, almost everyone has some immunity to SARS-CoV-2 due to infection or vaccination. As a result, most people’s immunological responses are probably different from those seen here. Greater diversity in the study population, such as a wider age range, may also lead to a wider range of responses.

People who have this distinct combination of immune cells in their noses before infection, for whatever reason, might be able to generate an immune response faster, according to Hollenbach. “Those folks are in for a fortunate break,”

For the researchers, the study was somewhat of a lucky break as well. Since almost everyone currently possesses some tolerance to COVID-19, it has been difficult to infect volunteers in subsequent challenge experiments. According to Lindeboom, “that’s what makes this study so unique.” “Hopefully, we won’t be able to conduct research on SARS-CoV-2 of this nature ever again.”